Skip Navigation
Skip to contents

Intest Res : Intestinal Research

IMPACT FACTOR

Articles

Page Path
HOME > Intest Res > Volume 12(1); 2014 > Article
Review Antimicrobial Proteins in Intestine and Inflammatory Bowel Diseases
Jung Mogg Kim
Intestinal Research 2014;12(1):20-33.
DOI: https://doi.org/10.5217/ir.2014.12.1.20
Published online: January 28, 2014

Department of Microbiology, Hanyang University College of Medicine, Seoul, Korea.

Correspondence to Jung Mogg Kim, Department of Microbiology, Hanyang University College of Medicine, 222 Wangsimni-ro, Seongdong-gu, Seoul 133-791, Korea. Tel: +82-2-2290-0645, Fax: +82-2-2282-0645, jungmogg@hanyang.ac.kr
• Received: October 21, 2013   • Revised: October 29, 2013   • Accepted: October 30, 2013

© Copyright 2014. Korean Association for the Study of Intestinal Diseases. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

prev next
  • 10,248 Views
  • 173 Download
  • 36 Web of Science
  • 36 Crossref
  • Mucosal surface of the intestinal tract is continuously exposed to a large number of microorganisms. To manage the substantial microbial exposure, epithelial surfaces produce a diverse arsenal of antimicrobial proteins (AMPs) that directly kill or inhibit the growth of microorganisms. Thus, AMPs are important components of innate immunity in the gut mucosa. They are frequently expressed in response to colonic inflammation and infection. Expression of many AMPs, including human β-defensin 2-4 and cathelicidin, is induced in response to invasion of pathogens or enteric microbiota into the mucosal barrier. In contrast, some AMPs, including human α-defensin 5-6 and human β-defensin 1, are constitutively expressed without microbial contact or invasion. In addition, specific AMPs are reported to be associated with inflammatory bowel disease (IBD) due to altered expression of AMPs or development of autoantibodies against AMPs. The advanced knowledge for AMPs expression in IBD can lead to its potential use as biomarkers for disease activity. Although the administration of exogenous AMPs as therapeutic strategies against IBD is still at an early stage of development, augmented induction of endogenous AMPs may be another interesting future research direction for the protective and therapeutic purposes. This review discusses new advances in our understanding of how intestinal AMPs protect against pathogens and contribute to pathophysiology of IBD.
Human intestines are constantly exposed to the threats of various microorganisms. Healthy intestinal mucosa is characterized by the definite distinction between epithelial surfaces and enteric microbiota, because direct contact between intestinal epithelial cells and enteric microbiota and the colonization of pathogen have negative impacts to the human body.1 These are commonly discriminated by mucus secreted by goblet cells. Among those, glycocalyx is present in apical surface of intestinal epithelial cells. The glycocalyx of small intestinal epithelium is a single mucus layer which is permeable to bacteria.2 Glycocalyx of the large intestine is organized into two layers of a firm inner region and an outer layer with permeability. Since the inner layer forms a physical barrier that prevents the contact with enteric microbiota, bacterial colonization is rarely observed. In contrast, bacteria such as Lactobacillus spp. and Bifidobacteria spp. are usually found to colonize the outer layer.3 This barrier makes intestinal microbiota to exist about 50 µm apart from intestinal epithelial cells in the colonic mucus of a mouse.4
The human body produces antimicrobial proteins (AMPs) as the part of the innate immune response to kill bacteria or prohibit the growth of microorganisms. AMPs are peptide antibiotics that act as an important effector of innate immunity. AMPs are commonly expressed in intestinal mucosa in constant contact with enteric microbiota. Thus, intestinal epithelial cells, paneth cells, and endogenous antimicrobial proteins expressed in different immune cells are expressed naturally without stimulation or their release is accelerated by external stimulation. Among those, peptides consisting of fewer than 50 amino acids are defined as antimicrobial peptides.5 Therefore, AMPs include antimicrobial peptides, and peptides are used interchangeably with AMPs in this review paper.
Colitis may occur due to enteric microbiota or the interaction between mucosa of pathogen and host. The induction of AMPs is profoundly related with the function of intestinal barriers. AMPs are involved in immune response, in addition to growth inhibition of pathogenic bacteria. Hence, an increase or decrease in the expression of AMPs during infectious and inflammatory processes can be used as a biomarker for specific diseases. Therefore, AMPs have emerged as new therapeutic agents that kill microorganisms resistant to currently existing antibiotics. This review paper discusses leading AMPs expressed in the intestinal tract and their functions, the association with inflammatory bowel diseases (IBD), and clinical applicability.
1. Defensin
Defensins are involved in innate immune responses of the gastrointestinal tract and mainly expressed in Paneth cells, epithelial cells, and immune cells. Defensins are cationic proteins abundant with cysteines and they are found in vertebrates, invertebrates and plants. Defensins consist of 18-45 amino acids, and classified into α-defensin and β-defensin according to the distribution of cysteines and disulfide bonds between cysteine residues.6 Defensins are classified into proteins constitutively expressed without infections or inflammations and inducibly expressed with stimulation.6
Defensins are characterized by a strong polarization of charges. Therefore, they easily bind with phospholipids on the surface of microorganisms with negative charges through electrical action. As a result, antimicrobial response is activated by forming pores in the cell membrane.7 Thus, the outer layer expands and the inner layer tightens in the lipid bilayer of bacteria cell membrane through membrane integration of defensins, and collapse and donut-shaped pores are resulted in bacteria cell membrane.8 These effects also work on fungi and viruses, in addition to bacteria. Among defensins, human β-defensin 3 (hBD-3) is reported to inhibit the biosynthetic stage of bacteria cell membrane by binding to lipid II, which is the basic composite unit of peptidoglycan similarly with penicillin.9

1) Human α-defensin (Human Neutrophil Peptide, HNP)

Human α-defensin is called neutrophil peptides (human neutrophil peptide, HNP) because it is produced mainly by neutrophils.10 Until now, only four types of human β-defensins (HBD) have been discovered and presented as HNP-1, -2, -3, and -4. Neutrophils which take crucial roles in innate immunity use HNP in destroying the phagocytic pathogens. Since neutrophils make up the largest percentage of all phagocytes in human body and circulate the entire body, HNPs are widely ranging antimicrobial peptides.
The association of human α-defensin with IBD has been investigated. Transcription factor 4 (TCF4), which is one of the transcriptional factors in the Wnt signaling pathway, is known as a gene regulating the expression of α-defensin.11 Genetic variation in TCF4 promoter region is reported to be associated with Crohn's disease.12 Moreover, a high rate of genetic mutation of lipoprotein receptor-related protein 6, which is an essential composition in the Wnt pathway, is observed in patients with Crohn's disease.12 The results suggested that a decrease in α-defensin expression may result in dysbiosis in enteric microbiota and a higher risk of IBD.13 However, the roles of HNPs on IBD still remain controversial.
HNP-1 and HNP-3 shows inhibition of cytotoxicity and Rho glucosylation in Caco-2 cells exposed to Clostridium difficile toxin B. In contrast, no specific action on defensive reaction was detected against C. difficile toxin A.14 Moreover, HNP-1 prohibits the release of interleukin (IL)-1β stimulated by lipopolysaccharide (LPS).15 The outcome implies that HNP-1 prevents inflammations induced by endotoxin of gram-negative bacteria. When HNP-1 was injected into the peritoneal cavity of a mouse model induced with enteritis using dextran sodium sulfate (DSS), more severe symptoms of colitis and a higher cytokine level in the colon were observed.16 The expression level of HNP1-3 was high in the mucosa of patients with progressive IBD, suggesting that this could be related with neutrophil infiltration.17 Plasma HNP 1-3 concentrations were found to be high in patients with IBD. The outcome is assumed to be attributable to the circulation of neutrophils.18,19 Although the antimicrobial action of HNP-4 is stronger than those of HNP1-3,20 the effect of HNP-4 on IBD has not been examined yet.

2) Human α-defensin 5 (HD-5) and Human α-defensin 6 (HD-6)

Human α-defensins (HD) 5 and 6 are only expressed in Paneth cells of the small intestine. These antimicrobial proteins are not expressed in the colon since Paneth cells are not present in the colon.10 Paneth cells are a type of specialized epithelial cells of the gut, and located in the crypt base of the small intestine. However, Paneth cell metaplasia is detected when chronic inflammations exist in the gastrointestinal tract. Under these pathologic conditions, HD-5 and HD-6 could be secreted from Paneth cells present in the other parts of the body besides the small intestine.21
These AMPs play various defensive reactions against infections and inflammations. Thus, HD-5 has disinfection ability against all bacterial species. Furthermore, HD-5 induced the expression of IL-8 in intestinal epithelial cells, and the administration of HD-5 decreased mortality rate in a mouse model with DSS-induced colitis.22 Transgenic mouse with overexpressed HD-5 showed high resistance against Salmonella infections.23 In addition, HD-5 defenses against cytotoxicity by inhibiting Rho glucosylation by C. difficile toxin B.14
A decrease in the expression of HD-5 and HD-6 was shown in patients with Crohn's disease in the ileum.24,25 Although some previous studies proposed that decreased expression of HD-5 and HD-6 is related with nucleotide oligomerization domain 2 (NOD2) mutation,26 some studies found no association between and α-defensin expression in Paneths cells.27 The expression of HD-5 detected in metaplastic Paneth cells in the colon of patients with IBD is likely to be a defensive reaction against bacteria during the incidence of enteritis.28,29

3) Mouse α-defensin (Cryptdin)

Mouse Paneth cell α-defensins, termed cryptdins, have not been found in human body.30 Cryptdin precursors are located in the granules of Paneth cells, and formed with disinfection ability through the interaction with matrix metalloproteinase-7 (MMP-7).30 Since the antimicrobial activity of cryptdin produced in MMP7-/- mice is lowered, the likelihood of developing enteritis is higher.15 Six cryptdins have been identified currently, and cryptdin-4 has the highest antimicrobial activity.31,32

4) Human β-defensin 1 (hBD-1)

Human β-defensin 1 (hBD-1) is an antimicrobial substance constitutively expressed in the human colonic and ileal epithelial cells regardless of enteritis. Therefore, hBD-1 is not expressed even though, stimuli such as IL-1α and others are applied to intestinal epithelial cell lines, Caco-2 and HT-29.33 The hBD-1 protein is encoded by the DEFB1 gene and gene expression of DEFB1 is regulated by peroxisome proliferator-activated receptor gamma (PPARγ). Therefore, the deficiency of PPARγ in the intestinal mucosa of mice leads to a reduction in the expression of mDefB10 identical to DEFB1 in humans, and lowered disinfection ability against intestinal microbiota which include Candida albicans, Bacteroides fragilis, Enterococcus faecalis, and Escherichia coli.34 Therefore, the expression of hBD-1 by PPARγ is assumed to play important roles in regulating a certain number of intestinal microbes.
Antimicrobial activity of hBD-1 against intestinal microbiota increases after the reduction of three disulfide bonds.35 Thus, the antimicrobial activity of hBD-1 needs to be evaluated under unique environmental conditions. Thioredoxin is a mediator facilitating reduction of hBD-1 in intestinal epithelia. Thioredoxin expression at very high levels is shown under inflammatory conditions such as tumors or rheumatoid arthritis.36 On the other hand, a decrease in thioredoxin expression is found at the inflammation site of Crohn's disease.35 Therefore, reduced thioredoxin expression seems to weaken defense mechanism against enteric microbiota by lowering the antimicrobial activity of hBD-1.

5) Human β-defensin (hBD-2, -3, -4)

Unlike consistently expressed hBD-1, human β-defensins 2-4 (hBD-2, -3, -4) are common AMPs which show an increase in expression levels in response to external stimuli. These are expressed in a very small amount in normal healthy colon. Stimuli accelerating hBD-2 secretion are various types of bacteria and cytokine. Flagellin and Campylobacter jejuni obtained from E. coli strain Nissle 1917, which is a probiotic for the treatment of ulcerative colitis, could facilitate hBD-2 production.37,38
The induction of hBD-2 is mediated by proinflammatory cytokines including IL-1β, tumor necrosis factor (TNF)-α, and IL-17 through nuclear factor-kappaB (NF-κB)- and AP-1-dependent pathways.38,39 Among all defensins, hBD-3 has the highest net-positive charge. The antimicrobial activities of hBD-1 and hBD-2 are weakened at high salt concentrations, and the activation of hBD-3 is maintained in physiological sodium concentration. Although hBD-1 and hBD-2 exhibit antimicrobial activities against gram-negative bacteria, hBD-3 shows a stronger antimicrobial action.40
The expression level of hBD-2 decreased in non-inflamed colonic mucosa of patients with IBD while, it increased in inflamed colonic mucosa.41 Although hBD-2 secretion increased in the colonic tissues, no significant changes were observed in serum hBD-2 concentration.18 Moreover, the expression levels of hBD-3 and hBD-4 increased in the colonic crypt of patients with ulcerative colitis while, expression levels remained the same in patients with Crohn's disease.42 Mouse β-defensin-3, the murine homologue of human hBD-2 greatly increased in the intestinal epithelial cells of a mouse model with DSS-induced colitis.43
Differences were found in the expression of hBD-2 mRNA between active Crohn's disease and ulcerative colitis. The expression levels of hBD-2 and hBD-3 increased considerably in patients with active ulcerative colitis while, they were prohibited in patients with Crohn's disease.44-46 In particular, disinfection ability against intestinal microbiota was relative lower in colonic mucosa of patients with Crohn's disease.47 However, the mechanism to explain the outcomes still remains unclear. Although the expression level of hBD-2 decreased in a study on European and American patients with IBD,48 the result was different in a New Zealand patient group,49 An increase in hBD-2 in patients with IBD has been suggested as one of the possible causes for secondary phenomenon of barrier disruption. Meanwhile, β-defensin has no protective actions against cytotoxicity of C. difficile toxin B unlike HD-5.14

6) θ-defensin

Humans do not produce θ-defensin protein because human θ-defensin genes contain a premature stop codon.50 The therapeutic effect of θ-defensin has not been identified yet. Synthetic θ-defensin (retrocyclin) has high antimicrobial activity and strong antiviral activity against human immunodeficiency virus.51 Moreover, modified θ-defensin (RC-1) inhibited the growth of Listeria monocytogenes in macrophages more remarkably than α-defensin HNP-1.52 The results suggest that θ-defensin is applicable to the human body.
2. Cathelicidin (Cathelicidin Anti-microbial Peptide, CAMP)
Cathelicidin antimicrobial peptides (CAMPs) are a family of polypeptides expressed in macrophages, neutrophils, intestinal epithelial cells, and others. They have anti-microbial effects against bacteria, virus, and fungi. CAMPs include human LL-37 and mouse cathelicidin-related antimicrobial peptide (mCRAMP). The mechanism of cathelicidins is very similar to those of defensins. Thus, cationic residues of α-helical peptide present in cathelicidins are inserted to the cell membrane by combining with bacterial plasma membrane. As a result, antimicrobial effect is activated by forming pores in the cell membrane.53,54 Cathelicidins are released from mucosal surfaces that face the external environment. CAMPs are also found in breast milk and amniotic fluid, and display antimicrobial abilities against Staphylococcus aureus, group A Streptococcus, invasive strains of E. coli O29, and others.55 Therefore, LL-37 is significantly involved in innate immune response of human newborns.
Cathelicidin secretion is induced by intestinal microbiota. Butyrate, a short-chain fatty acid metabolic substance, is known as a derivative of cathelicidin. Butyrate is an inhibitor of histone deacetylase, and trichostatin A also induces the expression of cathelicidin.56 PU.1 an E-twenty six family transcription factor induces the expression of CAMP genes by binding to CAMP promoter.57 Thus, vitamin D receptor and PU.1 are transferred to CAMP promoter and transcription is enhanced in cathelicidin genes of cells stimulated by secondary bile acids such as lithocholic acid, vitamin D, and butyrate.57 The expression of cathelicidin increased in the colon of patients with ulcerative colitis while, and showed no changes in the colon of patients with Crohn's disease.58 Symptoms of acute colitis were more severe in CAMP-/- mouse with the removal of cathelicidin.59 These conditions deteriorated with the administration of bacterial DNA, the toll-like receptor 9 (TLR9) ligand. The intestinal expression of cathelicidin decreased in TLR9-/- mouse model with DSS-induced enteritis using.59 The above results reveal that cathelicidins take crucial roles in defending the body against colitis.
When mCAMP was administered into the rectum of mouse model with DSS-induced enteritis, the expression of mucin-4 (MUC-4) gene increased in the colonic mucosa and restored its thickness. Consequently, colitis was cured.60 The administration of mCRAMP, n particular, reduced fecal microbiota numbers. According to a previous in vitro study, LL-37 inhibited wound healing effect and apoptosis in HT-29 and Caco-2 cells.61 Another study proposed that promoted cathelicidin induction showed treatment effect in an infection model. Thus, orally administered butyrate or phenylbutyrate in a rabbit model of Shigella increased the expression of cathelicidin in the colonic and rectal mucosa.62,63 Increased expression level was associated with improvment in clinical symptoms of infections. However, cathelicidin showed insignificant effects on Entamoeba histolytica due to the secretion of cysteine proteases which degrade cathelicidins.64
3. Protease Inhibitors: Elafin and Secretory Leukocyte Peptidase Inhibitor (SLPI)
The delicate balances between proteases and anti-protease activities partially regulate inflammatory process during colitis progression. Although proteases cause tissue damage during inflammatory states, protease inhibitors facilitate the stabilization and treatment of injured tissues.
Protease inhibitors are elafin and secretory leukocyte peptidase inhibitor (SLPI). Elafin is an elastase-specific inhibitor with anti-microbial action by regulating inflammations.65 SLPI is expressed mainly in the in the jejunum and colon, and prohibits a wide range of protease.66 Thus, it is reported to prohibit the function of human leukocyte elastase, cathepsin G, trypsin, neutrophil elastase, and mast cell chymase. Moreover, SLPI has anti-microbial activity against Salmonella Typhimurium.67
Some studies have reported that protease inhibitors are profoundly associated with the incidence of IBD. For example, elafin expression was considerably high in the intestinal tissues of patients with ulcerative colitis.68 According to another previous study on the tissues of patients with anulcerative colitis, elafin was not expressed in inflammation-free colonic mucosa while, the expression of elafin increased in colonic mucosa at the inflammation site.69 However, an increase in elafin expression still remains unclear in Crohn's disease. SLPI is the dominant protease inhibitor which increases within the intestinal mucosa of inflammation site in patients with ulcerative colitis. On the other hand, SLPI showed no increase in the inflammation-free intestinal mucosa or the large intestine of patients with Crohn's disease.69 Low expression of elafin and SLPI is related with high expression of MMP in patients with Crohn's disease, this condition poses a potential risk of increasing the incidence of fistula.69 High expression of elafin and SLPI in patients with ulcerative colitis is assumed to be caused by self-defense mechanism against enteritis.
In DSS- and trinitrobenzenesulfonic acid-induced colitis models, the overexpression of elafin through the introduction of genes by adenovirus alleviated colitis symptoms. During this process, a reduction in protein hydrolysis in the colon was found along with a decrease in cytokine and NF-κB activities.70 In a laboratory study, the overexpression of elafin significantly reduced TNF-α-induced permeability and IL-8 expression. The outcome indicates that elafin overexpression retains ability to sustain intestinal epithelial integrity and anti-inflammatory effects.70 Increased SLPI production is likely to be involved in the recovery of tissues during colitis progression. Consequently, the expression of SLPI was reduced in thymic stromal lymphopoietin-deficient mouse model.71 When enteritis was induced in this mouse model using DSS, the incidence of inflammation was similar to that of control group but, an increase in mortality rate was detected due to slow recovery of colitis. These consequences imply that SLPI plays important roles in the recovery process of damaged mucosa.71
4. Bactericidal/Permeability Increasing Protein (BPI)
Bactericidal/permeability increasing protein (BPI) is about 50 kDa glycoprotein that was first discovered in neutrophils. BPI is endogenously expressed in the epithelial cells of intestinal mucosa, and has strong antimicrobial effects on gram-negative bacteria. Thus, BPI kills gram-negative bacteria by binding to LPS, and prevents inflammatory response generated by LPS.72 GLU216Lys, a single nucleotide polymorphism genotype of BPI is reported to be associated with ulcerative colitis and Crohn's disease.73 An increase in BPI production was found in the colonic mucosa of patients with ulcerative colitis.74 Moreover, BPI level in the colonic mucosa is suggested to be correlated with the degree of ulcerative colitis and inflammation.74 As proven in an experimental study, a decrease in IL-8 expression by Salmonella in BPI-overexpressing Caco-2 cells implies that BPIs inhibit inflammation.75 Anti-neutrophil cytoplasmic auto-antibodies (ANCA) are produced in some patients with IBD, and ANCA is a BPI-targeting auto-antibody.76 Since IgG from patients with ulcerative colitis and Crohn's disease can neutralize BPI, the antimicrobial ability of BPI is consequently reduced. Auto-antibody ANCA against BPI raises mucosal injury in patients with IBD and the risk of diseases.77 The above outcomes reveal that ANCA is associated with the development of IBD.
5. C-type Lectin Family
AMPs belonging to the C-type lectin family are human hepatocarcinoma-intestine-pancreas/pancreatitis-associated protein (HIP/PAP) and mouse regenerating islet-derived protein 3γ (REG3γ). Similar structure of these proteins with C-type lectin exhibits antimicrobial effects by binding to peptidoglycan, a major component of bacterial plasma membrane.78 HIP/PAP and REG3γ are mainly produced in Paneth cells and endocrine cells around the intestinal epithelial cells of the gut and ascending colon in adults.79 These cells also secrete chromogranin A and synaptophysin, the biomarkers for endocrine cells. AMPs in this family were very highly expressed in germ-free mice exposed to bacteria and mice with DSS-induced colitis.80 Moreover, HIP/PAP expression increased in the colonic epithelial cells of patients with IBD.80 HIP/PAP is reported to be involved in cell proliferation and differentiation and the expression level was elevated in various types of tumor including colon cancer. Despite its antimicrobial action, the roles of HIP/PAP in the occurrence of colitis still remain unknown.
6. Lysozyme
Lysozyme is a hydrolase breaking the bonds in peptidoglycan layer which consists of an outer membrane of bacterial cell walls. Lysozyme is a leading substance involved in destruction of the cell membrane, and it hydrolyzes the glycosidic bonds between N-acetylglucosamine and N-acetyl-muramic acid of peptidoglycan layer in cell walls. Secretory phospholipase A2 is another antimicrobial enzyme produced in Paneth cells, and displays antimicrobial action by hydrolyzing phospholipids which are major components of bacterial cell walls.81
Lysozymes are abundant in mucus, tear, saliva, breast milk, and others, and a massive lysozyme is located in granular cells. Increased expression of lysozyme mRNA was observed in the colonic epithelial cells of patients with ulcerative colitis compare to those of control group.29 Lysozyme mRNA was produced in the colonic epithelial cells of patients with Crohn's disease, and lysozyme expression is reported to be correlated with the degree of inflammation.24 However, the use of fecal lysozyme concentration as a diagnostic marker of IBD still remains controversial. A study on the treatment effects of lysozyme on IBD was performed. Egg white is abundant with lysozyme. When lysozymes from egg white were injected to a porcine model with DSS-induced colitis, improvement in colitis symptoms and a decrease in the expression of TNF-α and IL-6 were observed.
7. Lactoferrin (Lactotransferrin)
Lactoferrin, also called as lactotransferrin, is a globular glycoprotein with a molecular mass of about 80 kDa. Lactoferrin is found in human cellular fluids including mucus, tear, saliva, breast milk, and others, and a massive amount is located within neutrophils like lysozyme. Considerably higher levels of lactoferrin are present in colostrum. Therefore, lactoferrin and lysozyme are considered circulating substances making up innate immune response system. The antimicrobial activities of lactoferrin are observed in various aspects. Since lactoferrin with high iron affinity binds iron and makes it unavailable to pathogens.82 Furthermore, lactoferrin can dissolve cells by enhancing membrane permeability by binding to the LPS layer of bacterial cell wall. In addition, it promotes phagocytosis of immune cells.83,84
Fecal lactoferrin concentration increased in patients with IBD, and remained the same in patients with irritable bowel syndrome. Hence, lactoferrin level is suggested to be used in diagnosing IBD.85 Measurement of lactoferrin is simple and cost-effective, and stability in stool samples is high. Moreover, a reduction in fecal lactoferrin concentration aligned with therapeutic response to mucosal treatment.86 Fecal lactoferrin concentration is reported to be higher in toxigenic bacteria of patient with C. difficile colitis than non-toxigenic bacteria.87
The effectiveness of IBD treatment using lactoferrin is briefly discussed in this section. When lactoferrin was orally administered to a model with DSS-induced colitis, colitis symptoms were alleviated according to doses and cytokine imbalance was resolved.88 Identical results were observed in a model with trinitrobenzenesulfonic acid-induced colitis.89 Lactoferricin and lactoferrampin, peptides derived from lactoferrin, are synthetic substances capable of killing Entamoeba histolytica. These are anticipated to replace metronidazole, an antibiotic drug.90
8. Hepcidin
Hepcidin is predominantly produced in the liver in the mature form of the 25 amino acid peptide derived from a preprohepcidin of 84 amino acids and a prohepcidin of 60 amino acids. Hepcidin, a 25-amino acid peptide hormone, is the principal regulator of plasma iron concentrations by blocking iron efflux from cells into plasma through the binding of hepcidin to its receptor, the iron export channel ferroportin present on the basolateral surface of intestinal epithelial cells and cell membrane of macrophages.91 Despite iron absorption in the gastrointestinal tract, intestinal iron absorption is reduced because hepcidin inhibits iron uptake from intestinal epithelial cells to hepatic portal system. In addition, hepcidin blocks cellular iron efflux by impeding the roles of ferroportin in macrophages. Through these processes, hepcidin maintains normal blood iron levels. Increased hepcidin level in chronic inflammatory conditions like IBD blocks the movement of iron from macrophages. This results in a reduction of the iron level in blood serum, leading to anemia.92 Since hepcidin restricts the use of iron by bacteria, the growth of pathogens could be prohibited.93
The roles of hepcidin in IBD patients are discussed. Serum hepcidin levels in patient groups of ulcerative colitis and Crohn's disease were significantly higher than those of control group.94 Serum hepcidin coincided with disease activity and C-reactive protein concentration. Prohepcidin, the precursor of hepcidin, was proportional to hemoglobin level while, hepcidin was inversely proportional to hemoglobin level. The outcome suggests that hepcidin is likely to be associated with IBD-related anemia.94 Hepcidin expression is dependent on bone morphogenetic proteins. When anti-bone morphogenetic protein reagent was injected to a colitis model using T cell transfer, an increase in blood iron level and a decrease in inflammatory cytokine expression were resulted by the inhibition of hepcidin expression.95 Therefore, the inhibition of hepcidin expression is anticipated to cure IBD-related anemia and alleviate colitis symptoms.
9. Lipocalin-2 (Lcn-2, Neutrophil Gelatinase-associated Lipocalin [NGAL], siderocalin)
Microorganisms use siderophores, iron chelating compounds to obtain iron.96 Iron-bound siderophores are ferric siderophore complex, and common examples are siderophore enterobactin (Ent) of gram-negative bacteria such as E. coli, Salmonella Enterica, and Klebsiella pneumoniae.97,98 In the human body, lipocalin-2 (Lcn-2) or siderocalin hampers bacterial growth by binding to ferric siderophore complex of bacteria.99
Lcn-2, also known as neutrophil gelatinase-associated lipocalin, is a 25 kDa antimicrobial protein abundant in neutrophil granules. Lcn-2 is produced in intestinal epithelial cells infected with enterotoxigenic B. fragilis (ETBF).100 ETBF infection also increases hBD-2 expression.33 However, the expression patterns manifested by ETBF infection in two anti-microbial proteins vary. Thus, hBD-2 is mainly released from basolateral surface in the early stage of infection while, Lcn-2 is secreted at both basolateral and apical cell surfaces in the late stage of infection. The expression of hBD-2 is regulated by NF-κB while, Lcn-2 is regulated by AP-1, a transcription factor. B. fragilis uses outer membrane proteins instead of siderophores for iron absorption.101-103 Lcn-2 produced from apical surface is assumed to act on other bacteria in addition to B. fragilis.100
Antibiotic resistance of bacteria is gradually increasing. Theoretically, there is the possibility of resistance in endogenous AMPs. However, endogenous AMPs have maintained the effectiveness on intestinal bacteria for a long period of time. The mechanism has not been clarified yet. Distribution of diverse antimicrobial protein families in the colon and consistently maintained cell wall or membrane structure targeting AMPs are suggested as possible mechanism.104 Pathogens including S. aureus, Salmonella spp. and Legionella pneumophila block attack from cation AMPs such as defensins by replacing anions in cell walls with cations.105-108 Moreover, S. aureus and group A Streptococcus could be deactivated through protein hydrolysis of AMPs.109,110 In Neisseria spp., AMP resistance was manifested through efflux pump.111 In Shigella spp., anti-micorbial activities against cathelicidin and β-defensin were reduced by inhibiting the synthesis of intrinsic AMPs in the intestines.112 Therefore, AMPs are anticipated to prohibit the response to decrease intestinal microbe numbers to below normal level, in addition to the prevention of excessive growth of intestinal bacteria.
Antimicrobial proteins regulate innate immune response through diverse methods in addition to directly destroying microorganisms. Cathelicidins and defensins constitute major AMP families with immune regulatory function.
1. Chemoattraction of Immune Cells by Antimicrobial Proteins
Cathelicidins and defensins directly regulate inflammatory response through chemotactic activities. The human cathelicidin LL-37 can migrate neutrophils, monocytes, and CD4 T cells to the inflammatory sites. The chemotactic ability is regulated by G protein-coupled formyl peptide receptor-like 1 (FPRL1), also known as formyl peptide receptor 2.113 Although the mouse cathelicidin (mCRAMP) has considerably different amino acid sequences of LL-37, FPRL1 or FPRL2 (also known as formyl peptide receptor 3) attracts the human and mouse cells dependently.114 Moreover, human α-defensin, hBD-3, and hBD-4 manifest chemotaxis towards monocytes and macrophages.115 LL-37 and hBD-2 attract mast cells.116 LL-37, in particular, stimulates mast cells to release histamine and induces the formation of new blood vessels.117
AMPs different in structures displays various activities in chemotaxis. For example, human α-defensin selectively induced the movement of naïve CD4+CD45RA+ and CD8+ T cells but did not move CD4+CD45RO+ memory T cells.118 However, β-defensin exhibited chemotactic response to immature dendritic cells and CD4+CD45RO+ memory T cells. The chemotactic effect of human defensin was inhibited by antibody against CC-chemokine receptor 6.119 These results indicate that AMPs can regulate inflammatory response by exhibiting chemokine action.
2. Regulation of Toll-like Receptor (TLR) Responses
TLR is a molecular structure existing on human plasma membrane or endosome surface and binds to pathogen-associated molecular patterns present on bacterial surface. Therefore, TLR molecule is a type of membrane-bound pattern recognition receptors (PRRs). As a result, NF-κB and others are activated to induce or inhibit inflammatory response through intracellular signal transmission in the human body.81 Cathelicidins, a leading example, are reported to act directly on bacterial LPS or TLR ligands such as self DNA.104 Cathelicidins influence TLR signaling by affecting the internalization of TLR ligands or changing cell surface membrane microdomain function.120,121 The human cathelicidin LL-37 increases the production of type I interferon by activating TLR-9 through the interaction with DNA. Consequently, cathelicidins influence the maturation of Th17 cells.121 AMPs expressed by pathogen infection can destroy the pathogen itself and neutralize excessive immune response at the same time. However, abnormal expression of antimicrobial proteins could elevate the risk of inflammation regulation disturbances and autoimmune disease. This is thought to be attributable to changes in sensitivity against self DNA.104 Therefore, the mechanism preventing excessive expression of AMPs exists in the human body.
The expression and release of AMPs are systematically controlled in the human body, since toxicity of AMPs can affect the human cell membrane. Excessive immune responses by AMPs expression need to be controlled.
1. Developmental Regulation
The human intestinal microbiota changes with age from the birth. Obligate anaerobes, mainly comprising Bifidobacterium spp. and Bacteroides spp. settle at birth and then, intestinal microbiota stabilizes gradually after weaning period.84 Intestinal AMPs are highly expressed at birth and in the early post-birth period. Control of AMPs expression is assumed to take roles in maintaining immune homeostasis during the developmental period of infant intestinal tissues.104 In a mouse model, antimicrobial proteins angiogenin 4 (Ang4) and REG3γ were strongly induced in the small intestine during the early post-birth period. The expression level of Ang4 increases by about 20 times higher during weaning period (about 17-21 days post birth) in conventionally raised mice and then, matured state is maintained.122 The expression level of REG3γ increases by about 3,000 times.78 To sum up the above results, the overexpression of AMPs is an important mechanism for host defense during periods of microbiota settlement and disappearance of passive immunity maintained by breastfeeding.
Cathelicidin expression shows inverse switching phenomenon. The expression level of cathelicidin is high during infant period and then, gradually decreases right before stopping breastfeeding.123 The expression of cathelicidin varies according to anatomical locations in adults. Cathelicidin expression is ceased in the small intestine and maintained at a high level in the colon. Likewise, cathelicidins highly expressed in the colon provide defensive activity against pathogen infection.124 The physiological association of a decrease in cathelicidin expression according to the maturation of the gut has not yet been fully verified.
2. Transcriptional Regulation by Microbiota
The expression of α-defensin mostly requires transcriptional factor TCF-4 in the Wnt pathway but, α-defensin is produced regardless of intestinal bacteria.125 Lysozymes, Secretory phospholipase A2, and some β-defensins do not require normal intestinal bacteria signaling.122,126,127 According to a study on germ-free mouse, bacterial signals are critical in the expression of some intestinal AMPs. For instance, the expression of human β-defensin (hBD-2) is regulated by intestinal bacteria.126 Moreover, AMPs such as Ang4 and REG3γ were deficient in germ-free mouse and generally up-regulated by microbiota.78,122
The PRR of the host can also regulate the expression of AMPs. For example, the stimulation of TLR is essential for REG3γ mRNA expression in intestinal epithelial cells. The expression level of antimicrobial protein REG3γ was lowered in myeloid differentiation primary response protein 88 (MyD88) knockout mice. The outcome demonstrates that TLR is crucial in AMPs expression.4,128-130 Moreover, both intestinal epithelial and Paneth cells recognize bacteria using TLRs and then, REG3γ expression is up-regulated.4,128,129 LPS binding to TLR4128,129 and flagellin binding to TLR5131 induce REG3γ expression. This process can be carried out without the aid of enteric microbiota. For instance, butyrate, a short-chain fatty acid produced through the fermentation of dietary fibers by intestinal microbes in the colon is important in the expression of cathelicidin LL-37.132
NOD2 can also control the expression of intestinal AMPs. NOD2 is a cytoplasmic PRR produced in Paneth cells, macrophages, and intestinal epithelial cells. NOD2 can activate NF-κB by recognizing muramyl dipeptide, a substructure of peptidoglycan.80 muramyl dipeptide facilitates the antimicrobial activity of crypts distributed in Paneth cells. Therefore, the composition of the intestinal microbiota changed noticeably in Nod2-/- mice.133 These results suggest that some AMPs are regulated intestinal microbiota.
3. Post-translational Regulation
Host cells secrete AMPs that are toxic to cell membranes and these proteins are potential factors to damage cell membranes. To prevent this problem, the activities of AMPs must be tightly regulated during storage in membrane-bound secretory granules. For instance, α-defensins are stored in Paneth cell granules as inactive pro-peptides. Mouse α-defensins (cryptdin) have to be processed in terminus of the pro-peptide by MMP7 to produce active peptides with antibacterial ability.134 In humans, trypsin cleaves α-defensins to their mature active peptides.135 REG3γ also requires N-terminal proteolytic process by trypsin to yield an active protein with antibacterial ability. After this process, proteins with antimicrobial activities are secreted into the gut lumen.136 Cathelicidins are synthesized as pro-peptides, in which signaling peptides called "cathelin pro-sequence" are located at N-terminal, and C-terminal area showing antimicrobial characteristics consists of cation area. Pro-peptides are converted to cathelicidins with antimicrobial activity by serine proteases.137
A recent study reported interesting results on the regulation of HD-6. Adequate antimicrobial activities are not detected with the presence of HD-6 alone. Dimer shaped HD-6 is processed to tetramer by binding to proteins present on the surface of bacteria and then, they are self-assembled into large oligomers. As a result, antimicrobial effect is finally exhibited as HD-6 undergoes self-assembly to form fibrils and nanonets that surround bacteria.138
Oxidation-reduction environment involves the activation of AMPs. In human cells abundant with oxygen, the antimicrobial effect of hBD-1 is low under this condition. On the other hand, the condition changes to the gut where oxygen is insufficient, and the antimicrobial effect of hBD-1 is remarkably strong. The outcome is assumed to be caused by the reduction of disulphide bridges and structural changes under conditions of limiting oxygen. The disulphide bridges of hBD-1 are reduced and antimicrobial activity increases drastically as an amphipathic arrangement of cationic and hydrophobic residues is broken up.139 Antimicrobial activities against Bifidobacteria spp., Lactobacillus spp., and Candida albicans are more effective when hBD-1 is reduced to linear peptides. Not reduced hBD-1 does not act on those bacteria.35
4. Secretion Regulation
The secretion of AMPs seems to be regulated by intestinal microbiota. For example, Paneth cells lead the production of most AMPs including α-defensin and lysozyme. Paneth cells secrete the intracellular content of granules to the intestinal tract when they are exposed to living bacteria or bacterial molecules such as LPS.140 The release of AMPs is anticipated to be accurately regulated in response to microorganisms which pose potential threats to human health. However, the detection mechanisms of microorganisms regulating the secretion of AMPs by Paneth cells have not been clarified yet. The expression and production of AMPs are assumed to be controlled by complex networks formed by interactions between microorganisms and nutritional signals.104 More efforts need to be exerted to further investigate these regulation networks. Successful studies will enable the implementation of new therapeutic strategies aiming for the enhancement of endogenous AMPs production.
Attempts have been made to synthesize small-sized antimicrobial peptides using endogenous AMPs expressed in the body.30 One of difficulties in the development is the lack of knowledge on peptide structures involved in antimicrobial or anti-inflammatory activities. AMPs listed above greatly vary in amino acid arrangement , molecular weight, and molecular structure.5 Peptide structures can be easily identified by measuring antimicrobial activities of synthetic peptides manufactured with some changes in amino acid sequence in AMPs with short peptide sequences. For example, cathelicidins are short, linear peptides with 37 amino acids, and many studies have reported synthetic peptides with artificially changed structures.141,142 These artificial approaches are difficult in AMPs with high molecular masses.
The development of synthetic peptides is in progress using natural AMPs normally present in nature. For example, coprisin is a 9-amino acid peptide (LLCIALRKK) derived from an insect called Korean dung beetle. This peptide exhibits antimicrobial activities by destructing bacterial cell wall. In an animal testing performed on mice, coprisins were found to prevent inflammation and mucosal damage caused by C. difficile infection.143 In addition, telavacin and dalbavacin, semi-synthetic glycopeptides showed antimicrobial activities against vancomycin-resistant Gram-positive bacteria.144 According to a clinical trial, orally administered peptides are reported to be effective in improving C. difficile colitis.145 Newly introduced synthetic antimicrobial peptides are expected to be used as candidate materials for preventing and treating IBD and intestinal bacterial infections.
AMPs, enteric microbiota, and the interaction of immune regulation in the intestine are being actively investigated. An increase in some AMPs expression is observed in IBD and intestinal infections. Specific antimicrobial materials can be used as biomarkers for estimating disease activity. Moreover, the development of therapeutic method is currently in progress applying the fact that decreased secretion of AMPs exists in IBD. An abnormal expression of defensin was detected in patients with Crohn's disease in the ileum, and assessing the applicability of recombinant antimicrobial proteins HD-5 in these patients is a representative example. The treatment effects of several AMPs have been proved in animal testing. Although new groups of small-sized AMPs have been developed, this technology is still at an early-stage of development. For example, only a few studies have been performed on the stability of administered peptides or proteins, transfer methods to inflammation sites, efficacy and safety. Orally administered AMPs have to reach the intestines by avoiding the attack from gastric acid. Moreover, the comparison of the effectiveness between AMPs and antibiotics, and the effects of AMPs in already colonized enteric microbiota need to be further investigated. In addition, the chemotactic characteristics of AMPs have to be taken into consideration.
Despite the above difficulties, attempts have been made to resolve those problems. For example, orally administered AMPs have been encapsulated against gastric juice. Since the stability of most AMPs is low in the blood, the expression of AMP genes has been attempted using virus. However, problems on the stability and transfer method of administered AMPs still restrict clinical trials. As an alternative measure, enhancing innate immunity by increasing the induction of naturally expressed AMPs in the body has been proposed. For instance, calcipotriol ointment (vitamin D analogue used for the treatment of psoriasis) used on healthy men's skin increases the production of cathelicidin.146 Furthermore, 1,25-dihydroxyvitamin is known to induce the expression of cathelicidin,147 and phenylbutyrate promotes the expression of cathelicidin in various cell lines.148 E. coli Nissle 1917 (Mutaflor®, Mutaflor capsules have been proven to heal mild UC) and other probiotics including E. coli and Lactobacillus reuteri are known to increase the expression of hBD-2.37,38,149 Moreover, the expression of hBD-2 is also elevated by 1,25-dihydroxyvitamin D3.147 The induction of AMP expression is currently realizable in laboratory and clinical trials.150 From host's perspective, knowledge expansion on AMPs is anticipated to contribute in clarifying the pathogenic mechanism of IBD and finding cure methods.

Financial support: This work was supported by Basic Science Research Program (NRF-2013R1A1A2A10004404) and MRC program (NRF-2008-0062287) through the National Research Foundation of Korea funded by the Ministry of Education, Science, and Technology (MEST).

Conflict of interest: None.

  • 1. Kim JM. Inflammatory bowel diseases and enteric microbiota. Korean J Gastroenterol 2010;55:4–18.PMID: 20098062.ArticlePubMed
  • 2. Johansson ME, Ambort D, Pelaseyed T, et al. Composition and functional role of the mucus layers in the intestine. Cell Mol Life Sci 2011;68:3635–3641.PMID: 21947475.ArticlePubMedPMC
  • 3. Subramani DB, Johansson ME, Dahlen G, Hansson GC. Lactobacillus and Bifidobacterium species do not secrete protease that cleaves the MUC2 mucin which organises the colon mucus. Benef Microbes 2010;1:343–350.PMID: 21831773.ArticlePubMed
  • 4. Vaishnava S, Yamamoto M, Severson KM, et al. The antibacterial lectin RegIIIgamma promotes the spatial segregation of microbiota and host in the intestine. Science 2011;334:255–258.PMID: 21998396.ArticlePubMedPMC
  • 5. Pasupuleti M, Schmidtchen A, Malmsten M. Antimicrobial peptides: key components of the innate immune system. Crit Rev Biotechnol 2012;32:143–171.PMID: 22074402.ArticlePubMed
  • 6. Cederlund A, Gudmundsson GH, Agerberth B. Antimicrobial peptides important in innate immunity. FEBS J 2011;278:3942–3951.PMID: 21848912.ArticlePubMed
  • 7. Kagan BL, Selsted ME, Ganz T, Lehrer RI. Antimicrobial defensin peptides form voltage-dependent ion-permeable channels in planar lipid bilayer membranes. Proc Natl Acad Sci U S A 1990;87:210–214.PMID: 1688654.ArticlePubMedPMC
  • 8. Papo N, Shai Y. Can we predict biological activity of antimicrobial peptides from their interactions with model phospholipid membranes? Peptides 2003;24:1693–1703.PMID: 15019200.ArticlePubMed
  • 9. Sass V, Schneider T, Wilmes M, et al. Human beta-defensin 3 inhibits cell wall biosynthesis in Staphylococci. Infect Immun 2010;78:2793–2800.PMID: 20385753.ArticlePubMedPMC
  • 10. Lehrer RI, Lu W. Alpha-defensins in human innate immunity. Immunol Rev 2012;245:84–112.PMID: 22168415.ArticlePubMed
  • 11. van Es JH, Jay P, Gregorieff A, et al. Wnt signalling induces maturation of Paneth cells in intestinal crypts. Nat Cell Biol 2005;7:381–386.PMID: 15778706.ArticlePubMedPDF
  • 12. Koslowski MJ, Kubler I, Chamaillard M, et al. Genetic variants of Wnt transcription factor TCF-4 (TCF7L2) putative promoter region are associated with small intestinal Crohn's disease. PLoS One 2009;4:e4496PMID: 19221600.ArticlePubMedPMC
  • 13. Swidsinski A, Weber J, Loening-Baucke V, Hale LP, Lochs H. Spatial organization and composition of the mucosal flora in patients with inflammatory bowel disease. J Clin Microbiol 2005;43:3380–3389.PMID: 16000463.ArticlePubMedPMC
  • 14. Giesemann T, Guttenberg G, Aktories K. Human alpha-defensins inhibit Clostridium difficile toxin B. Gastroenterology 2008;134:2049–2058.PMID: 18435932.ArticlePubMed
  • 15. Shi J, Aono S, Lu W, et al. A novel role for defensins in intestinal homeostasis: regulation of IL-1beta secretion. J Immunol 2007;179:1245–1253.PMID: 17617617.ArticlePubMedPMC
  • 16. Hashimoto S, Uto H, Kanmura S, et al. Human neutrophil peptide-1 aggravates dextran sulfate sodium-induced colitis. Inflamm Bowel Dis 2012;18:667–675.PMID: 21928371.ArticlePubMed
  • 17. Cunliffe RN, Kamal M, Rose FR, James PD, Mahida YR. Expression of antimicrobial neutrophil defensins in epithelial cells of active inflammatory bowel disease mucosa. J Clin Pathol 2002;55:298–304.PMID: 11919217.ArticlePubMedPMC
  • 18. Yamaguchi N, Isomoto H, Mukae H, et al. Concentrations of alpha- and beta-defensins in plasma of patients with inflammatory bowel disease. Inflamm Res 2009;58:192–197.PMID: 19184352.ArticlePubMed
  • 19. Kanmura S, Uto H, Numata M, et al. Human neutrophil peptides 1-3 are useful biomarkers in patients with active ulcerative colitis. Inflamm Bowel Dis 2009;15:909–917.PMID: 19107772.ArticlePubMed
  • 20. Ericksen B, Wu Z, Lu W, Lehrer RI. Antibacterial activity and specificity of the six human {alpha}-defensins. Antimicrob Agents Chemother 2005;49:269–275.PMID: 15616305.ArticlePubMedPMC
  • 21. Shen B, Porter EM, Reynoso E, et al. Human defensin 5 expression in intestinal metaplasia of the upper gastrointestinal tract. J Clin Pathol 2005;58:687–694.PMID: 15976333.ArticlePubMedPMC
  • 22. Ishikawa C, Tanabe H, Maemoto A, et al. Precursor processing of human defensin-5 is essential to the multiple functions in vitro and in vivo. J Innate Immun 2010;2:66–76.PMID: 20375624.ArticlePubMed
  • 23. Salzman NH, Ghosh D, Huttner KM, Paterson Y, Bevins CL. Protection against enteric salmonellosis in transgenic mice expressing a human intestinal defensin. Nature 2003;422:522–526.PMID: 12660734.ArticlePubMedPDF
  • 24. Wehkamp J, Salzman NH, Porter E, et al. Reduced Paneth cell alpha-defensins in ileal Crohn's disease. Proc Natl Acad Sci U S A 2005;102:18129–18134.PMID: 16330776.ArticlePubMedPMC
  • 25. Elphick D, Liddell S, Mahida YR. Impaired luminal processing of human defensin-5 in Crohn's disease: persistence in a complex with chymotrypsinogen and trypsin. Am J Pathol 2008;172:702–713.PMID: 18258845.ArticlePubMedPMC
  • 26. Wehkamp J, Harder J, Weichenthal M, et al. NOD2 (CARD15) mutations in Crohn's disease are associated with diminished mucosal alpha-defensin expression. Gut 2004;53:1658–1664.PMID: 15479689.ArticlePubMedPMC
  • 27. Simms LA, Doecke JD, Walsh MD, Huang N, Fowler EV, Radford-Smith GL. Reduced alpha-defensin expression is associated with inflammation and not NOD2 mutation status in ileal Crohn's disease. Gut 2008;57:903–910.PMID: 18305068.ArticlePubMed
  • 28. Cunliffe RN, Rose FR, Keyte J, Abberley L, Chan WC, Mahida YR. Human defensin 5 is stored in precursor form in normal Paneth cells and is expressed by some villous epithelial cells and by metaplastic Paneth cells in the colon in inflammatory bowel disease. Gut 2001;48:176–185.PMID: 11156637.ArticlePubMedPMC
  • 29. Fahlgren A, Hammarstrom S, Danielsson A, Hammarstrom ML. Increased expression of antimicrobial peptides and lysozyme in colonic epithelial cells of patients with ulcerative colitis. Clin Exp Immunol 2003;131:90–101.PMID: 12519391.ArticlePubMedPMC
  • 30. Ho S, Pothoulakis C, Koon HW. Antimicrobial peptides and colitis. Curr Pharm Des 2013;19:40–47.PMID: 22950497.ArticlePubMedPMC
  • 31. Ouellette AJ, Satchell DP, Hsieh MM, Hagen SJ, Selsted ME. Characterization of luminal paneth cell alpha-defensins in mouse small intestine. Attenuated antimicrobial activities of peptides with truncated amino termini. J Biol Chem 2000;275:33969–33973.PMID: 10942762.ArticlePubMed
  • 32. Masuda K, Sakai N, Nakamura K, Yoshioka S, Ayabe T. Bactericidal activity of mouse alpha-defensin cryptdin-4 predominantly affects noncommensal bacteria. J Innate Immun 2011;3:315–326.PMID: 21099205.ArticlePubMed
  • 33. Yoon YM, Lee JY, Yoo D, et al. Bacteroides fragilis enterotoxin induces human beta-defensin-2 expression in intestinal epithelial cells via a mitogen-activated protein kinase/I kappaB kinase/NF-kappaB-dependent pathway. Infect Immun 2010;78:2024–2033.PMID: 20231411.ArticlePubMedPMC
  • 34. Peyrin-Biroulet L, Beisner J, Wang G, et al. Peroxisome proliferator-activated receptor gamma activation is required for maintenance of innate antimicrobial immunity in the colon. Proc Natl Acad Sci U S A 2010;107:8772–8777.PMID: 20421464.ArticlePubMedPMC
  • 35. Schroeder BO, Wu Z, Nuding S, et al. Reduction of disulphide bonds unmasks potent antimicrobial activity of human beta-defensin 1. Nature 2011;469:419–423.PMID: 21248850.ArticlePubMedPDF
  • 36. Maurice MM, Nakamura H, Gringhuis S, et al. Expression of the thioredoxin-thioredoxin reductase system in the inflamed joints of patients with rheumatoid arthritis. Arthritis Rheum 1999;42:2430–2439.PMID: 10555039.ArticlePubMed
  • 37. Möndel M, Schroeder BO, Zimmermann K, et al. Probiotic E. coli treatment mediates antimicrobial human beta-defensin synthesis and fecal excretion in humans. Mucosal Immunol 2009;2:166–172.PMID: 19129752.ArticlePubMedPMCPDF
  • 38. Wehkamp J, Harder J, Wehkamp K, et al. NF-kappaB- and AP-1-mediated induction of human beta defensin-2 in intestinal epithelial cells by Escherichia coli Nissle 1917: a novel effect of a probiotic bacterium. Infect Immun 2004;72:5750–5758.PMID: 15385474.ArticlePubMedPMC
  • 39. Gaffen SL. Structure and signalling in the IL-17 receptor family. Nat Rev Immunol 2009;9:556–567.PMID: 19575028.ArticlePubMedPMCPDF
  • 40. Ganz T. Defensins: antimicrobial peptides of innate immunity. Nat Rev Immunol 2003;3:710–720.PMID: 12949495.ArticlePubMedPDF
  • 41. Wehkamp J, Fellermann K, Herrlinger KR, et al. Human beta-defensin 2 but not beta-defensin 1 is expressed preferentially in colonic mucosa of inflammatory bowel disease. Eur J Gastroenterol Hepatol 2002;14:745–752.PMID: 12169983.ArticlePubMed
  • 42. Fahlgren A, Hammarstrom S, Danielsson A, Hammarstrom ML. beta-Defensin-3 and -4 in intestinal epithelial cells display increased mRNA expression in ulcerative colitis. Clin Exp Immunol 2004;137:379–385.PMID: 15270856.ArticlePubMedPMC
  • 43. Rahman A, Fahlgren A, Sundstedt C, Hammarstrom S, Danielsson A, Hammarstrom ML. Chronic colitis induces expression of beta-defensins in murine intestinal epithelial cells. Clin Exp Immunol 2011;163:123–130.PMID: 21039426.ArticlePubMedPMC
  • 44. Tollin M, Bergman P, Svenberg T, Jornvall H, Gudmundsson GH, Agerberth B. Antimicrobial peptides in the first line defence of human colon mucosa. Peptides 2003;24:523–530.PMID: 12860195.ArticlePubMed
  • 45. Wehkamp J, Harder J, Weichenthal M, et al. Inducible and constitutive beta-defensins are differentially expressed in Crohn's disease and ulcerative colitis. Inflamm Bowel Dis 2003;9:215–223.PMID: 12902844.ArticlePubMed
  • 46. Aldhous MC, Noble CL, Satsangi J. Dysregulation of human beta-defensin-2 protein in inflammatory bowel disease. PLoS One 2009;4:e6285PMID: 19617917.ArticlePubMedPMC
  • 47. Nuding S, Fellermann K, Wehkamp J, Stange EF. Reduced mucosal antimicrobial activity in Crohn's disease of the colon. Gut 2007;56:1240–1247.PMID: 17456510.ArticlePubMedPMC
  • 48. Fellermann K, Stange DE, Schaeffeler E, et al. A chromosome 8 gene-cluster polymorphism with low human beta-defensin 2 gene copy number predisposes to Crohn disease of the colon. Am J Hum Genet 2006;79:439–448.PMID: 16909382.ArticlePubMedPMC
  • 49. Bentley RW, Pearson J, Gearry RB, et al. Association of higher DEFB4 genomic copy number with Crohn's disease. Am J Gastroenterol 2010;105:354–359.PMID: 19809410.ArticlePubMedPDF
  • 50. Selsted ME. Theta-defensins: cyclic antimicrobial peptides produced by binary ligation of truncated alpha-defensins. Curr Protein Pept Sci 2004;5:365–371.PMID: 15544531.ArticlePubMed
  • 51. Penberthy WT, Chari S, Cole AL, Cole AM. Retrocyclins and their activity against HIV-1. Cell Mol Life Sci 2011;68:2231–2242.PMID: 21553001.ArticlePubMedPMC
  • 52. Arnett E, Lehrer RI, Pratikhya P, Lu W, Seveau S. Defensins enable macrophages to inhibit the intracellular proliferation of Listeria monocytogenes. Cell Microbiol 2011;13:635–651.PMID: 21143570.ArticlePubMed
  • 53. Bals R, Wilson JM. Cathelicidins-a family of multifunctional antimicrobial peptides. Cell Mol Life Sci 2003;60:711–720.PMID: 12785718.ArticlePubMedPMC
  • 54. Sochacki KA, Barns KJ, Bucki R, Weisshaar JC. Real-time attack on single Escherichia coli cells by the human antimicrobial peptide LL-37. Proc Natl Acad Sci U S A 2011;108:E77–E81.PMID: 21464330.ArticlePubMedPMC
  • 55. Murakami M, Dorschner RA, Stern LJ, Lin KH, Gallo RL. Expression and secretion of cathelicidin antimicrobial peptides in murine mammary glands and human milk. Pediatr Res 2005;57:10–15.PMID: 15531744.ArticlePubMed
  • 56. Schauber J, Iffland K, Frisch S, et al. Histone-deacetylase inhibitors induce the cathelicidin LL-37 in gastrointestinal cells. Mol Immunol 2004;41:847–854.PMID: 15261456.ArticlePubMed
  • 57. Termén S, Tollin M, Rodriguez E, et al. PU.1 and bacterial metabolites regulate the human gene CAMP encoding antimicrobial peptide LL-37 in colon epithelial cells. Mol Immunol 2008;45:3947–3955.PMID: 18657865.ArticlePubMed
  • 58. Schauber J, Rieger D, Weiler F, et al. Heterogeneous expression of human cathelicidin hCAP18/LL-37 in inflammatory bowel diseases. Eur J Gastroenterol Hepatol 2006;18:615–621.PMID: 16702850.ArticlePubMed
  • 59. Koon HW, Shih DQ, Chen J, et al. Cathelicidin signaling via the Toll-like receptor protects against colitis in mice. Gastroenterology 2011;141:1852–1863.e3.PMID: 21762664.ArticlePubMedPMC
  • 60. Tai EK, Wong HP, Lam EK, et al. Cathelicidin stimulates colonic mucus synthesis by up-regulating MUC1 and MUC2 expression through a mitogen-activated protein kinase pathway. J Cell Biochem 2008;104:251–258.PMID: 18059019.ArticlePubMed
  • 61. Otte JM, Zdebik AE, Brand S, et al. Effects of the cathelicidin LL-37 on intestinal epithelial barrier integrity. Regul Pept 2009;156:104–117.PMID: 19328825.ArticlePubMed
  • 62. Raqib R, Sarker P, Bergman P, et al. Improved outcome in shigellosis associated with butyrate induction of an endogenous peptide antibiotic. Proc Natl Acad Sci U S A 2006;103:9178–9183.PMID: 16740661.ArticlePubMedPMC
  • 63. Sarker P, Ahmed S, Tiash S, et al. Phenylbutyrate counteracts Shigella mediated downregulation of cathelicidin in rabbit lung and intestinal epithelia: a potential therapeutic strategy. PLoS One 2011;6:e20637PMID: 21673991.ArticlePubMedPMC
  • 64. Cobo ER, He C, Hirata K, et al. Entamoeba histolytica induces intestinal cathelicidins but is resistant to cathelicidin-mediated killing. Infect Immun 2012;80:143–149.PMID: 22083705.ArticlePubMedPMC
  • 65. Alam SR, Newby DE, Henriksen PA. Role of the endogenous elastase inhibitor, elafin, in cardiovascular injury: from epithelium to endothelium. Biochem Pharmacol 2012;83:695–704.PMID: 22100985.ArticlePubMed
  • 66. Scott A, Weldon S, Taggart CC. SLPI and elafin: multifunctional antiproteases of the WFDC family. Biochem Soc Trans 2011;39:1437–1440.PMID: 21936829.ArticlePubMed
  • 67. Si-Tahar M, Merlin D, Sitaraman S, Madara JL. Constitutive and regulated secretion of secretory leukocyte proteinase inhibitor by human intestinal epithelial cells. Gastroenterology 2000;118:1061–1071.PMID: 10833481.ArticlePubMed
  • 68. Flach CF, Eriksson A, Jennische E, Lange S, Gunnerek C, Lonnroth I. Detection of elafin as a candidate biomarker for ulcerative colitis by whole-genome microarray screening. Inflamm Bowel Dis 2006;12:837–842.PMID: 16954802.ArticlePubMed
  • 69. Schmid M, Fellermann K, Fritz P, Wiedow O, Stange EF, Wehkamp J. Attenuated induction of epithelial and leukocyte serine antiproteases elafin and secretory leukocyte protease inhibitor in Crohn's disease. J Leukoc Biol 2007;81:907–915.PMID: 17200145.ArticlePubMed
  • 70. Motta JP, Magne L, Descamps D, et al. Modifying the protease, antiprotease pattern by elafin overexpression protects mice from colitis. Gastroenterology 2011;140:1272–1282.PMID: 21199654.ArticlePubMed
  • 71. Reardon C, Lechmann M, Brustle A, et al. Thymic stromal lymphopoetin-induced expression of the endogenous inhibitory enzyme SLPI mediates recovery from colonic inflammation. Immunity 2011;35:223–235.PMID: 21820333.ArticlePubMedPMC
  • 72. Balakrishnan A, Marathe SA, Joglekar M, Chakravortty D. Bactericidal/permeability increasing protein: a multifaceted protein with functions beyond LPS neutralization. Innate Immun 2013;19:339–347.PMID: 23160386.ArticlePubMed
  • 73. Akin H, Tahan G, Ture F, et al. Association between bactericidal/permeability increasing protein (BPI) gene polymorphism (Lys216Glu) and inflammatory bowel disease. J Crohns Colitis 2011;5:14–18.PMID: 21272798.ArticlePubMedPDF
  • 74. Haapamäki MM, Haggblom JO, Gronroos JM, Pekkala E, Alanen K, Nevalainen TJ. Bactericidal/permeability-increasing protein in colonic mucosa in ulcerative colitis. Hepatogastroenterology 1999;46:2273–2277.PMID: 10521980.PubMed
  • 75. Canny G, Cario E, Lennartsson A, et al. Functional and biochemical characterization of epithelial bactericidal/permeability-increasing protein. Am J Physiol Gastrointest Liver Physiol 2006;290:G557–G567.PMID: 16282362.ArticlePubMed
  • 76. Schultz H. From infection to autoimmunity: a new model for induction of ANCA against the bactericidal/permeability increasing protein (BPI). Autoimmun Rev 2007;6:223–227.PMID: 17317612.ArticlePubMed
  • 77. Schinke S, Fellermann K, Herlyn K, et al. Autoantibodies against the bactericidal/permeability-increasing protein from inflammatory bowel disease patients can impair the antibiotic activity of bactericidal/permeability-increasing protein. Inflamm Bowel Dis 2004;10:763–770.PMID: 15626895.ArticlePubMed
  • 78. Cash HL, Whitham CV, Behrendt CL, Hooper LV. Symbiotic bacteria direct expression of an intestinal bactericidal lectin. Science 2006;313:1126–1130.PMID: 16931762.ArticlePubMedPMC
  • 79. Hervieu V, Christa L, Gouysse G, et al. HIP/PAP, a member of the reg family, is expressed in glucagon-producing enteropancreatic endocrine cells and tumors. Hum Pathol 2006;37:1066–1075.PMID: 16867870.ArticlePubMed
  • 80. Yuk JM, Jo EK. Toll-like receptors and innate immunity. J Bacteriol Virol 2011;41:225–235.Article
  • 81. Hong S, Park S, Yu JW. Pyrin domain (PYD)-containing inflammasome in innate immunity. J Bacteriol Virol 2011;41:133–146.Article
  • 82. Kim SP, Lee GW, Kim CM, Shin SH. Coordinate regulation of Vibrio vulnificus heme receptor hupA expression by cyclic AMP-receptor protein and ferric uptake regulator. J Bacteriol Virol 2012;42:294–304.Article
  • 83. Drago-Serrano ME, de la Garza-Amaya M, Luna JS, Campos-Rodriguez R. Lactoferrin-lipopolysaccharide (LPS) binding as key to antibacterial and antiendotoxic effects. Int Immunopharmacol 2012;12:1–9.PMID: 22101278.ArticlePubMed
  • 84. Kim JM. Roles of enteric microbial composition and metabolism in health and diseases. Korean J Gastroenterol 2013;62:191–205.PMID: 24162706.ArticlePubMed
  • 85. Sidhu R, Wilson P, Wright A, et al. Faecal lactoferrin--a novel test to differentiate between the irritable and inflamed bowel? Aliment Pharmacol Ther 2010;31:1365–1370.PMID: 20331581.ArticlePubMed
  • 86. Abraham BP, Kane S. Fecal markers: calprotectin and lactoferrin. Gastroenterol Clin North Am 2012;41:483–495.PMID: 22500530.ArticlePubMed
  • 87. LaSala PR, Ekhmimi T, Hill AK, Farooqi I, Perrotta PL. Quantitative fecal lactoferrin in toxin-positive and toxin-negative Clostridium difficile specimens. J Clin Microbiol 2013;51:311–313.PMID: 23135940.ArticlePubMedPMC
  • 88. Togawa J, Nagase H, Tanaka K, et al. Oral administration of lactoferrin reduces colitis in rats via modulation of the immune system and correction of cytokine imbalance. J Gastroenterol Hepatol 2002;17:1291–1298.PMID: 12423274.ArticlePubMed
  • 89. Togawa J, Nagase H, Tanaka K, et al. Lactoferrin reduces colitis in rats via modulation of the immune system and correction of cytokine imbalance. Am J Physiol Gastrointest Liver Physiol 2002;283:G187–G195.PMID: 12065306.ArticlePubMed
  • 90. López-Soto F, Leon-Sicairos N, Nazmi K, Bolscher JG, de la Garza M. Microbicidal effect of the lactoferrin peptides lactoferricin17-30, lactoferrampin265-284, and lactoferrin chimera on the parasite Entamoeba histolytica. Biometals 2010;23:563–568.PMID: 20140481.ArticlePubMed
  • 91. Fuqua BK, Vulpe CD, Anderson GJ. Intestinal iron absorption. J Trace Elem Med Biol 2012;26:115–119.PMID: 22575541.ArticlePubMed
  • 92. Ganz T. Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood 2003;102:783–788.PMID: 12663437.ArticlePubMed
  • 93. Drakesmith H, Prentice AM. Hepcidin and the iron-infection axis. Science 2012;338:768–772.PMID: 23139325.ArticlePubMed
  • 94. Oustamanolakis P, Koutroubakis IE, Messaritakis I, Malliaraki N, Sfiridaki A, Kouroumalis EA. Serum hepcidin and prohepcidin concentrations in inflammatory bowel disease. Eur J Gastroenterol Hepatol 2011;23:262–268.PMID: 21285884.ArticlePubMed
  • 95. Wang L, Trebicka E, Fu Y, et al. The bone morphogenetic protein-hepcidin axis as a therapeutic target in inflammatory bowel disease. Inflamm Bowel Dis 2012;18:112–119.PMID: 21351217.ArticlePubMed
  • 96. Miethke M, Skerra A. Neutrophil gelatinase-associated lipocalin expresses antimicrobial activity by interfering with L-norepinephrine-mediated bacterial iron acquisition. Antimicrob Agents Chemother 2010;54:1580–1589.PMID: 20086155.ArticlePubMedPMC
  • 97. Chan YR, Liu JS, Pociask DA, et al. Lipocalin 2 is required for pulmonary host defense against Klebsiella infection. J Immunol 2009;182:4947–4956.PMID: 19342674.ArticlePubMedPMC
  • 98. Fischbach MA, Lin H, Zhou L, et al. The pathogen-associated iroA gene cluster mediates bacterial evasion of lipocalin 2. Proc Natl Acad Sci U S A 2006;103:16502–16507.PMID: 17060628.ArticlePubMedPMC
  • 99. Flo TH, Smith KD, Sato S, et al. Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron. Nature 2004;432:917–921.PMID: 15531878.ArticlePubMed
  • 100. Yoo do Y, Ko SH, Jung J, Kim YJ, Kim JS, Kim JM. Bacteroides fragilis enterotoxin upregulates lipocalin-2 expression in intestinal epithelial cells. Lab Invest 2013;93:384–396.PMID: 23381626.ArticlePubMedPDF
  • 101. Otto BR, Sparrius M, Verweij-van Vught AM, MacLaren DM. Iron-regulated outer membrane protein of Bacteroides fragilis involved in heme uptake. Infect Immun 1990;58:3954–3958.PMID: 2254022.ArticlePubMedPMC
  • 102. Otto BR, Verweij-van Vught AM, MacLaren DM. Transferrins and heme-compounds as iron sources for pathogenic bacteria. Crit Rev Microbiol 1992;18:217–233.PMID: 1532495.ArticlePubMed
  • 103. Sijbrandi R, Den Blaauwen T, Tame JR, Oudega B, Luirink J, Otto BR. Characterization of an iron-regulated alpha-enolase of Bacteroides fragilis. Microbes Infect 2005;7:9–18.PMID: 15716066.ArticlePubMed
  • 104. Gallo RL, Hooper LV. Epithelial antimicrobial defence of the skin and intestine. Nat Rev Immunol 2012;12:503–516.PMID: 22728527.ArticlePubMedPMCPDF
  • 105. Peschel A, Otto M, Jack RW, Kalbacher H, Jung G, Gotz F. Inactivation of the dlt operon in Staphylococcus aureus confers sensitivity to defensins, protegrins, and other antimicrobial peptides. J Biol Chem 1999;274:8405–8410.PMID: 10085071.ArticlePubMed
  • 106. Robey M, O'Connell W, Cianciotto NP. Identification of Legionella pneumophila rcp, a pagP-like gene that confers resistance to cationic antimicrobial peptides and promotes intracellular infection. Infect Immun 2001;69:4276–4286.PMID: 11401964.ArticlePubMedPMC
  • 107. Gunn JS. The Salmonella PmrAB regulon: lipopolysaccharide modifications, antimicrobial peptide resistance and more. Trends Microbiol 2008;16:284–290.PMID: 18467098.ArticlePubMed
  • 108. Peschel A, Collins LV. Staphylococcal resistance to antimicrobial peptides of mammalian and bacterial origin. Peptides 2001;22:1651–1659.PMID: 11587793.ArticlePubMed
  • 109. Kraus D, Peschel A. Staphylococcus aureus evasion of innate antimicrobial defense. Future Microbiol 2008;3:437–451.PMID: 18651815.ArticlePubMed
  • 110. Nelson DC, Garbe J, Collin M. Cysteine proteinase SpeB from Streptococcus pyogenes - a potent modifier of immunologically important host and bacterial proteins. Biol Chem 2011;392:1077–1088.PMID: 22050223.ArticlePubMed
  • 111. Shafer WM, Veal WL, Lee EH, Zarantonelli L, Balthazar JT, Rouquette C. Genetic organization and regulation of antimicrobial efflux systems possessed by Neisseria gonorrhoeae and Neisseria meningitidis. J Mol Microbiol Biotechnol 2001;3:219–224.PMID: 11321577.PubMed
  • 112. Islam D, Bandholtz L, Nilsson J, et al. Downregulation of bactericidal peptides in enteric infections: a novel immune escape mechanism with bacterial DNA as a potential regulator. Nat Med 2001;7:180–185.PMID: 11175848.ArticlePubMedPDF
  • 113. De Yang , Chen Q, Schmidt AP, et al. LL-37, the neutrophil granule- and epithelial cell-derived cathelicidin, utilizes formyl peptide receptor-like 1 (FPRL1) as a receptor to chemoattract human peripheral blood neutrophils, monocytes, and T cells. J Exp Med 2000;192:1069–1074.PMID: 11015447.ArticlePubMedPMC
  • 114. Kurosaka K, Chen Q, Yarovinsky F, Oppenheim JJ, Yang D. Mouse cathelin-related antimicrobial peptide chemoattracts leukocytes using formyl peptide receptor-like 1/mouse formyl peptide receptor-like 2 as the receptor and acts as an immune adjuvant. J Immunol 2005;174:6257–6265.PMID: 15879124.ArticlePubMed
  • 115. Yang D, Biragyn A, Kwak LW, Oppenheim JJ. Mammalian defensins in immunity: more than just microbicidal. Trends Immunol 2002;23:291–296.PMID: 12072367.ArticlePubMed
  • 116. Niyonsaba F, Iwabuchi K, Someya A, et al. A cathelicidin family of human antibacterial peptide LL-37 induces mast cell chemotaxis. Immunology 2002;106:20–26.PMID: 11972628.ArticlePubMedPMC
  • 117. Zanetti M. The role of cathelicidins in the innate host defenses of mammals. Curr Issues Mol Biol 2005;7:179–196.PMID: 16053249.PubMed
  • 118. Yang D, Chertov O, Oppenheim JJ. Participation of mammalian defensins and cathelicidins in anti-microbial immunity: receptors and activities of human defensins and cathelicidin (LL-37). J Leukoc Biol 2001;69:691–697.PMID: 11358975.ArticlePubMedPDF
  • 119. Yang D, Chertov O, Bykovskaia SN, et al. Beta-defensins: linking innate and adaptive immunity through dendritic and T cell CCR6. Science 1999;286:525–528.PMID: 10521347.ArticlePubMed
  • 120. Di Nardo A, Braff MH, Taylor KR, et al. Cathelicidin antimicrobial peptides block dendritic cell TLR4 activation and allergic contact sensitization. J Immunol 2007;178:1829–1834.PMID: 17237433.ArticlePubMed
  • 121. Lande R, Gregorio J, Facchinetti V, et al. Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature 2007;449:564–569.PMID: 17873860.ArticlePubMedPDF
  • 122. Hooper LV, Stappenbeck TS, Hong CV, Gordon JI. Angiogenins: a new class of microbicidal proteins involved in innate immunity. Nat Immunol 2003;4:269–273.PMID: 12548285.ArticlePubMedPDF
  • 123. Ménard S, Forster V, Lotz M, et al. Developmental switch of intestinal antimicrobial peptide expression. J Exp Med 2008;205:183–193.PMID: 18180308.ArticlePubMedPMC
  • 124. Iimura M, Gallo RL, Hase K, Miyamoto Y, Eckmann L, Kagnoff MF. Cathelicidin mediates innate intestinal defense against colonization with epithelial adherent bacterial pathogens. J Immunol 2005;174:4901–4907.PMID: 15814717.ArticlePubMed
  • 125. Putsep K, Axelsson LG, Boman A, et al. Germ-free and colonized mice generate the same products from enteric prodefensins. J Biol Chem 2000;275:40478–40482.PMID: 11010975.ArticlePubMed
  • 126. O'Neil DA, Porter EM, Elewaut D, et al. Expression and regulation of the human beta-defensins hBD-1 and hBD-2 in intestinal epithelium. J Immunol 1999;163:6718–6724.PMID: 10586069.PubMed
  • 127. Hooper LV, Wong MH, Thelin A, Hansson L, Falk PG, Gordon JI. Molecular analysis of commensal host-microbial relationships in the intestine. Science 2001;291:881–884.PMID: 11157169.ArticlePubMed
  • 128. Vaishnava S, Behrendt CL, Ismail AS, Eckmann L, Hooper LV. Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host-microbial interface. Proc Natl Acad Sci U S A 2008;105:20858–20863.PMID: 19075245.ArticlePubMedPMC
  • 129. Brandl K, Plitas G, Schnabl B, DeMatteo RP, Pamer EG. MyD88-mediated signals induce the bactericidal lectin RegIII gamma and protect mice against intestinal Listeria monocytogenes infection. J Exp Med 2007;204:1891–1900.PMID: 17635956.ArticlePubMedPMC
  • 130. Lim YJ, Jo YH, Kim HJ, Park JK. The synergistic effects of antimicrobial peptides on the growth inhibition of Salmonella Typhimurium through Imd pathway in Drosophila intestine. J Bacteriol Virol 2013;43:120–130.Article
  • 131. Kinnebrew MA, Ubeda C, Zenewicz LA, Smith N, Flavell RA, Pamer EG. Bacterial flagellin stimulates Toll-like receptor 5-dependent defense against vancomycin-resistant Enterococcus infection. J Infect Dis 2010;201:534–543.PMID: 20064069.ArticlePubMedPMCPDF
  • 132. Schauber J, Svanholm C, Termen S, et al. Expression of the cathelicidin LL-37 is modulated by short chain fatty acids in colonocytes: relevance of signalling pathways. Gut 2003;52:735–741.PMID: 12692061.ArticlePubMedPMC
  • 133. Petnicki-Ocwieja T, Hrncir T, Liu YJ, et al. Nod2 is required for the regulation of commensal microbiota in the intestine. Proc Natl Acad Sci U S A 2009;106:15813–15818.PMID: 19805227.ArticlePubMedPMC
  • 134. Wilson CL, Ouellette AJ, Satchell DP, et al. Regulation of intestinal alpha-defensin activation by the metalloproteinase matrilysin in innate host defense. Science 1999;286:113–117.PMID: 10506557.ArticlePubMed
  • 135. Ghosh D, Porter E, Shen B, et al. Paneth cell trypsin is the processing enzyme for human defensin-5. Nat Immunol 2002;3:583–590.PMID: 12021776.ArticlePubMedPDF
  • 136. Mukherjee S, Partch CL, Lehotzky RE, et al. Regulation of C-type lectin antimicrobial activity by a flexible N-terminal prosegment. J Biol Chem 2009;284:4881–4888.PMID: 19095652.ArticlePubMedPMC
  • 137. Sørensen O, Arnljots K, Cowland JB, Bainton DF, Borregaard N. The human antibacterial cathelicidin, hCAP-18, is synthesized in myelocytes and metamyelocytes and localized to specific granules in neutrophils. Blood 1997;90:2796–2803.PMID: 9326247.ArticlePubMed
  • 138. Chu H, Pazgier M, Jung G, et al. Human alpha-defensin 6 promotes mucosal innate immunity through self-assembled peptide nanonets. Science 2012;337:477–481.PMID: 22722251.ArticlePubMedPMC
  • 139. Jäger S, Stange EF, Wehkamp J. Inflammatory bowel disease: an impaired barrier disease. Langenbecks Arch Surg 2013;398:1–12.PMID: 23160753.ArticlePubMed
  • 140. Ayabe T, Satchell DP, Wilson CL, Parks WC, Selsted ME, Ouellette AJ. Secretion of microbicidal alpha-defensins by intestinal Paneth cells in response to bacteria. Nat Immunol 2000;1:113–118.PMID: 11248802.ArticlePubMedPDF
  • 141. Burton MF, Steel PG. The chemistry and biology of LL-37. Nat Prod Rep 2009;26:1572–1584.PMID: 19936387.ArticlePubMed
  • 142. Pathan FK, Venkata DA, Panguluri SK. Recent patents on antimicrobial peptides. Recent Pat DNA Gene Seq 2010;4:10–16.PMID: 20218955.ArticlePubMed
  • 143. Kang JK, Hwang JS, Nam HJ, et al. The insect peptide coprisin prevents Clostridium difficile-mediated acute inflammation and mucosal damage through selective antimicrobial activity. Antimicrob Agents Chemother 2011;55:4850–4857.PMID: 21807975.ArticlePubMedPMC
  • 144. Guskey MT, Tsuji BT. A comparative review of the lipoglycopeptides: oritavancin, dalbavancin, and telavancin. Pharmacotherapy 2010;30:80–94.PMID: 20030476.ArticlePubMed
  • 145. Van Bambeke F. Glycopeptides and glycodepsipeptides in clinical development: a comparative review of their antibacterial spectrum, pharmacokinetics and clinical efficacy. Curr Opin Investig Drugs 2006;7:740–749.PubMed
  • 146. Weber G, Heilborn JD, Chamorro Jimenez CI, Hammarsjo A, Torma H, Stahle M. Vitamin D induces the antimicrobial protein hCAP18 in human skin. J Invest Dermatol 2005;124:1080–1082.PMID: 15854055.ArticlePubMed
  • 147. Wang TT, Dabbas B, Laperriere D, et al. Direct and indirect induction by 1,25-dihydroxyvitamin D3 of the NOD2/CARD15-defensin beta2 innate immune pathway defective in Crohn disease. J Biol Chem 2010;285:2227–2231.PMID: 19948723.ArticlePubMed
  • 148. Steinmann J, Halldorsson S, Agerberth B, Gudmundsson GH. Phenylbutyrate induces antimicrobial peptide expression. Antimicrob Agents Chemother 2009;53:5127–5133.PMID: 19770273.ArticlePubMedPMC
  • 149. Schlee M, Harder J, Koten B, Stange EF, Wehkamp J, Fellermann K. Probiotic lactobacilli and VSL#3 induce enterocyte beta-defensin 2. Clin Exp Immunol 2008;151:528–535.PMID: 18190603.ArticlePubMedPMC
  • 150. Yi H. Development and application of cell-penetrating peptides. J Bacteriol Virol 2013;43:177–185.Article

Figure & Data

REFERENCES

    Citations

    Citations to this article as recorded by  
    • Intestinal Epithelial Axin1 Deficiency Protects Against Colitis via Altered Gut Microbiota
      Shari Garrett, Yongguo Zhang, Yinglin Xia, Jun Sun
      Engineering.2024; 35: 241.     CrossRef
    • Evaluation of potential antiviral activities of antimicrobial peptides in fish mucus
      Irmak Dik, Burak Dik, Öznur Tufan, Ayşe Er
      Fundamental & Clinical Pharmacology.2024; 38(4): 695.     CrossRef
    • A COMBINATION REVIEW ON EFFECT OF CITRUS JUICE AND METRONIDAZOLE IN INFLAMMATORY BOWEL DISEASE
      Deeksha, Shalini Saini, Meenakshi Bhatt
      International Journal of Research -GRANTHAALAYAH.2023;[Epub]     CrossRef
    • Oral Delivery of Mouse β-Defensin 14 (mBD14)-Producing Lactococcus lactis NZ9000 Attenuates Experimental Colitis in Mice
      Haizhi Tian, Jiahong Li, Xiaopei Chen, Zhengnan Ren, Xiaohua Pan, Weining Huang, Madhav Bhatia, Li-Long Pan, Jia Sun
      Journal of Agricultural and Food Chemistry.2023; 71(13): 5185.     CrossRef
    • Alterations in fecal β-defensin-3 secretion as a marker of instability of the gut microbiota
      Zarwa Saqib, Giada De Palma, Jun Lu, Michael Surette, Premysl Bercik, Stephen Michael Collins
      Gut Microbes.2023;[Epub]     CrossRef
    • COVID-19 and its Therapeutics: Special Emphasis on Mesenchymal Stem Cells Based Therapy
      Yogesh Kumar Verma, Ranjan Verma, Nishant Tyagi, Amanpreet Behl, Subodh Kumar, Gurudutta U. Gangenahalli
      Stem Cell Reviews and Reports.2021; 17(1): 113.     CrossRef
    • Cathelicidin – A Novel Potential Marker of Pediatric Inflammatory Bowel Disease
      Paulina Krawiec, Elżbieta Pac-Kożuchowska
      Journal of Inflammation Research.2021; Volume 14: 163.     CrossRef
    • Protective effects of potential probiotic Lactobacillus rhamnosus (MTCC-5897) fermented whey on reinforcement of intestinal epithelial barrier function in a colitis-induced murine model
      Harpreet Kaur, Taruna Gupta, Suman Kapila, Rajeev Kapila
      Food & Function.2021; 12(13): 6102.     CrossRef
    • Human β-Defensin 2 and Its Postulated Role in Modulation of the Immune Response
      Martyna Cieślik, Natalia Bagińska, Andrzej Górski, Ewa Jończyk-Matysiak
      Cells.2021; 10(11): 2991.     CrossRef
    • Detection of Marker Associated with CTC in Colorectal Cancer in Mononuclear Cells of Patients with Benign Inflammatory Intestinal Diseases
      Johanna Born, Alexander Hendricks, Charlotte Hauser, Jan-Hendrik Egberts, Thomas Becker, Christian Röder, Susanne Sebens
      Cancers.2021; 14(1): 47.     CrossRef
    • Mucosal expression of defensin-5, soluble phospholipase A2 and lysozyme in the intestine in a rat model of acute liver failure and its relationship to intestinal bacterial translocation
      Silin Chen, Xiaopeng Li, Ming Li, Qing Mei, Juanjun Huang, Zhenping Wu, Lunli Zhang
      Gastroenterología y Hepatología.2020; 43(6): 293.     CrossRef
    • High circulating elafin levels are associated with Crohn’s disease-associated intestinal strictures
      Jiani Wang, Christina Ortiz, Lindsey Fontenot, Ying Xie, Wendy Ho, S. Anjani Mattai, David Q. Shih, Hon Wai Koon, Pal Bela Szecsi
      PLOS ONE.2020; 15(4): e0231796.     CrossRef
    • Toxicomicrobiomics: The Human Microbiome vs. Pharmaceutical, Dietary, and Environmental Xenobiotics
      Nehal Adel Abdelsalam, Ahmed Tarek Ramadan, Marwa Tarek ElRakaiby, Ramy Karam Aziz
      Frontiers in Pharmacology.2020;[Epub]     CrossRef
    • Mucosal expression of defensin-5, soluble phospholipase A2 and lysozyme in the intestine in a rat model of acute liver failure and its relationship to intestinal bacterial translocation
      Silin Chen, Xiaopeng Li, Ming Li, Qing Mei, Juanjun Huang, Zhenping Wu, Lunli Zhang
      Gastroenterología y Hepatología (English Edition).2020; 43(6): 293.     CrossRef
    • Mesenchymal Stromal Cells as Potential Antimicrobial for Veterinary Use—A Comprehensive Review
      Keith A. Russell, Livia C. Garbin, Jonathan M. Wong, Thomas G. Koch
      Frontiers in Microbiology.2020;[Epub]     CrossRef
    • Walnut phenolic extract inhibits nuclear factor kappaB signaling in intestinal epithelial cells, and ameliorates experimental colitis and colitis-associated colon cancer in mice
      Seong-Joon Koh, Youn-I Choi, Yuri Kim, Yoo-Sun Kim, Sang Woon Choi, Ji Won Kim, Byeong Gwan Kim, Kook Lae Lee
      European Journal of Nutrition.2019; 58(4): 1603.     CrossRef
    • Tight Junction Proteins and Signaling Pathways in Cancer and Inflammation: A Functional Crosstalk
      Ajaz A. Bhat, Srijayaprakash Uppada, Iman W. Achkar, Sheema Hashem, Santosh K. Yadav, Muralitharan Shanmugakonar, Hamda A. Al-Naemi, Mohammad Haris, Shahab Uddin
      Frontiers in Physiology.2019;[Epub]     CrossRef
    • Gene and Mirna Regulatory Networks During Different Stages of Crohn’s Disease
      Sare Verstockt, Gert De Hertogh, Jan Van der Goten, Bram Verstockt, Maaike Vancamelbeke, Kathleen Machiels, Leentje Van Lommel, Frans Schuit, Gert Van Assche, Paul Rutgeerts, Marc Ferrante, Séverine Vermeire, Ingrid Arijs, Isabelle Cleynen
      Journal of Crohn's and Colitis.2019; 13(7): 916.     CrossRef
    • Impact of the Food Additive Titanium Dioxide (E171) on Gut Microbiota-Host Interaction
      Gabriela Pinget, Jian Tan, Bartlomiej Janac, Nadeem O. Kaakoush, Alexandra Sophie Angelatos, John O'Sullivan, Yen Chin Koay, Frederic Sierro, Joel Davis, Shiva Kamini Divakarla, Dipesh Khanal, Robert J. Moore, Dragana Stanley, Wojciech Chrzanowski, Lauren
      Frontiers in Nutrition.2019;[Epub]     CrossRef
    • Duodenal expression of antimicrobial peptides in dogs with idiopathic inflammatory bowel disease and intestinal lymphoma
      M. Nakazawa, S. Maeda, M. Omori, K. Kaji, N. Yokoyama, T. Nakagawa, J.K. Chambers, K. Uchida, K. Ohno, T. Yonezawa, N. Matsuki
      The Veterinary Journal.2019; 249: 47.     CrossRef
    • Integrative Analysis of Transcriptomic and Proteomic Profiling in Inflammatory Bowel Disease Colon Biopsies
      Liang Jin, Li Li, Chenqi Hu, Jesus Paez-Cortez, Yingtao Bi, Michael Macoritto, Sherry Cao, Yu Tian
      Inflammatory Bowel Diseases.2019; 25(12): 1906.     CrossRef
    • Performance evaluation of antimicrobial peptide ll-37 and hepcidin and β-defensin-2 secreted by mesenchymal stem cells
      Reza Esfandiyari, Raheleh Halabian, Elham Behzadi, Hamid Sedighian, Ramezan Jafari, Abbas Ali Imani Fooladi
      Heliyon.2019; 5(10): e02652.     CrossRef
    • Intestinal barrier integrity and inflammatory bowel disease: Stem cell‐based approaches to regenerate the barrier
      Fredrik E.O. Holmberg, Jannie Pedersen, Peter Jørgensen, Christoffer Soendergaard, Kim B. Jensen, Ole H. Nielsen
      Journal of Tissue Engineering and Regenerative Medicine.2018; 12(4): 923.     CrossRef
    • Growth characteristics of Chlamydia trachomatis in human intestinal epithelial Caco-2 cells
      Ildikó Lantos, Dezső P Virok, Tímea Mosolygó, Zsolt Rázga, Katalin Burián, Valéria Endrész
      Pathogens and Disease.2018;[Epub]     CrossRef
    • The DH31/CGRP enteroendocrine peptide triggers intestinal contractions favoring the elimination of opportunistic bacteria
      Olivia Benguettat, Rouba Jneid, Julie Soltys, Rihab Loudhaief, Alexandra Brun-Barale, Dani Osman, Armel Gallet, Karel Talavera
      PLOS Pathogens.2018; 14(9): e1007279.     CrossRef
    • P17, an Original Host Defense Peptide from Ant Venom, Promotes Antifungal Activities of Macrophages through the Induction of C-Type Lectin Receptors Dependent on LTB4-Mediated PPARγ Activation
      Khaddouj Benmoussa, Hélène Authier, Mélissa Prat, Mohammad AlaEddine, Lise Lefèvre, Mouna Chirine Rahabi, José Bernad, Agnès Aubouy, Elsa Bonnafé, Jérome Leprince, Bernard Pipy, Michel Treilhou, Agnès Coste
      Frontiers in Immunology.2017;[Epub]     CrossRef
    • Lessons to be learned from serum biomarkers in psoriasis and IBD – the potential role in SpA
      Maureen C. Turina, Robert Landewé, Dominique Baeten
      Expert Review of Clinical Immunology.2017; 13(4): 333.     CrossRef
    • Cxcr2 signaling and the microbiome suppress inflammation, bile duct injury, and the phenotype of experimental biliary atresia
      Junbae Jee, Reena Mourya, Pranavkumar Shivakumar, Lin Fei, Michael Wagner, Jorge A. Bezerra, Gianfranco D. Alpini
      PLOS ONE.2017; 12(8): e0182089.     CrossRef
    • Metronidazole-induced encephalopathy in a patient with Crohn's disease
      Jihye Kim, Jaeyoung Chun, Jae Yong Park, Seung Wook Hong, Joo Young Lee, Jin Woo Kang, Seongjun Hwang, Sang-Bae Ko, Jong Pil Im, Joo Sung Kim
      Intestinal Research.2017; 15(1): 124.     CrossRef
    • Intestinal stem cells and intestinal homeostasis in health and in inflammation: A review
      Alexander L.A. Bloemendaal, Nicolas C. Buchs, Bruce D. George, Richard J. Guy
      Surgery.2016; 159(5): 1237.     CrossRef
    • Antimicrobial peptides and wound healing: biological and therapeutic considerations
      Maria Luisa Mangoni, Alison M. McDermott, Michael Zasloff
      Experimental Dermatology.2016; 25(3): 167.     CrossRef
    • The Roles of Cathelicidin LL-37 in Inflammatory Bowel Disease
      Lihua Sun, Wensheng Wang, Weidong Xiao, Hua Yang
      Inflammatory Bowel Diseases.2016; 22(8): 1986.     CrossRef
    • A glance at … dietary emulsifiers, the human intestinal mucus and microbiome, and dietary fiber
      Michael J. Glade, Michael M. Meguid
      Nutrition.2016; 32(5): 609.     CrossRef
    • Antimicrobial and antiviral effects of human defensins: pathogenetic value and prospective application to medicinal therapy
      Vladimir I Vaschenko, Vladimir N Vil’yaninov, Petr D Shabanov
      Reviews on Clinical Pharmacology and Drug Therapy.2016; 14(2): 3.     CrossRef
    • Cross-Regulation of Innate and Adaptive Immunity: A New Perspective for the Pathogenesis of Inflammatory Bowel Disease
      Da Yeon Oh, Seong-Joon Koh
      Gut and Liver.2015;[Epub]     CrossRef
    • Epigenetic Alterations in Inflammatory Bowel Disease and Cancer
      Joo Mi Yi, Tae Oh Kim
      Intestinal Research.2015; 13(2): 112.     CrossRef

    • PubReader PubReader
    • Cite
      CITE
      export Copy Download
      Close
      Download Citation
      Download a citation file in RIS format that can be imported by all major citation management software, including EndNote, ProCite, RefWorks, and Reference Manager.

      Format:
      • RIS — For EndNote, ProCite, RefWorks, and most other reference management software
      • BibTeX — For JabRef, BibDesk, and other BibTeX-specific software
      Include:
      • Citation for the content below
      Antimicrobial Proteins in Intestine and Inflammatory Bowel Diseases
      Intest Res. 2014;12(1):20-33.   Published online January 28, 2014
      Close
    • XML DownloadXML Download
    Related articles
    Antimicrobial Proteins in Intestine and Inflammatory Bowel Diseases
    Antimicrobial Proteins in Intestine and Inflammatory Bowel Diseases

    Intest Res : Intestinal Research
    Close layer
    TOP