OJI  Vol.2 No.2 , June 2012
Regulatory role of defensins in inflammatory bowel disease
Abstract: Defensins are endogenous antimicrobial peptides (AMPs) produced by professional phago- cytes, Paneth cells, and epithelial cells at mucosal surfaces, which mediate innate immunity through their potent antimicrobial activity in the intestinal tract. In addition, defensins also regulate the function of diverse host immune cells, thereby play an important role in both innate and adaptive immune responses against pathogenic microbes. Abundant evidences have proved that attenuated changes in defensins expression are observed in inflammatory bowel disease (IBD). Further studies have discovered the concentration of different defensins subgroups has the relationship with various clinical characteristics of IBD and that mucosal surface destruction causes defensins deficiency as a result of in- flammatory damage. This article is to review new current approaches on defensins expression in the intestinal mucosa, particularly in IBD and their potential roles in immune responses in the gut mucosa.
Cite this paper: Chen, C. , Yadav, P. , Wang, X. and Liu, Z. (2012) Regulatory role of defensins in inflammatory bowel disease. Open Journal of Immunology, 2, 78-84. doi: 10.4236/oji.2012.22010.

[1]   Xavier, R.J. and Podolsky, D.K. (2007) Unravelling the pathogenesis of inflammatory bowel disease. Nature, 448,427-434. doi:10.1038/nature06005

[2]   Brown, S.J. and Mayer, L. (2007) The immune response in inflammatory bowel disease. The American Journal of Gastroenterology, 102, 2058-2069. doi:10.1111/j.1572-0241.2007.01343.x

[3]   Mudter, J. (2011) What’s new about inflammatory bowel diseases in 2011. World Journal of Gastroenterology, 17, 3177.

[4]   Liu, Z., Yadav, P.K., Su, J.L., et al. (2009) Potential role of Th17 cells in the pathogenesis of inflammatory bowel disease. World Journal of Gastroenterology, 15, 5784-5788. doi:10.3748/wjg.15.5784

[5]   Peyrin-Biroulet, L., Vignal, C., Dessein, R., et al. (2009) NODs in defence: From vulnerable antimicrobial peptides to chronic inflammation. Trends in Microbiology, 14, 432-438. doi:10.1016/j.tim.2006.08.008

[6]   Peters, B.M., Shirtliff, M.E. and Jabra-Rizk, M.A. (2010) Antimicrobial peptides: Primeval molecules or future drugs? Public Library of Science Pathogens, 6, 1001067. doi:10.1371/journal.ppat.1001067

[7]   Steinstraesser, L., Kraneburg, U., Jacobsen, F. and Al-Benna, S. (2011) Host defense peptides and their antimicrobial-immunomodulatory duality. Immunobiology, 216, 322-333. doi:10.1016/j.imbio.2010.07.003

[8]   Hazlett, L. and Wu, M. (2011) Defensins in innate immunity. Cell and Tissue Research, 343, 175-188. doi:10.1007/s00441-010-1022-4

[9]   Arijs, I., De, Hertogh, G., Lemaire, K., et al. (2009) Mucosal gene expression of antimicrobial peptides in inflammatory bowel disease before and after first infliximab treatment. Public Library of Science Pathogens One, 4, 79-84. doi:10.1371/journal.pone.0007984

[10]   Zasloff, M. (2002) Antimicrobial peptides of multicellular organisms. Nature, 415, 389-395. doi:10.1038/415389a

[11]   Szyk, A., Wu, Z., Tucker, K., et al. (2006) Crystal structures of human alpha-defensins HNP4, HD5, and HD6. Protein Science, 15, 2749-2760. doi:10.1110/ps.062336606

[12]   Duclohier, H. (2010) Antimicrobial peptides and peptaibols, substitutes for conventional antibiotics. Current Pharmaceutical, 16, 3212-3223. doi:10.2174/138161210793292500

[13]   Tecle, T., Tripathi, S. and Hartshorn, K.L. (2010) Review: Defensins and cathelicidins in lung immunity. Innate Immunity, 16, 151-159. doi:10.1177/1753425910365734

[14]   Underwood, M.A. and Bevins, C.L. (2010) Defensin-barbed innate immunity: Clinical associations in the pediatric population. Pediatrics, 125, 1237-1247. doi:10.1542/peds.2009-3289

[15]   Zilbauer, M., Jenke, A., Wenzel, G., et al. (2011) Intestinal alpha-defensin expression in pediatric inflammatory bowel disease. Inflammatory Bowel Disease, 17, 2076-2086. doi:10.1002/ibd.21577

[16]   Ferguson, L.R., Browning, B.L., Huebner, C., et al. (2008) Single nucleotide polymorphisms in human Paneth cell defensin A5 may confer susceptibility to inflammatory bowel disease in a New Zealand Caucasian population. Digestive and Liver Disease, 40, 723-730. doi:10.1016/j.dld.2008.02.011

[17]   Shi, J. (2007) Defensins and Paneth cells in inflammatory bowel disease. Inflammatory Bowel Diseases, 13, 1284-1292. doi:10.1002/ibd.20197

[18]   Ramasundara, M., Leach, S.T. and Lemberg, D.A. (2009) Defensins and inflammation: The role of defensins in inflammatory bowel disease. Journal of Gastroenterology and Hepatology, 24, 202-208. doi:10.2217/fmb.09.104

[19]   Zilbauer, M., Jenke, A. and Wenzel, G.. (2010) Expression of human beta-defensins in children with chronic inflamematory bowel disease. Public Library of Science Pathogens, 5, e15389. doi:10.1371/journal.pone.0015389

[20]   Kohlgraf, K.G., Pingel, L.C., Dietrich, D.E., et al. (2010) Defensins as anti-inflammatory compounds and mucosal adjuvants. Future Microbiology, 5, 99-113. doi:10.2217/fmb.09.104

[21]   Doss, M., White, M.R., Tecle, T., et al. (2010) Human defensins and LL-37 in mucosal immunity. Journal of Leukocyte Biology, 87, 79-92. doi:10.1189/jlb.0609382

[22]   Bocchinfuso, G., Palleschi, A., Orioni, B., et al. (2009) Different mechanisms of action of antimicrobial peptides: Insights from fluorescence spectroscopy experiments and molecular dynamics simulations. Journal of Peptide Science, 15, 550-558. doi:10.1002/psc.1144

[23]   Cunliffe, R.N. (2003) Alpha-defensins in the gastrointestinal tract. Molecular Immunology, 40, 463-467. doi:10.1016/S0161-5890(03)00157-3

[24]   Wehkamp, J., Schmid, M. and Stange, E.F. (2007) Defensins and other antimicrobial peptides in inflammatory bowel disease. Current Opinion in Gastroenterology, 23, 370-378. doi:10.1097/MOG.0b013e328136c580

[25]   Cunliffe, R.N., Rose, F.R., Keyte, J., et al. (2001) Human defensin-5 (HD-5) is processed upon Paneth cell granule secretion, and its expression is induced inflammatory bowel disease (IBD). Gut, 48, 176-185. doi:10.1136/gut.48.2.176

[26]   Ding, J., Chou, Y.Y. and Chang, T.L. (2009) Defensins in viral infections. Journal of Innate Immunity, 1, 413-420. doi:10.1159/000226256

[27]   Simms, L.A., Doecke, J.D., Walsh, M.D., et al. (2008) Reduced alpha-defensin expression is associated with inflammation and not NOD2 mutation status in ileal Crohn’s disease. Gut, 57, 903-910. doi:10.1136/gut.2007.142588

[28]   Fu, L.B., Yu, J.L. and Liu, W.H. (2011) Biological characteristics of defensin and its disease-resistance genetic engineering. Hereditas, 33, 512-519. doi:10.3724/SP.J.1005.2011.00512

[29]   Wehkamp, J., Koslowski, M., Wang, G., et al. (2008) Barrier dysfunction due to distinct defensin deficiencies in small intestinal and colonic Crohn’s disease. Mucosal Immunology, 1, 67-74. doi:10.1038/mi.2008.48

[30]   Rehaume, L.M. and Hancock, R.E. (2008) Neutrophil- derived defensins as modulators of innate immune func- tion. Critical Reviews in Immunology, 28, 185-200.

[31]   Pazgier, M., Hoover, D.M., Yang, D., et al. (2006) Hu- man beta-defensins. Cellular and Molecular Life Sciences, 63, 1294-1313. doi:10.1007/s00018-005-5540-2

[32]   Escribese, M.M., Rodriguez-Garcia, M., Sperling, R., et al. (2011) Alpha-defensins 1-3 release by dendritic cells is reduced by estrogen. Reproductive Biology and Endo-crinology, 9, 118. doi:10.1186/1477-7827-9-118

[33]   Milewski, L., Dziunycz, P., Barcz, E., et al. (2011) Increased levels of human neutrophil peptides 1, 2, and 3 in peritoneal fluid of patients with endometriosis: Association with neutrophils, T cells and IL-8. Journal of Reproductive Immunology, 91, 64-70. doi:10.1016/j.jri.2011.05.008

[34]   Ouellette, A.J. (2011) Paneth cell α-defensins in enteric innate immunity. Cellular and Molecular Life Sciences, 68, 2215-2229. doi:10.1007/s00018-011-0714-6

[35]   Chamaillard, M. and Dessein, R. (2011) Defensins couple dysbiosis to primary immunodeficiency in Crohn’s disease. World Journal of Gastroenterology, 17, 567-571. doi:10.3748/wjg.v17.i5.567

[36]   Wu, Z., Ericksen, B., Tucker, K., et al. (2004) Synthesis and characterization of human alpha-defensins 4-6. The Journal of Peptide Research, 64, 118-125. doi:10.1111/j.1399-3011.2004.00179.x

[37]   Nagaoka, I., Niyonsaba, F., Tsutsumi-Ishii, Y., et al. (2008) Evaluation of the effect of human beta-defensins on neurophil apoptosis. International Immunology, 20, 543-553. doi:10.1093/intimm/dxn012

[38]   Ghannam, S., Dejou, C., Pedretti, N., et al. (2010) CCL20 and β-defensin-2 induce arrest of human Th17 cells on inflamed endothelium in vitro under flow conditions. Journal Immunology, 186, 1411-1420. doi:10.4049/jimmunol.1000597

[39]   Biragyn, A., Coscia, M., Nagashima, K., et al. (2008) Murine beta-defensin 2 promotes TLR-4/My D88-medi- ated and NF-kappaB-dependent atypical death of APCs via activation of TNFR2. Journal of Leukocyte Biology, 83, 998-1008. doi:10.1189/jlb.1007700

[40]   Droin, N., Hendra, J.B., Ducoroy, P., et al. (2009) Human defensins as cancer biomarkers and antitumour molecules. Journal of Proteomics, 72, 918-927. doi:10.1016/j.jprot.2009.01.002

[41]   Yadav, P.K., Chen, C. and Liu, Z. (2011) Potential role of NK cells in the pathogenesis of inflammatory bowel disease. Journal of Biomedicine Biotechnology, 2011, Article ID: 348530.

[42]   Wehkamp, J. and Stange, E.F. (2008) Is there a role for defensins in IBD? Inflammatory Bowel Diseases, 14, 85-87. doi:10.1002/ibd.20698

[43]   Wehkamp, J., Salzman, N.H., Porter, E., et al. (2005) Reduced Paneth cell α-defensins in ileal Crohn’s disease. Proceeding of the National Academy of Sciences of the USA, 102, 18129-18134. doi:10.1073/pnas.0505256102

[44]   Balducci, E., Bonucci, A., Picchianti, M., et al. (2011) Structural and functional consequences induced by post-translational modifications in α-defensins. International Journal of Peptides, 2011, Article ID: 594723.

[45]   Biswas, A., Liu, Y.J., Hao, L., et al. (2010) Induction and rescue of Nod2-dependent Th1-driven granulomatous inflammation of the ileum. Proceeding of the National Academy of Sciences of the USA, 107, 14739-14744. doi:10.1073/pnas.1003363107

[46]   Wehkamp, J. and Stange, E.F. (2010) Paneth’s disease. Journal of Crohn’s and Colitis, 4, 523-531. doi:10.1016/j.crohns.2010.05.010

[47]   Zilbauer, M., Jenke, A., Wenzel, G., et al. (2011) Intestinal alpha-defensin expression in pediatric inflammatory bowel disease. Inflammatory Bowel Diseases, 17, 2076-2086. doi:10.1002/ibd.21577

[48]   You, X.J., Bryant, P.J. and Jurnak, F. (2007) Expression of Wnt pathway components frizzled and disheveled in colon cancer arising in patients with inflammatory bowel disease. Oncology Reports, 18, 691-694.

[49]   Sato, T., van, Es, J.H. and Snippert, H.J. (2011) Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature, 469, 415-418.

[50]   Beisner, J., Stange, E.F. and Wehkamp, J. (2010) Paneth cell function-Implications in pediatric Crohn disease. An International Journal of Gastroenterology and Hepatology on Microbes, 2, 47-51. doi:10.4161/gmic.2.1.14649

[51]   Wehkamp, J., Wang, G., Kübler, I., et al. (2007) The Paneth cell alpha-defensin deficiency of ileal Crohn’s disease is linked to Wnt/Tcf-4. Journal of Immunology, 179, 3109-3118.

[52]   Kanmura, S., Uto, H., Numata, M., et al. (2009) Human neutrophil peptides 1-3 are useful biomarkers in patients with active ulcerative colitis. Inflammatory Bowel Diseases, 15, 909-917. doi:10.1002/ibd.20854

[53]   Inaba, Y., Ashida, T., Ito, T., et al. (2010) Expression of the antimicrobial peptide alpha-defensin/cryptdins in intestinal crypts decreases at the initial phase of intestinal inflammation in a model of inflammatory bowel disease, IL-10-deficient mice. Inflammatory Bowel Diseases, 16, 1488- 1495. doi:10.1002/ibd.21253

[54]   Yamaguchi, N., Isomoto, H., Mukae, H., et al. (2009) Concentrations of alpha- and beta-defensins in plasma of patients with inflammatory bowel disease. Inflammation Research, 58, 192-197. doi:10.1007/s00011-008-8120-8

[55]   Ou, G., Baranov, V., Lundmark, E., et al. (2009) Contribution of intestinal epithelial cells to innate immunity of the human gut—Studies on polarized monolayers of colon carcinoma cells. Scandinavian Journal of Immunology, 69, 150-161. doi:10.1111/j.1365-3083.2008.02208.x

[56]   Zhang, H.H., Yang, X.M., Xie, Q.M., et al. (2010) The potent adjuvant effects of chicken beta-defensin-1 when genetically fused with infectious bursal disease virus VP2 gene. Veterinary Immunology and Immunopathology, 136, 92-97. doi:10.1016/j.vetimm.2010.02.018

[57]   Kocsis, A.K., Lakatos, P.L., Somogyvári, F., et al. (2008) Association of beta-defensin 1 single nucleotide polymerphisms with Crohn’s disease. Scandinavian Journal of Gastroenterology, 43, 299-307.

[58]   Rahman, A., Fahlgren, A., Sitohy, B., et al. (2007) Beta-defensin production by human colonic plasma cells: A new look at plasma cells in ulcerative colitis. Inflammatory Bowel Diseases, 13, 847-855. doi:10.1002/ibd.20141

[59]   Gutiérrez, A., Holler, E., Zapater, P., et al. (2011) Antimicrobial peptide response to blood translocation of bacterial DNA in Crohn’s disease is affected by NOD2/ CARD15 genotype. Inflammatory Bowel Diseases, 17, 1641-1650.

[60]   Chamaillard, M. and Dessein, R. (2011) Defensins couple dysbiosis to primary immunodeficiency in Crohn’s disease. World Journal of Gastroenterology, 17, 567-571. doi:10.3748/wjg.v17.i5.567

[61]   Semple, F., Webb, S., Li, H.N., et al. (2010) Human beta-defensin 3 has immunosuppressive activity in vitro and in vivo. European Journal of Immunology, 40, 1073-1078. doi:10.1002/eji.200940041

[62]   Chang, Y.Y. and Ouyang, Q. (2008) Expression and significance of mucosal beta-defensin-2, TNFalpha and IL-1beta in ulcerative colitis. The Chinese Journal of Internal Medicine, 47, 11-14.

[63]   Salzman, N.H., Underwood, M.A. and Bevins, C.L. (2007) Paneth cells, defensins, and the commensal microbiota: A hypothesis on intimate interplay at the intestinal mucosa. Seminars in Immunology, 19, 70-83. doi:10.1016/j.smim.2007.04.002

[64]   Aldhous, M.C., Noble, C.L. and Satsangi, J. (2009) Dysregulation of human β-defensin-2 protein in inflammatory bowel disease. Public Library of Science Pathogens One, 4, e6285. doi:10.1371/journal.pone.0006285

[65]   Gersemann, M., Wehkamp, J., Fellermann, K., et al. (2008) Crohn’s disease-defect in innate defence. World Journal of Gastroenterology, 14, 5499-5503. doi:10.3748/wjg.14.5499

[66]   Schneider, J.J., Unholzer, A., Schaller, M., et al. (2005) Human defensins. The Journal of Molecular Medicine, 83, 587-595.