Abstract
Host defence peptides are a conserved component of the innate immune response in all complex life forms. In humans, the major classes of host defence peptides include the α- and β-defensins and the cathelicidin, hCAP-18/LL-37. These peptides are expressed in the granules of neutrophils and by a wide variety of tissue types. They have many roles in the immune response including both indirect and direct antimicrobial activity, the ability to act as chemokines as well as induce chemokine production leading to recruitment of leukocytes to the site of infection, the promotion of wound healing and an ability to modulate adaptive immunity. It appears that many of these properties are mediated though direct interaction of peptides with the cells of the innate immune response including monocytes, dendritic cells, T cells and epithelial cells. The importance of these peptides in immune responses has been demonstrated since animals defective in the expression of certain host defence peptides showgreater susceptibility to bacterial infections. In the very few instances in which human patients have been demonstrated to have defective host defence peptide expression, these individuals suffer from frequent infections. Although studies of the immunomodulatory properties of these peptides are in their infancy, there is a growing body of evidence suggesting that the immunomodulatory properties of these small, naturally occurring molecules might be harnessed for development as novel therapeutic agents.
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References
Aarbiou J, Ertmann M, van Wetering S, van Noort P, Rook D, Rabe KF, Litvinov SV, van Krieken JH, de Boer WI, Hiemstra PS (2002) Human neutrophil defensins induce lung epithelial cell proliferation in vitro. J Leukoc Biol 72:167–174
Aarbiou J, Verhoosel RM, Van Wetering S, De Boer WI, Van Krieken JH, Litvinov SV, Rabe KF, Hiemstra PS (2004) Neutrophil defensins enhance lung epithelial wound closure and mucin gene expression in vitro. Am J Respir Cell Mol Biol 30:193–201
Agerberth B, Charo J, Werr J, Olsson B, Idali F, Lindbom L, Kiessling R, Jornvall H, Wigzell H, Gudmundsson GH (2000) The human antimicrobial and chemotactic peptides LL-37 and alpha-defensins are expressed by specific lymphocyte and monocyte populations. Blood 96:3086–3093
An LL, Yang YH, Ma XT, Lin YM, Li G, Song YH, Wu KF (2004) LL-37 enhances adaptive immune response in murine model challenged with tumour cells. Leuk Res 29:535–543
Aragon AS, Pereira HA, Baca OG (1995) A cationic antimicrobial peptide enhances the infectivity of Coxiella burnetii. Acta Virol 39:223–226
Ashitani J, Mukae H, Hiratsuka T, Nakazato M, Kumamoto K, Matsukura S (2002) Elevated levels of alpha-defensins in plasma and BAL fluid of patients with active pulmonary tuberculosis. Chest 121:519–526
Baconnais S, Tirouvanziam R, Zahm JM, de Bentzmann S, Peault B, Balossier G, Puchelle E (1999) Ion composition and rheology of airway liquid from cystic fibrosis fetal tracheal xenografts. Am J Respir Cell Mol Biol 20:605–611
Bals R, Goldman MJ, Wilson JM (1998a) Mouse beta-defensin 1 is a salt-sensitive antimicrobial peptide present in epithelia of the lung and urogenital tract. Infect Immun 66:1225–1232
Bals R, Wang X, Wu Z, Freeman T, Bafna V, Zasloff M, Wilson JM (1998b) Human beta-defensin 2 is a salt-sensitive peptide antibiotic expressed in human lung. J Clin Invest 102:874–880
Bals R, Wang X, Zasloff M, Wilson JM (1998c) The peptide antibiotic LL-37/hCAP-18 is expressed in epithelia of the human lungwhere it has broad antimicrobial activity at the airway surface. Proc Natl Acad Sci U S A 95:9541–9546
Bals R, Weiner DJ, Moscioni AD, Meegalla RL, Wilson JM (1999) Augmentation of innate host defense by expression of a cathelicidin antimicrobial peptide. Infect Immun 67:6084–6089
Banchereau J, Briere F, Caux C, Davoust J, Lebecque S, Liu YJ, Pulendran B, Palucka K (2000) Immunobiology of dendritic cells. Annu Rev Immunol 18:767–811
Becker MN, Diamond G, Verghese MW, Randell SH (2000) CD14-dependent lipopolysaccharide-induced beta-defensin-2 expression in human tracheobronchial epithelium. J Biol Chem 275:29731–29736
Befus AD, Mowat C, Gilchrist M, Hu J, Solomon S, Bateman A (1999) Neutrophil defensins induce histamine secretion from mast cells: mechanisms of action. J Immunol 163:947–953
Bensch KW, Raida M, Magert HJ, Schulz-Knappe P, Forssmann WG (1995) hBD-1: a novel beta-defensin from human plasma. FEBS Lett 368:331–335
Biragyn A, Surenhu M, Yang D, Ruffini PA, Haines BA, Klyushnenkova E, Oppenheim JJ, Kwak LW (2001) Mediators of innate immunity that target immature, but not mature, dendritic cells induce antitumor immunity when genetically fused with nonimmunogenic tumor antigens. J Immunol 167:6644–6653
Biragyn A, Ruffini PA, Leifer CA, Klyushnenkova E, Shakhov A, Chertov O, Shirakawa AK, Farber JM, Segal DM, Oppenheim JJ, Kwak LW (2002) Toll-like receptor 4-dependent activation of dendritic cells by beta-defensin 2. Science 298:1025–1029
Boonstra A, Asselin-Paturel C, Gilliet M, Crain C, Trinchieri G, Liu YJ, O’Garra A (2003) Flexibility of mouse classical and plasmacytoid-derived dendritic cells in directing T helper type 1 and 2 cell development: dependency on antigen dose and differential toll-like receptor ligation. J Exp Med 197:101–109
Bowdish DME, Davidson DJ, Speert DP, Hancock REW (2004) The Human cationic peptide LL-37 induces activation of the extracellular signal-regulated kinase and p38 kinase pathways in primary human monocytes. J Immunol 172:3758–3765
Bowdish DM, Davidson DJ, Lau YE, Lee K, Scott MG, Hancock RE (2005) Impact of LL-37 on anti-infective immunity. J Leukoc Biol 77:451–459
Brogden KA, Heidari M, Sacco RE, Palmquist D, Guthmiller JM, Johnson GK, Jia HP, Tack BF, McCray PB (2003) Defensin-induced adaptive immunity in mice and its potential in preventing periodontal disease. Oral Microbiol Immunol 18:95–99
Buhimschi IA, Jabr M, Buhimschi CS, Petkova AP, Weiner CP, Saed GM (2004) The novel antimicrobial peptide beta3-defensin is produced by the amnion: a possible role of the fetalmembranes in innate immunity of the amniotic cavity. Am J Obstet Gynecol 191:1678–1687
Butmarc J, Yufit T, Carson P, Falanga V (2004) Human beta-defensin-2 expression is increased in chronic wounds. Wound Repair Regen 12:439–443
Chalifour A, Jeannin P, Gauchat JF, Blaecke A, Malissard M, N’Guyen T, Thieblemont N, Delneste Y (2004) Direct bacterial protein PAMP recognition by human NK cells involves TLRs and triggers alpha-defensin production. Blood 104:1778–1783
Chaly YV, Paleolog EM, Kolesnikova TS, Tikhonov II, Petratchenko EV, Voitenok NN (2000) Neutrophil alpha-defensin human neutrophil peptide modulates cytokine production in human monocytes and adhesion molecule expression in endothelial cells. Eur Cytokine Netw 11:257–266
Chen CI, Schaller-Bals S, Paul KP, Wahn U, Bals R (2004) Beta-defensins and LL-37 in bronchoalveolar lavage fluid of patients with cystic fibrosis. J Cyst Fibros 3:45–50
Chertov O, Michiel DF, Xu L, Wang JM, Tani K, Murphy WJ, Longo DL, Taub DD, Oppenheim JJ (1996) Identification of defensin-1, defensin-2, and CAP37/azurocidin as T-cell chemoattractant proteins released from interleukin-8-stimulated neutrophils. J Biol Chem 271:2935–2940
Chung WO, Dale BA (2004) Innateimmune response of oral and foreskin keratinocytes: utilization of different signaling pathways by various bacterial species. Infect Immun 72:352–358
Ciornei CD, Egesten A, Bodelsson M (2003) Effects of humancathelicidin antimicrobial peptide LL-37 on lipopolysaccharide-induced nitric oxide release from rat aorta in vitro. Acta Anaesthesiol Scand 47:213–220
Cole AM, Dewan P, Ganz T (1999) Innate antimicrobial activity of nasal secretions. Infect Immun 67:3267–3275
Cole AM, Tahk S, Oren A, Yoshioka D, Kim YH, Park A, Ganz T (2001) Determinants of Staphylococcus aureus nasal carriage. Clin Diagn Lab Immunol 8:1064–1069
Cole AM, Liao HI, Stuchlik O, Tilan J, Pohl J, Ganz T (2002) Cationic polypeptides are required for antibacterial activity of human airway fluid. J Immunol 169:6985–6991
Conejo-Garcia JR, Benencia F, Courreges MC, Kang E, Mohamed-Hadley A, Buckanovich RJ, Holtz DO, Jenkins A, Na H, Zhang L, Wagner DS, Katsaros D, Caroll R, Coukos G (2004) Tumor-infiltrating dendritic cell precursors recruited by a betadefensin contribute to vasculogenesis under the influence of Vegf-A. Nat Med 10:950–958
Cunliffe RN, Rose FR, Keyte J, Abberley L, Chan WC, Mahida YR (2001) 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 48:176–185
Daher KA, Selsted ME, Lehrer RI (1986) Direct inactivation of viruses by human granulocyte defensins. J Virol 60:1068–1074
Davidson DJ, Currie AJ, Reid GS, Bowdish DM, MacDonald KL, Ma RC, Hancock RE, Speert DP (2004) The cationic antimicrobial peptide LL-37 modulates dendritic cell differentiation and dendritic cell-induced T cell polarization. J Immunol 172:1146–1156
De Jong EC, Vieira PL, Kalinski P, Schuitemaker JH, Tanaka Y, Wierenga EA, Yazdanbakhsh M, Kapsenberg ML (2002) Microbial compounds selectively induce Th1 cell-promoting or Th2 cell-promoting dendritic cells in vitro with diverse Th cell-polarizing signals. J Immunol 168:1704–1709
De Y, Chen Q, Schmidt AP, Anderson GM, Wang JM, Wooters J, Oppenheim JJ, Chertov O (2000) 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 192:1069–1074
Dhaliwal W, Bajaj-Elliott M, Kelly P (2003) Intestinal defensin gene expression in human populations. Mol Immunol 40:469–475
Dorschner RA, Pestonjamasp VK, Tamakuwala S, Ohtake T, Rudisill J, Nizet V, Agerberth B, Gudmundsson GH, Gallo RL (2001) Cutaneous injury induces the release of cathelicidin anti-microbial peptides active against group A Streptococcus. J Invest Dermatol 117:91–97
Duits LA, Nibbering PH, van Strijen E, Vos JB, Mannesse-Lazeroms SP, van Sterkenburg MA, Hiemstra PS (2003) Rhinovirus increases human beta-defensin-2 and-3 mRNA expression in cultured bronchial epithelial cells. FEMS Immunol Med Microbiol 38:59–64
Duits LA, Ravensbergen B, Rademaker M, Hiemstra PS, Nibbering PH (2002) Expression of beta-defensin 1 and 2 mRNA by human monocytes, macrophages and dendritic cells. Immunology 106:517–525
Durr M, Peschel A (2002) Chemokines meet defensins: the merging concepts of chemoattractants and antimicrobial peptides in host defense. Infect Immun 70:6515–6517
Elssner A, Duncan M, Gavrilin M, Wewers MD (2004) A novel P2X7 receptor activator, the human cathelicidin-derived peptide LL37, induces IL-1 beta processing and release. J Immunol 172:4987–4994
Emes RD, Goodstadt L, Winter EE, Ponting CP (2003) Comparison of the genomes of human and mouse lays the foundation of genome zoology. Hum Mol Genet 12:701–709
Erdag G, Morgan JR (2002) Interleukin-1 alpha and interleukin-6 enhance the antibacterial properties of cultured composite keratinocyte grafts. Ann Surg 235:113–124
Fahlgren A, Hammarstrom S, Danielsson A, Hammarstrom ML (2003) Increased expression of antimicrobial peptides and lysozyme in colonic epithelial cells of patients with ulcerative colitis. Clin Exp Immunol 131:90–101
Fleischmann J, Selsted ME, Lehrer RI (1985) Opsonic activity of MCP-1 and MCP-2, cationic peptides from rabbit alveolar macrophages. Diagn Microbiol Infect Dis 3:233–242
Fritz JH, Brunner S, Birnstiel ML, Buschle M, Gabain A, Mattner F, Zauner W (2004) The artificial antimicrobial peptide KLKLLLLLKLK induces predominantly a TH2-type immune response to co-injected antigens. Vaccine 22:3274–3284
Frye M, Bargon J, Dauletbaev N, Weber A, Wagner TO, Gropp R (2000a) Expression of human alpha-defensin 5 (HD5) mRNA in nasal and bronchial epithelial cells. J Clin Pathol 53:770–773
Frye M, Bargon J, Lembcke B, Wagner TO, Gropp R (2000b) Differential expression of human alpha-and beta-defensins mRNA in gastrointestinal epithelia. Eur J Clin Invest 30:695–701
Ganz T, Selsted ME, Szklarek D, Harwig SS, Daher K, Bainton DF, Lehrer RI (1985) Defensins. Natural peptide antibiotics of human neutrophils. J Clin Invest 76:1427–1435
Ganz T, Metcalf JA, Gallin JI, Boxer LA, Lehrer RI (1988) Microbicidal/cytotoxic proteins of neutrophils are deficient in two disorders: Chediak-Higashi syndrome and “specific” granule deficiency. J Clin Invest 82:552–556
Garcia JR, Krause A, Schulz S, Rodriguez-Jimenez FJ, Kluver E, Adermann K, Forssmann U, Frimpong-Boateng A, Bals R, Forssmann WG (2001) Human betadefensin 4: a novel inducible peptide with a specific salt-sensitive spectrum of antimicrobial activity. FASEB J 15:1819–1821
Giacometti A, Cirioni O, Ghiselli R, Mocchegiani F, D’Amato G, Circo R, Orlando F, Skerlavaj B, Silvestri C, Saba V, Zanetti M, Scalise G (2004) Cathelicidin peptide sheep myeloid antimicrobial peptide-29 prevents endotoxin-induced mortality in rat models of septic shock. Am J Respir Crit Care Med 169:187–194
Grutkoski PS, Graeber CT, Lim YP, Ayala A, Simms HH (2003) Alpha-defensin 1 (human neutrophilprotein 1) as an antichemotactic agent for human polymer phonuclear leukocytes. Antimicrob Agents Chemother 47:2666–2668
Guo CJ, Tan N, Song L, Douglas SD, Ho WZ (2004) Alpha-defensins inhibit HIV infection of macrophages through upregulation of CC-chemokines. Aids 18:1217–1218
Halmerbauer G, Arri S, Schierl M, Strauch E, Koller DY (2000) The relationship of eosinophil granule proteins to ions in the sputum of patients with cystic fibrosis. Clin Exp Allergy 30:1771–1776
Harder J, Bartels J, Christophers E, Schroder JM (1997) A peptide antibiotic from human skin. Nature 387:861
Harder J, Bartels J, Christophers E, Schroder JM (2001) Isolation and characterization of human beta-defensin-3, a novel human inducible peptide antibiotic. J Biol Chem 276:5707–5713
Hase K, Murakami M, Iimura M, Cole SP, Horibe Y, Ohtake T, Obonyo M, Gallo RL, Eckmann L, Kagnoff MF (2003) Expression of LL-37 by human gastric epithelial cells as a potential host defensemechanism againstHelicobacter pylori. Gastroenterology 125:1613–1625
Heilborn JD, Nilsson MF, Kratz G, Weber G, Sorensen O, Borregaard N, Stahle-Backdahl M (2003) The cathelicidin anti-microbial peptide LL-37 is involved in re-epithelialization of human skin wounds and is lacking in chronic ulcer epithelium. J Invest Dermatol 120:379–389
Hieshima K, Ohtani H, Shibano M, Izawa D, Nakayama T, Kawasaki Y, Shiba F, Shiota M, Katou F, Saito T, Yoshie O (2003) CCL28 has dual roles in mucosal immunity as a chemokine with broad-spectrum antimicrobial activity. J Immunol 170:1452–1461
Hiratsuka T, Mukae H, Iiboshi H, Ashitani J, Nabeshima K, Minematsu T, Chino N, Ihi T, Kohno S, Nakazato M (2003) Increased concentrations of human betadefensins in plasma and bronchoalveolar lavage fluid of patients with diffuse panbronchiolitis. Thorax 58:425–430
Hornef MW, Frisan T, Vandewalle A, Normark S, Richter-Dahlfors A (2002) Toll-like receptor 4 resides in the Golgi apparatus and colocalizes with internalized lipopolysaccharide in intestinal epithelial cells. J Exp Med 195:559–570
Hoshino K, Ogawa K, Hishitani T, Kitazawa R (2003) Influence of heart surgery on magnesium concentrations in pediatric patients. Pediatr Int 45:39–44
Islam D, Bandholtz L, Nilsson J, Wigzell H, Christensson B, Agerberth B, Gudmundsson G (2001) Downregulation of bactericidal peptides in enteric infections: a novel immune escape mechanism with bacterial DNA as a potential regulator. Nat Med 7:180–185
Jones DE, Bevins CL (1992) Paneth cells of the human small intestine express an antimicrobial peptide gene. J Biol Chem 267:23216–23225
Jones DE, Bevins CL (1993) Defensin-6 mRNA in human Paneth cells: implications for antimicrobial peptides in host defense of the humanbowel. FEBS Lett 315:187–192
Kelly P, Feakins R, Domizio P, Murphy J, Bevins C, Wilson J, McPhail G, Poulsom R, Dhaliwal W (2004) Paneth cell granule depletion in the human small intestine under infective and nutritional stress. Clin Exp Immunol 135:303–309
Kirikae T, Hirata M, Yamasu H, Kirikae F, Tamura H, Kayama F, Nakatsuka K, Yokochi T, Nakano M (1998a) Protective effects of a human 18-kilodalton cationic antimicrobial protein (CAP18)-derived peptide againstmurine endotoxemia. Infect Immun 66:1861–1868
Koczulla R, von Degenfeld G, Kupatt C, Krotz F, Zahler S, Gloe T, Issbrucker K, Unterberger P, Zaiou M, Lebherz C, Karl A, Raake P, Pfosser A, Boekstegers P, Welsch U, Hiemstra PS, Vogelmeier C, Gallo RL, Clauss M, Bals R (2003) An angiogenic role for the human peptide antibiotic LL-37/hCAP-18. J Clin Invest 111:1665–1672
Krisanaprakornkit S, Kimball JR, Weinberg A, Darveau RP, Bainbridge BW, Dale BA (2000) Inducible expression of human beta-defensin 2 by Fusobacterium nucleatum in oral epithelial cells: multiple signaling pathways and role of commensal bacteria in innate immunity and the epithelial barrier. Infect Immun 68:2907–2915
Krisanaprakornkit S, Kimball JR, Dale BA (2002) Regulation of humanbeta-defensin-2 in gingival epithelial cells: the involvement of mitogen-activated protein kinase pathways, but not the NF-kappaB transcription factor family. J Immunol 168:316–324
Kumar J, Okada S, Clayberger C, Krensky AM (2001) Granulysin: a novel antimicrobial. Expert Opin Investig Drugs 10:321–329
Lala A, Lindemann RA, Miyasaki KT (1992) The differential effects of polymorphonuclear leukocyte secretion on human natural killer cell activity. Oral Microbiol Immunol 7:89–95
Langenkamp A, Messi M, Lanzavecchia A, Sallusto F (2000) Kinetics of dendritic cell activation: impact on priming of TH1, TH2 and nonpolarized T cells. Nat Immunol 1:311–316
Lanzavecchia A, Sallusto F (2001) Regulation of T cell immunity by dendritic cells. Cell 106:263–266
Larrick JW, Hirata M, Balint RF, Lee J, Zhong J, Wright SC (1995) Human CAP18: a novel antimicrobial lipopolysaccharide-binding protein. Infect Immun 63:1291–1297
Larrick JW, Hirata M, Zheng H, Zhong J, Bolin D, Cavaillon JM, Warren HS, Wright SC (1994) A novel granulocyte-derived peptide with lipopolysaccharide-neutralizing activity. J Immunol 152:231–240
Larrick JW, Lee J, Ma S, Li X, Francke U, Wright SC, Balint RF (1996) Structural, functional analysis and localization of the human CAP18 gene. FEBS Lett 398:74–80
Lau YE, Rozek A, Scott MG, Goosney DL, Davidson DJ, Hancock RE (2005) Interaction and cellular localization of the human host defense peptide LL-37 with lung epithelial cells. Infect Immun 73:583–591
Lehrer RI, Ganz T (2002) Defensins of vertebrate animals. Curr Opin Immunol 14:96–102
Lehrer RI, Ganz T, Szklarek D, Selsted ME (1988) Modulation of the in vitro candidacidal activity of human neutrophil defensins by target cell metabolism and divalent cations. J Clin Invest 81:1829–1835
Levy O, Ooi CE, Elsbach P, Doerfler ME, Lehrer RI, Weiss J (1995) Antibacterial proteins of granulocytes differ in interaction with endotoxin. Comparison of bactericidal/permeability-increasing protein, p15s, and defensins. J Immunol 154:5403–5410
Lillard JW Jr, Boyaka PN, Chertov O, Oppenheim JJ, McGhee JR (1999) Mechanisms for induction of acquired host immunity by neutrophil peptide defensins. Proc Natl Acad Sci U S A 96:651–656
Liu L, Roberts AA, Ganz T (2003) By IL-1 signaling, monocyte-derived cells dramatically enhance the epidermal antimicrobial response to lipopolysaccharide. J Immunol 170:575–580
Liu YJ (2001) Dendritic cell subsets and lineages, and their functions in innate and adaptive immunity. Cell 106:259–262
Maxwell AI, Morrison GM, Dorin JR (2003) Rapid sequence divergence in mammalian beta-defensins by adaptive evolution. Mol Immunol 40:413–421
Medzhitov R, Janeway C Jr (2000) Innate immunity. N Engl J Med 343:338–344
Morrison G, Kilanowski F, Davidson D, Dorin J (2002) Characterization of the mouse beta defensin 1, defb1, mutant mouse model. Infect Immun 70:3053–3060
Moser C, Weiner DJ, Lysenko E, Bals R, Weiser JN, Wilson JM (2002) Beta-defensin 1 contributes to pulmonary innate immunity in mice. Infect Immun 70:3068–3072
Moser M, Murphy KM (2000) Dendritic cell regulation of TH1-TH2 development. Nat Immunol 1:199–205
Muller CA, Markovic-Lipkovski J, Klatt T, Gamper J, Schwarz G, Beck H, Deeg M, Kalbacher H, Widmann S, Wessels JT, Becker V, Muller GA, Flad T (2002) Human alpha-defensins HNPs-1,-2, and-3 in renal cell carcinoma: influences on tumor cell proliferation. Am J Pathol 160:1311–1324
Murakami M, Ohtake T, Dorschner RA, Gallo RL (2002a) Cathelicidin antimicrobial peptides are expressed in salivary glands and saliva. J Dent Res 81:845–850
Murakami M, Ohtake T, Dorschner RA, Schittek B, Garbe C, Gallo RL (2002b) Cathelicidin anti-microbial peptide expression in sweat, an innate defense system for the skin. J Invest Dermatol 119:1090–1095
Murakami M, Lopez-Garcia B, Braff M, Dorschner RA, Gallo RL (2004) Postsecretory processing generates multiple cathelicidins for enhanced topical antimicrobial defense. J Immunol 172:3070–3077
Murakami M, Dorschner RA, Stern LJ, Lin KH, Gallo RL (2005) Expression and secretion of cathelicidin antimicrobial peptides in murine mammary glands and human milk. Pediatr Res 57:10–15
Murphy CJ, Foster BA, Mannis MJ, Selsted ME, Reid TW (1993) Defensins are mitogenic for epithelial cells and fibroblasts. J Cell Physiol 155:408–413
Nagaoka I, Hirota S, Niyonsaba F, Hirata M, Adachi Y, Tamura H, Heumann D (2001) Cathelicidin family of antibacterial peptides CAP18 and CAP11 inhibit the expression of TNF-alpha by blocking the binding of LPS to CD14(+) cells. J Immunol 167:3329–3338
Nagaoka I, Hirota S, Yomogida S, Ohwada A, Hirata M (2000) Synergistic actions of antibacterial neutrophil defensins and cathelicidins. Inflamm Res 49:73–79
Naik S, Kelly EJ, Meijer L, Pettersson S, Sanderson IR (2001) Absence of Toll-like receptor 4 explains endotoxin hyporesponsiveness in human intestinal epithelium. J Pediatr Gastroenterol Nutr 32:449–453
Nell MJ, Sandra Tjabringa G, Vonk MJ, Hiemstra PS, Grote JJ (2004) Bacterial products increase expression of the human cathelicidin hCAP-18/LL-37 in cultured human sinus epithelial cells. FEMS Immunol Med Microbiol 42:225–231
Nishimura E, Eto A, Kato M, Hashizume S, Imai S, Nisizawa T, Hanada N (2004) Oral streptococci exhibit diverse susceptibility to human beta-defensin-2: antimicrobial effects of hBD-2 on oral streptococci. Curr Microbiol 48:85–87
Nishimura M, Abiko Y, Kurashige Y, Takeshima M, Yamazaki M, Kusano K, Saitoh M, Nakashima K, Inoue T, Kaku T (2004) Effect of defensin peptides on eukaryotic cells: primary epithelial cells, fibroblasts and squamous cell carcinoma cell lines. J Dermatol Sci 36:87–95
Niyonsaba F, Someya A, Hirata M, Ogawa H, Nagaoka I (2001) Evaluation of the effects of peptide antibiotics human beta-defensins-1/-2 and LL-37 on histamine release and prostaglandin D(2) production frommast cells. Eur J Immunol 31:1066–1075
Niyonsaba F, Iwabuchi K, Matsuda H, Ogawa H, Nagaoka I (2002a) Epithelial cell-derived human beta-defensin-2 acts as a chemotaxin for mast cells through a pertussis toxin-sensitive and phospholipase C-dependent pathway. Int Immunol 14:421–426
Niyonsaba F, Iwabuchi K, Someya A, Hirata M, Matsuda H, Ogawa H, Nagaoka I (2002b) A cathelicidin family of human antibacterial peptide LL-37 induces mast cell chemotaxis. Immunology 106:20–26
Niyonsaba F, Hirata M, Ogawa H, Nagaoka I (2003) Epithelial cell-derived antibacterial peptides human beta-defensins and cathelicidin: multifunctional activities on mast cells. Curr Drug Targets Inflamm Allergy 2:224–231
Niyonsaba F, Ogawa H, Nagaoka I (2004) Humanbeta-defensin-2 functions as a chemotactic agent for tumour necrosis factor-alpha-treated human neutrophils. Immunology 111:273–281
Nizet V, Ohtake T, Lauth X, Trowbridge J, Rudisill J, Dorschner RA, Pestonjamasp V, Piraino J, Huttner K, Gallo RL (2001) Innate antimicrobial peptide protects the skin from invasive bacterial infection. Nature 414:454–457
Nomura I, Goleva E, Howell MD, Hamid QA, Ong PY, Hall CF, Darst MA, Gao B, Boguniewicz M, Travers JB, Leung DY (2003) Cytokine milieu of atopic dermatitis, as compared to psoriasis, skin prevents induction of innate immune response genes. J Immunol 171:3262–3269
Nyberg P, Rasmussen M, Bjorck L (2004) Alpha 2-macroglobulin-proteinase complexes protect Streptococcus pyogenes from killing by the antimicrobial peptide LL-37. J Biol Chem 279:52820–52823
Ogushi K, Wada A, Niidome T, Mori N, Oishi K, Nagatake T, Takahashi A, Asakura H, Makino S, Hojo H, Nakahara Y, Ohsaki M, Hatakeyama T, Aoyagi H, Kurazono H, Moss J, Hirayama T (2001) Salmonella enteritidis FliC (flagella filament protein) induces human beta-defensin-2 mRNA production by Caco-2 cells. J Biol Chem 276:30521–30526
Ohgami K, Ilieva IB, Shiratori K, Isogai E, Yoshida K, Kotake S, Nishida T, Mizuki N, Ohno S (2003) Effect of human cationic antimicrobial protein 18 peptide on endotoxin-induced uveitis in rats. Invest Ophthalmol Vis Sci 44:4412–4418
O’Neil DA, Porter EM, Elewaut D, Anderson GM, Eckmann L, Ganz T, Kagnoff MF (1999) Expression and regulation of the human beta-defensins hBD-1 and hBD-2 in intestinal epithelium. J Immunol 163:6718–6724
Ong PY, Ohtake T, Brandt C, Strickland I, Boguniewicz M, Ganz T, Gallo RL, Leung DY (2002) Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N Engl J Med 347:1151–1160
Palfree RG, Sadro LC, Solomon S (1993) The gene encoding the human corticostatin HP-4 precursor contains a recent 86-base duplication and is located on chromosome 8. Mol Endocrinol 7:199–205
Panyutich AV, Panyutich EA, Krapivin VA, Baturevich EA, Ganz T (1993) Plasma defensin concentrations are elevated in patients with septicemia or bacterial meningitis. J Lab Clin Med 122:202–207
Parmley RT, Gilbert CS, Boxer LA (1989) Abnormal peroxidase-positive granules in “specific granule” deficiency. Blood 73:838–844
Pasare C, Medzhitov R (2003) Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science 299:1033–1036
Perregaux DG, Bhavsar K, Contillo L, Shi J, Gabel CA (2002) Antimicrobial peptides initiate IL-1 beta posttranslational processing: a novel role beyond innate immunity. J Immunol 168:3024–3032
Pulendran B, Banchereau J, Maraskovsky E, Maliszewski C (2001) Modulating the immune response with dendritic cells and their growth factors. Trends Immunol 22:41–47
Putsep K, Axelsson LG, Boman A, Midtvedt T, Normark S, Boman HG, Andersson M (2000) Germ-free and colonized mice generate the same products from enteric prodefensins. J Biol Chem 275:40478–40482
Putsep K, Carlsson G, Boman HG, Andersson M (2002) Deficiency of antibacterial peptides in patients withmorbus Kostmann: an observation study. Lancet 360:1144–1149
Quayle AJ, Porter EM, Nussbaum AA, Wang YM, Brabec C, Yip KP, Mok SC (1998) Gene expression, immunolocalization, and secretion of human defensin-5 in human female reproductive tract. Am J Pathol 152:1247–1258
Ross DJ, Cole AM, Yoshioka D, Park AK, Belperio JA, Laks H, Strieter RM, Lynch JP, 3rd, Kubak B, Ardehali A, Ganz T (2004) Increased bronchoalveolar lavage human beta-defensin type 2 in bronchiolitis obliterans syndrome after lung transplantation. Transplantation 78:1222–1224
Sakamoto N, Mukae H, Fujii T, Ishii H, Yoshioka S, Kakugawa T, Sugiyama K, Mizuta Y, Kadota JI, Nakazato M, Kohno S (2005) Differential effects of alpha-and betadefensin on cytokine production by cultured human bronchial epithelial cells. Am J Physiol Lung Cell Mol Physiol 288:L508–L513
Salzman NH, Ghosh D, Huttner KM, Paterson Y, Bevins CL (2003) Protection against enteric salmonellosis in transgenic mice expressing a human intestinal defensin. Nature 422:522–526
Sawa T, Kurahashi K, Ohara M, Gropper MA, Doshi V, Larrick JW, Wiener-Kronish JP (1998) Evaluation of antimicrobial and lipopolysaccharide-neutralizing effects of a synthetic CAP18 fragment against Pseudomonas aeruginosa in a mouse model. Antimicrob Agents Chemother 42:3269–3275
Sawyer JG, Martin NL, Hancock RE (1988) Interaction ofmacrophage cationic proteins with the outer membrane of Pseudomonas aeruginosa. Infect Immun 56:693–698
Schutte BC, Mitros JP, Bartlett JA, Walters JD, Jia HP, Welsh MJ, Casavant TL, Mc-Cray PB Jr (2002) Discovery of five conserved beta-defensin gene clusters using a computational search strategy. Proc Natl Acad Sci U S A 99:2129–2133
Scott MG, Davidson DJ, Gold MR, Bowdish D, Hancock RE (2002) The human antimicrobial peptide LL-37 is a multifunctional modulator of innate immune responses. J Immunol 169:3883–3891
Scott MG, Vreugdenhil AC, Buurman WA, Hancock RE, Gold MR (2000) Cutting edge: cationic antimicrobial peptides block the binding of lipopolysaccharide (LPS) to LPS binding protein. J Immunol 164:549–553
Selsted ME, Harwig SS, Ganz T, Schilling JW, Lehrer RI (1985) Primary structures of three human neutrophil defensins. J Clin Invest 76:1436–1439
Singh A, Bateman A, Zhu QZ, Shimasaki S, Esch F, Solomon S (1988) Structure of a novel human granulocyte peptide with anti-ACTH activity. Biochem Biophys Res Commun 155:524–529
Singh PK, Jia HP, Wiles K, Hesselberth J, Liu L, Conway BA, Greenberg EP, Valore EV, Welsh MJ, Ganz T, Tack BF, McCray PB Jr (1998) Production of beta-defensins by human airway epithelia. Proc Natl Acad Sci U S A 95:14961–14966
Singh PK, Tack BF, McCray PB Jr, Welsh MJ (2000) Synergistic and additive killing by antimicrobial factors found in human airway surface liquid. Am J Physiol Lung Cell Mol Physiol 279: L799–L805
Sorensen OE, Follin P, Johnsen AH, Calafat J, Tjabringa GS, Hiemstra PS, Borregaard N (2001) Human cathelicidin, hCAP-18, is processed to the antimicrobial peptide LL-37 by extracellular cleavage with proteinase 3. Blood 97:3951–3959
Sorensen OE, Gram L, Johnsen AH, Andersson E, Bangsboll S, Tjabringa GS, Hiemstra PS, Malm J, Egesten A, Borregaard N (2003) Processing of seminal plasma hCAP-18 to ALL-38 by gastricsin: a novel mechanism of generating antimicrobial peptides in vagina. J Biol Chem 278:28540–28546
Sparkes RS, Kronenberg M, Heinzmann C, Daher KA, Klisak I, Ganz T, Mohandas T (1989) Assignment of defensin gene(s) to human chromosome 8p23. Genomics 5:240–244
Spencer LT, Paone G, Krein PM, Rouhani FN, Rivera-Nieves J, Brantly ML (2003) The role of human neutrophil peptides in lung inflammation associated with α1-antitrypsin deficiency. Am J Physiol Lung Cell Mol Physiol 286:L514–520
Tamamura H, Imai M, Ishihara T, Masuda M, Funakoshi H, Oyake H, Murakami T, Arakaki R, Nakashima H, Otaka A, Ibuka T, Waki M, Matsumoto A, Yamamoto N, Fujii N (1998) Pharmacophore identification of a chemokine receptor (CXCR4) antagonist, T22 ([Tyr(5,12),Lys7]-polyphemusin II), which specifically blocks T cell-line-tropic HIV-1 infection. Bioorg Med Chem 6:1033–1041
Tanaka D, Miyasaki KT, Lehrer RI (2000) Sensitivity of Actinobacillus actinomycetemcomitans and Capnocytophaga spp. to the bactericidal action of LL-37: a cathelicidin found in human leukocytes and epithelium. Oral Microbiol Immunol 15:226–231
Tani K, Murphy WJ, Chertov O, Salcedo R, Koh CY, Utsunomiya I, Funakoshi S, Asai O, Herrmann SH, Wang JM, Kwak LW, Oppenheim JJ (2000) Defensins act as potent adjuvants that promote cellular and humoral immune responses in mice to a lymphoma idiotype and carrier antigens. Int Immunol 12:691–700
Territo MC, Ganz T, Selsted ME, Lehrer R (1989) Monocyte-chemotactic activity of defensins from human neutrophils. J Clin Invest 84:2017–2020
Turner J, Cho Y, Dinh NN, Waring AJ, Lehrer RI (1998) Activities of LL-37, a cathelin-associated antimicrobial peptide of human neutrophils. Antimicrob Agents Chemother 42:2206–2214
Van Wetering S, Mannesse-Lazeroms SP, Van Sterkenburg MA, Daha MR, Dijkman JH, Hiemstra PS (1997a) Effect of defensins on interleukin-8 synthesis in airway epithelial cells. Am J Physiol 272: L888–L896
Van Wetering S, Mannesse-Lazeroms SP, van Sterkenburg MA, Hiemstra PS (2002) Neutrophil defensins stimulate the release of cytokines by airway epithelial cells: modulation by dexamethasone. Inflamm Res 51:8–15
VanderMeer TJ, Menconi MJ, Zhuang J, Wang H, Murtaugh R, Bouza C, Stevens P, Fink MP (1995) Protective effects of a novel 32-amino acid C-terminal fragment of CAP18 in endotoxemic pigs. Surgery 117:656–662
Vora P, Youdim A, Thomas LS, Fukata M, Tesfay SY, Lukasek K, Michelsen KS, Wada A, Hirayama T, Arditi M, Abreu MT (2004) β-defensin-2 expression is regulated by TLR signaling in intestinal epithelial cells. J Immunol 173:5398–5405
Wang TT, Nestel FP, Bourdeau V, Nagai Y, Wang Q, Liao J, Tavera-Mendoza L, Lin R, Hanrahan JW, Mader S, White JH (2004) Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. J Immunol 173:2909–2912
Wang Y, Agerberth B, Lothgren A, Almstedt A, Johansson J (1998) Apolipoprotein A-I binds and inhibits the human antibacterial/cytotoxic peptide LL-37. J Biol Chem 273:33115–33118
Wehkamp J, Schmidt K, Herrlinger KR, Baxmann S, Behling S, Wohlschlager C, Feller AC, Stange EF, Fellermann K (2003) Defensin pattern in chronic gastritis: HBD-2 is differentially expressed with respect to Helicobacter pylori status. J Clin Pathol 56:352–357
Weiss J (2003) Bactericidal/permeability-increasing protein (BPI) and lipopolysaccharide-binding protein (LBP): structure, function and regulation in host defence against Gram-negative bacteria. Biochem Soc Trans 31:785–790
Welling MM, Hiemstra PS, van den Barselaar MT, Paulusma-Annema A, Nibbering PH, Pauwels EK, Calame W (1998) Antibacterial activity of human neutrophil defensins in experimental infections inmice is accompanied by increased leukocyte accumulation. J Clin Invest 102:1583–1590
White SH, Wimley WC, Selsted ME (1995) Structure, function, and membrane integration of defensins. Curr Opin Struct Biol 5:521–527
Wilde CG, Griffith JE, Marra MN, Snable JL, Scott RW (1989) Purification and characterization of human neutrophil peptide 4, a novelmember of the defensin family. J Biol Chem 264:11200–11203
Wilson CL, Ouellette AJ, Satchell DP, Ayabe T, Lopez-Boado YS, Stratman JL, Hultgren SJ, Matrisian LM, Parks WC (1999) Regulation of intestinal alpha-defensin activation by the metalloproteinase matrilysin in innate host defense. Science 286:113–117.
Yan H, Hancock RE (2001) Synergistic interactions between mammalian antimicrobial defense peptides. Antimicrob Agents Chemother 45:1558–1560
Yang D, Chertov O, Bykovskaia SN, Chen Q, Buffo MJ, Shogan J, Anderson M, Schroder JM, Wang JM, Howard OM, Oppenheim JJ (1999) Beta-defensins: linking innate and adaptive immunity through dendritic and T cell CCR6. Science 286:525–528
Yang D, Chen Q, Chertov O, Oppenheim JJ (2000a) Human neutrophil defensins selectively chemoattract naive T and immature dendritic cells. J Leukoc Biol 68:9–14
Yang D, Chen Q, Schmidt AP, Anderson GM, Wang JM, Wooters J, Oppenheim JJ, Chertov O (2000b) 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 192:1069–1074
Yang D, Biragyn A, Kwak LW, Oppenheim JJ (2002)Mammalian defensins in immunity: more than just microbicidal. Trends Immunol 23:291–296
Yang D, Chen Q, Hoover DM, Staley P, Tucker KD, Lubkowski J, Oppenheim JJ (2003) Many chemokines including CCL20/MIP-3alpha display antimicrobial activity. J Leukoc Biol 74:448–455
Zaiou M, Nizet V, Gallo RL (2003) Antimicrobial and protease inhibitory functions of the human cathelicidin (hCAP18/LL-37) prosequence. J Invest Dermatol 120:810–816
Zanetti M (2004) Cathelicidins, multifunctional peptides of the innate immunity. J Leukoc Biol 75:39–48
Zhang H, Downey GP, Suter PM, Slutsky AS, Ranieri VM (2002) Conventional mechanical ventilation is associated with bronchoalveolar lavage-induced activation of polymorphonuclear leukocytes: a possible mechanism to explain the systemic consequences of ventilator-induced lung injury in patients with ARDS. Anesthesiology 97:1426–1433
Zhang K, Lu Q, Zhang Q, Hu X (2004) Regulation of activities of NK cells and CD4 expression in T cells by human HNP-1,-2, and-3. Biochem Biophys Res Commun 323:437–444
Zhao C, Wang I, Lehrer RI (1996) Widespread expression of beta-defensin hBD-1 in human secretory glands and epithelial cells. FEBS Lett 396:319–322
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Bowdish, D.M.E., Davidson, D.J., Hancock, R.E.W. (2006). Immunomodulatory Properties of Defensins and Cathelicidins. In: Shafer, W.M. (eds) Antimicrobial Peptides and Human Disease. Current Topics in Microbiology and Immunology, vol 306. Springer, Berlin, Heidelberg . https://doi.org/10.1007/3-540-29916-5_2
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