Cell and Tissue Research

, Volume 343, Issue 1, pp 213–225

Biological roles of host defense peptides: lessons from transgenic animals and bioengineered tissues

  • Tova Dybvig
  • Marina Facci
  • Volker Gerdts
  • Heather L. Wilson


Host defense peptides (HDPs) have long been recognized as microbicidal agents, but their roles as modulators of innate and adaptive immunity have only more recently been appreciated. The study of transgenic animal and tissue models has provided platforms to improve our understanding of the immune modulatory functions of HDPs. Here, the characterization of transgenic animals or tissue models that over-express and/or are deficient for specific HDPs is reviewed. We also attempt to reconcile this data with evidence from human studies monitoring HDP expression at constitutive levels and/or in conjunction with inflammation, infection models, or disease states. We have excluded activities ascribed to HDPs derived exclusively from in vitro experiments. An appreciation of the way that HDPs promote innate immunity or influence the adaptive immune response is necessary in order to exploit their therapeutic or adjuvant potential and to open new perspectives in understanding the basis of immunity. The potential applications for HDPs are discussed.


Host defense peptide Innate immunity Transgenics Bioengineered Knock-out 


  1. Aberg KM, Man MQ, Gallo RL, Ganz T, Crumrine D, Brown BE, et al (2008) Co-regulation and interdependence of the mammalian epidermal permeability and antimicrobial barriers. J Invest Dermatol 128:917–925PubMedCrossRefGoogle Scholar
  2. Agerberth B, Charo J, Werr J, Olsson B, Idali F, Lindbom L, et al (2000) The human antimicrobial and chemotactic peptides LL-37 and alpha-defensins are expressed by specific lymphocyte and monocyte populations. Blood 96:3086–3093PubMedGoogle Scholar
  3. 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 67:6084–6089PubMedGoogle Scholar
  4. Bdeir K, Higazi AA, Kulikovskaya I, Christofidou-Solomidou M, Vinogradov SA, Allen TC, et al (2010) Neutrophil alpha-defensins cause lung injury by disrupting the capillary-epithelial barrier. Am J Respir Crit Care Med 181:935–946PubMedCrossRefGoogle Scholar
  5. Bergman P, Johansson L, Wan H, Jones A, Gallo RL, Gudmundsson GH, et al (2006) Induction of the antimicrobial peptide CRAMP in the blood-brain barrier and meninges after meningococcal infection. Infect Immun 74:6982–6991PubMedCrossRefGoogle Scholar
  6. Boirivant M, Strober W (2007) The mechanism of action of probiotics. Curr Opin Gastroenterol 23:679–692PubMedCrossRefGoogle Scholar
  7. Boman HG (1991) Antibacterial peptides: key components needed in immunity. Cell 65:205–207PubMedCrossRefGoogle Scholar
  8. Boman HG (2003) Antibacterial peptides: basic facts and emerging concepts. J Intern Med 254:197–215PubMedCrossRefGoogle Scholar
  9. Bowdish DM, Davidson DJ, Scott MG, Hancock RE (2005) Immunomodulatory activities of small host defense peptides. Antimicrob Agents Chemother 49:1727–1732PubMedCrossRefGoogle Scholar
  10. Brogden KA, Ackermann M, Huttner KM (1997) Small, anionic, and charge-neutralizing propeptide fragments of zymogens are antimicrobial. Antimicrob Agents Chemother 41:1615–1617PubMedGoogle Scholar
  11. Brogden KA, Ackermann M, Huttner KM (1998) Detection of anionic antimicrobial peptides in ovine bronchoalveolar lavage fluid and respiratory epithelium. Infect Immun 66:5948–5954PubMedGoogle Scholar
  12. Brogden KA, Ackermann MR, McCray PB Jr, Huttner KM (1999) Differences in the concentrations of small, anionic, antimicrobial peptides in bronchoalveolar lavage fluid and in respiratory epithelia of patients with and without cystic fibrosis. Infect Immun 67:4256–4259PubMedGoogle Scholar
  13. Buchau AS, Morizane S, Trowbridge J, Schauber J, Kotol P, Bui JD, Gallo RL (2010) The host defense peptide cathelicidin is required for NK cell-mediated suppression of tumor growth. J Immunol 184:369–378PubMedCrossRefGoogle Scholar
  14. Bultman SJ, Michaud EJ, Woychik RP (1992) Molecular characterization of the mouse agouti locus. Cell 71:1195–1204PubMedCrossRefGoogle Scholar
  15. Candille SI, Kaelin CB, Cattanach BM, Yu B, Thompson DA, Nix MA, et al (2007) A -defensin mutation causes black coat color in domestic dogs. Science 318:1418–1423PubMedCrossRefGoogle Scholar
  16. Carretero M, Del Río M, García M, Escámez MJ, Mirones I, Rivas L, et al (2004) A cutaneous gene therapy approach to treat infection through keratinocyte-targeted overexpression of antimicrobial peptides. FASEB 18:1931–1933Google Scholar
  17. Chan YR, Liu JS, Pociask DA, Zheng M, Mietzner TA, Berger T, et al (2009) Lipocalin 2 is required for pulmonary host defense against Klebsiella infection. J Immunol 182:4947–4956PubMedCrossRefGoogle Scholar
  18. Chen QX, Lv C, Huang LX, Cheng BL, Xie GH, Wu SJ, Fang XM (2007) Genomic variations within DEFB1 are associated with the susceptibility to and the fatal outcome of severe sepsis in Chinese Han population. Genes Immun 8:439–443PubMedCrossRefGoogle Scholar
  19. Cheung QCK, Turner PV, Song C, Wu D, Cai HY, MacInnes JI, Li J (2008) Enhanced resistance to bacterial infection in protegrin-1 transgenic mice. Antimicrob Agents Chemother 52:1812–1819PubMedCrossRefGoogle Scholar
  20. Chen Q, Hakimi M, Wu S, Jin Y, Cheng B, Wang H, et al (2010) Increased genomic copy number of DEFA1/DEFA3 is associated with susceptibility to severe sepsis in Chinese Han population. Anesthesiology 112:1428–1434PubMedCrossRefGoogle Scholar
  21. Chhajlani V, Wikberg JES (1992) Molecular cloning and expression of the human melanocyte stimulating hormone receptor cDNA. FEBS Lett 309:417–420PubMedCrossRefGoogle Scholar
  22. Chromek M, Slamová Z, Bergman P, Kovács L, Podracká L, Ehrén I, et al (2006) The antimicrobial peptide cathelicidin protects the urinary tract against invasive bacterial infection. Nat Med 12:636–641PubMedCrossRefGoogle Scholar
  23. Ciornei CD, Sigurdardóttir T, Schmidtchen A, Bodelsson M (2005) Antimicrobial and chemoattractant activity, lipopolysaccharide neutralization, cytotoxicity, and inhibition by serum of analogs of human cathelicidin LL-37. Antimicrob Agents Chemother 49:2845–2850PubMedCrossRefGoogle Scholar
  24. Clarke LL, Gawenis LR, Bradford EM, Judd LM, Boyle KT, Simpson JE, et al (2004) Abnormal Paneth cell granule dissolution and compromised resistance to bacterial colonization in the intestine of CF mice. Am J Physiol Gastrointest Liver Physiol 286:G1050–G1058PubMedCrossRefGoogle Scholar
  25. Devine DA (2003) Antimicrobial peptides in defence of the oral and respiratory tracts. Mol Immunol 40:431–443PubMedCrossRefGoogle Scholar
  26. Di Nardo A, Braff MH, Taylor KR, Na C, Granstein RD, McInturff JE, et al (2007) Cathelicidin antimicrobial peptides block dendritic cell TLR4 activation and allergic contact sensitization. J Immunol 178:1829–1834PubMedGoogle Scholar
  27. Draper DL, Landers DV, Krohn MA, Hillier SL, Wiesenfeld HC, Heine RP (2000) Levels of vaginal secretory leukocyte protease inhibitor are decreased in women with lower reproductive tract infections. Am J Obstet Gynecol 183:1243–1248PubMedCrossRefGoogle Scholar
  28. Eagan TM, Damås JK, Ueland T, Voll-Aanerud M, Mollnes TE, Hardie JA, Bakke PS, Aukrust P (2010) Neutrophil gelatinase associated lipocalin: a biomarker in chronic obstructive pulmonary disease. Chest 138:888–895CrossRefGoogle Scholar
  29. Elahi S, Buchanan RM, Attah-Poku S, Townsend HG, Babiuk LA, Gerdts V (2006) The host defense peptide beta-defensin 1 confers protection against Bordetella pertussis in newborn piglets. Infect Immun 74:2338–2352PubMedCrossRefGoogle Scholar
  30. Fahlgren A, Hammarstrom S, Danielsson A, Hammarstrom ML (2004) beta-Defensin-3 and -4 in intestinal epithelial cells display increased mRNA expression in ulcerative colitis. Clin Exp Immunol 137:379–385PubMedCrossRefGoogle Scholar
  31. Fales-Williams AJ, Gallup JM, Ramírez-Romero R, Brogden KA, Ackermann MR (2002) Increased anionic peptide distribution and intensity during progression and resolution of bacterial pneumonia. Clin Diagn Lab Immunol 9:28–32PubMedGoogle Scholar
  32. Fernandez-Jimenez N, Castellanos-Rubio A, Plaza-Izurieta L, Gutierrez G, Castaño L, Vitoria JC, Bilbao JR (2010) Analysis of beta-defensin and Toll-like receptor gene copy number variation in celiac disease. Hum Immunol 71:833–836PubMedCrossRefGoogle Scholar
  33. Finlay BB, Hancock RE (2004) Can innate immunity be enhanced to treat microbial infections? Nat Rev Microbiol 2:497–504PubMedCrossRefGoogle Scholar
  34. Gallo KA, Johnson GL (2002) Mixed-lineage kinase control of JNK and p38 MAPK pathways. Nat Rev Mol Cell Biol 3:663–672PubMedCrossRefGoogle Scholar
  35. Gallo RL, Murakami M, Ohtake T, Zaiou M (2002) Biology and clinical relevance of naturally occurring antimicrobial peptides. J Allergy Clin Immunol 110:823–831PubMedCrossRefGoogle Scholar
  36. Gambichler T, Skrygan M, Tomi NS, Othlinghaus N, Brockmeyer NH, Altmeyer P, Kreuter A (2008) Differential mRNA expression of antimicrobial peptides and proteins in atopic dermatitis as compared to psoriasis vulgaris and healthy skin. Int Arch Allergy Immunol 147:17–24PubMedCrossRefGoogle Scholar
  37. 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 82:552–556PubMedCrossRefGoogle Scholar
  38. Ghali S, Bhatt KA, Dempsey MP, Jones DM, Singh S, Aarabi S, et al (2009) Treating chronic wound infections with genetically modified free flaps. Plast Reconstr Surg 123:1157–1168PubMedCrossRefGoogle Scholar
  39. Ghosh A, Lee S, Dziarski R, Chakravarti S (2009) A novel antimicrobial peptidoglycan recognition protein in the cornea. Invest Ophthalmol Vis Sci 50:4185–4191PubMedCrossRefGoogle Scholar
  40. Gudmundsson GH, Agerberth B (1999) Neutrophil antibacterial peptides, multifunctional effector molecules in the mammalian immune system. J Immunol Meth 232:45–54CrossRefGoogle Scholar
  41. Hancock RE (2001) Cationic peptides: effectors in innate immunity and novel antimicrobials. Lancet Infect Dis 1:156–164PubMedCrossRefGoogle Scholar
  42. Hancock REW, Lehrer R (1998) Cationic peptides: a new source of antibiotics. Trends Biotechnol 16:82–88PubMedCrossRefGoogle Scholar
  43. Hancock RE, Scott MG (2000) The role of antimicrobial peptides in animal defenses. Proc Natl Acad Sci USA 97:8856–8861PubMedCrossRefGoogle Scholar
  44. 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 276:5707–5713PubMedCrossRefGoogle Scholar
  45. Heilborn JD, Nilsson MF, Kratz G, Weber G, Sørensen O, Borregaard N, Ståhle-Bäckdahl 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 120:379–389PubMedCrossRefGoogle Scholar
  46. Heilborn JD, Nilsson MF, Jimenez CI, Sandstedt B, Borregaard N, Tham E, et al (2005) Antimicrobial protein hCAP18/LL-37 is highly expressed in breast cancer and is a putative growth factor for epithelial cells. Int J Cancer 114:713–719PubMedCrossRefGoogle Scholar
  47. Hirsch T, Spielmann M, Zuhaili B, Fossum M, Metzig M, Koehler T, et al (2009) Human beta-defensin-3 promotes wound healing in infected diabetic wounds. J Gene Med 11:220–228PubMedCrossRefGoogle Scholar
  48. Horne AW, Stock SJ, King AE (2008) Innate immunity and disorders of the female reproductive tract. Reproduction 135:739–749PubMedCrossRefGoogle Scholar
  49. Howell MD, Jones JF, Kisich KO, Streib JE, Gallo RL, Leung DY (2004) Selective killing of vaccinia virus by LL-37: implications for eczema vaccinatum. J Immunol 172:1763–1767PubMedGoogle Scholar
  50. Howell MD, Wollenberg A, Gallo RL, Flaig M, Streib JE, Wong C, et al (2006) Cathelicidin deficiency predisposes to eczema herpeticum. J Allergy Clin Immunol 117:836–841PubMedCrossRefGoogle Scholar
  51. Hsieh J-C, Pan CY, Chen JY (2010) Tilapia hepcidin (TH)2-3 as a transgene in transgenic fish enhances resistance to Vibrio vulnificus infection and causes variations in immune-related genes after infection by different bacterial species. Fish Shellfish Immunol 29:430–439PubMedCrossRefGoogle Scholar
  52. Huang LC, Reins RY, Gallo RL, McDermott AM (2007) Cathelicidin-deficient (Cnlp -/-) mice show increased susceptibility to Pseudomonas aeruginosa keratitis. Invest Ophthalmol Vis Sci 48:4498–4508PubMedCrossRefGoogle Scholar
  53. Iimura M, Gallo RL, Hase K, Miyamoto Y, Eckmann L, Kagnoff MF (2005) Cathelicidin mediates innate intestinal defense against colonization with epithelial adherent bacterial pathogens. J Immunol 174:4901–4907PubMedGoogle Scholar
  54. Jacobsen F, Mittler D, Hirsch T, Gerhards A, Lehnhardt M, Voss B, et al (2005) Transient cutaneous adenoviral gene therapy with human host defense peptide hCAP-18/LL-37 is effective for the treatment of burn wound infections. Gene Ther 12:1494–1502PubMedCrossRefGoogle Scholar
  55. Jansen PAM, Rodijk-Olthuis D, Hollox EJ, Kamsteeg M, Tjabringa GS, Jongh GJ de, et al (2009) Beta-defensin-2 protein is a serum biomarker for disease activity in psoriasis and reaches biologically relevant concentrations in lesional skin. PLoS ONE 4:e4725PubMedCrossRefGoogle Scholar
  56. King AE, Critchley HO, Kelly RW (2000) Presence of secretory leukocyte protease inhibitor in human endometrium and first trimester decidua suggests an antibacterial protective role. Mol Hum Reprod 6:191–196PubMedCrossRefGoogle Scholar
  57. King A, Critchley HO, Kelly RW (2003) Innate immune defences in the human endometrium. Reprod Biol Endocrinol 1:116PubMedCrossRefGoogle Scholar
  58. Klungland H, Vage DI (2003) Pigmentary switches in domestic animal species. Ann NY Acad Sci 994:331–338PubMedCrossRefGoogle Scholar
  59. Koczulla R, Degenfeld G von, Kupatt C, Krötz F, Zahler S, Gloe T, et al (2003) An angiogenic role for the human peptide antibiotic LL-37/hCAP-18. J Clin Invest 111:1665–1672PubMedGoogle Scholar
  60. Lande R, Gregorio J, Facchinetti V, Chatterjee B, Wang YH, Homey B, et al (2007) Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature 449:564–569PubMedCrossRefGoogle Scholar
  61. LeBlanc PM, Yeretssian G, Rutherford N, Doiron K, Nadiri A, Zhu L, et al (2008) Caspase-12 modulates NOD signaling and regulates antimicrobial peptide production and mucosal immunity. Cell Host Microbe 3:146–157PubMedCrossRefGoogle Scholar
  62. Lee PH, Ohtake T, Zaiou M, Murakami M, Rudisill JA, Lin KH, Gallo RL (2005) Expression of an additional cathelicidin antimicrobial peptide protects against bacterial skin infection. Proc Natl Acad Sci USA 102:3750–3755PubMedCrossRefGoogle Scholar
  63. Lentsch AB, Jordan JA, Czermak BJ, Diehl KM, Younkin EM, Sarma V, Ward PA (1999) Inhibition of NF-kappaB activation and augmentation of IkappaBbeta by secretory leukocyte protease inhibitor during lung inflammation. Am J Pathol 154:239–247PubMedGoogle Scholar
  64. Levinson P, Kaul R, Kimani J, Ngugi E, Moses S, MacDonald KS, et al (2009) Levels of innate immune factors in genital fluids: association of alpha defensins and LL-37 with genital infections and increased HIV acquisition. AIDS 23:309–317PubMedCrossRefGoogle Scholar
  65. Li D, Li J, Duan Y, Zhou X (2004) Expression of LL-37, human beta defensin-2, and CCR6 mRNA in patients with psoriasis vulgaris. J Huazhong Univ Sci Technolog Med Sci 24:404–406PubMedCrossRefGoogle Scholar
  66. Lin C-Y, Yang PH, Kao CL, Huang HI, Tsai HJ (2010) Transgenic zebrafish eggs containing bactericidal peptide is a novel food supplement enhancing resistance to pathogenic infection of fish. Fish Shellfish Immunol 28:419–427PubMedCrossRefGoogle Scholar
  67. Marre ML, Darcy CT, Yinh J, Akira S, Uematsu S, Steere AC, Hu LT (2010) The role of adrenomedullin in Lyme disease. Infect Immun (in press)Google Scholar
  68. Mathews M, Jia HP, Guthmiller JM, Losh G, Graham S, Johnson GK, et al (1999) Production of beta-defensin antimicrobial peptides by the oral mucosa and salivary glands. Infect Immun 67:2740–2745PubMedGoogle Scholar
  69. Matzner M, Al Samie AR, Winkler HM, Nemeth J, Grasnek A, Indra A, et al (2010) Low serum levels of cathelicidin LL-37 in leprosy. Acta Trop (in press)Google Scholar
  70. McMichael JW, Maxwell AI, Hayashi K, Taylor K, Wallace WA, Govan JR, et al (2005) Antimicrobial activity of murine lung cells against Staphylococcus aureus is increased in vitro and in vivo after elafin gene transfer. Infect Immun 73:3609–3617PubMedCrossRefGoogle Scholar
  71. Mookherjee N, Brown KL, Bowdish DM, Doria S, Falsafi R, Hokamp K, et al (2006) Modulation of the TLR-mediated inflammatory response by the endogenous human host defense peptide LL-37. J Immunol 176:2455–2464PubMedGoogle Scholar
  72. Morioka Y, Yamasaki K, Leung D, Gallo RL (2008) Cathelicidin antimicrobial peptides inhibit hyaluronan-induced cytokine release and modulate chronic allergic dermatitis. J Immunol 181:3915–3922PubMedGoogle Scholar
  73. 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 70:3068–3072PubMedCrossRefGoogle Scholar
  74. Munk C, Wei G, Yang OO, Waring AJ, Wang W, Hong T, et al (2003) The theta-defensin, retrocyclin, inhibits HIV-1 entry. AIDS Res Hum Retroviruses 19:875–881PubMedCrossRefGoogle Scholar
  75. Murakami M, Ohtake T, Dorschner RA, Gallo RL (2002a) Cathelicidin antimicrobial peptides are expressed in salivary glands and saliva. J Dent Res 81:845–850PubMedCrossRefGoogle Scholar
  76. 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 119:1090–1095PubMedCrossRefGoogle Scholar
  77. 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 57:10–15PubMedCrossRefGoogle Scholar
  78. Nguyen TX, Cole AM, Lehrer RI (2003) Evolution of primate theta-defensins: a serpentine path to a sweet tooth. Peptides 24:1647–1654PubMedCrossRefGoogle Scholar
  79. Nicolas G, Bennoun M, Porteu A, Mativet S, Beaumont C, Grandchamp B, et al (2002) Severe iron deficiency anemia in transgenic mice expressing liver hepcidin. Proc Natl Acad Sci USA 99:4596–4601PubMedCrossRefGoogle Scholar
  80. Nizet V, Ohtake T, Lauth X, Trowbridge J, Rudisill J, Dorschner RA, et al (2001) Innate antimicrobial peptide protects the skin from invasive bacterial infection. Nature 414:454–457PubMedCrossRefGoogle Scholar
  81. Norkina O, Burnett TG, De Lisle RC (2004) Bacterial overgrowth in the cystic fibrosis transmembrane conductance regulator null mouse small intestine. Infect Immun 72:6040–6049PubMedCrossRefGoogle Scholar
  82. Ong PY, Ohtake T, Brandt C, Strickland I, Boguniewicz M, Ganz T, et al (2002) Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N Engl J Med 347:1151–1160PubMedCrossRefGoogle Scholar
  83. Oren A, Ganz T, Liu L, Meerloo T (2003) In human epidermis, beta-defensin 2 is packaged in lamellar bodies. Exp Mol Pathol 74:180–182PubMedCrossRefGoogle Scholar
  84. Otte J-M, Kiehne K, Herzig KH (2003) Antimicrobial peptides in innate immunity of the human intestine. J Gastroenterol 38:717–726PubMedCrossRefGoogle Scholar
  85. Ouellette AJ (2005) Paneth cell alpha-defensins: peptide mediators of innate immunity in the small intestine. Springer Semin Immunopathol 27:133–146PubMedCrossRefGoogle Scholar
  86. Pacora P, Maymon E, Gervasi MT, Gomez R, Edwin SS, Yoon BH, Romero R (2000) Lactoferrin in intrauterine infection, human parturition, and rupture of fetal membranes. Am J Obstet Gynecol 183:904–910PubMedCrossRefGoogle Scholar
  87. Pak V, Budikhina A, Pashenkov M, Pinegin B (2007) Neutrophil activity in chronic granulomatous disease. Adv Exp Med Biol 601:69–74PubMedCrossRefGoogle Scholar
  88. Peng KC, Pan CY, Chou HN, Chen JY (2010) Using an improved Tol2 transposon system to produce transgenic zebrafish with epinecidin-1 which enhanced resistance to bacterial infection. Fish Shellfish Immunol 28:905–917PubMedCrossRefGoogle Scholar
  89. Phadke SM, Deslouches B, Hileman SE, Montelaro RC, Wiesenfeld HC, Mietzner TA (2005) Antimicrobial peptides in mucosal secretions: the importance of local secretions in mitigating infection. J Nutr 135:1289–1293PubMedGoogle Scholar
  90. Pillay K, Coutsoudis A, Agadzi-Naqvi AK, Kuhn L, Coovadia HM, Janoff EN (2001) Secretory leukocyte protease inhibitor in vaginal fluids and perinatal human immunodeficiency virus type 1 transmission. J Infect Dis 183:653–656PubMedCrossRefGoogle Scholar
  91. Pütsep K, Carlsson G, Boman HG, Andersson M (2002) Deficiency of antibacterial peptides in patients with morbus Kostmann: an observation study. Lancet 360:1144–1149PubMedCrossRefGoogle Scholar
  92. Robbins LS, Nadeau JH, Johnson KR, Kelly MA, Roselli-Rehfuss L, Baack E, et al (1993) Pigmentation phenotypes of variant extension locus alleles result from point mutations that alter MSH receptor function. Cell 72:827–834PubMedCrossRefGoogle Scholar
  93. Roy CN, Mak HH, Akpan I, Losyev G, Zurakowski D, Andrews NC (2007) Hepcidin antimicrobial peptide transgenic mice exhibit features of the anemia of inflammation. Blood 109:4038–4044PubMedCrossRefGoogle Scholar
  94. Sallenave J-M, Cunningham GA, James RM, McLachlan G, Haslett C (2003) Regulation of pulmonary and systemic bacterial lipopolysaccharide responses in transgenic mice expressing human elafin. Infect Immun 71:3766–3774PubMedCrossRefGoogle Scholar
  95. Salzman NH, Ghosh D, Huttner KM, Paterson Y, Bevins C (2003) Protection against enteric salmonellosis in transgenic mice expressing a human intestinal defensin. Nature 422:522–526PubMedCrossRefGoogle Scholar
  96. Salzman NH, Hung K, Haribhai D, Chu H, Karlsson-Sjöberg J, Amir E, et al (2010) Enteric defensins are essential regulators of intestinal microbial ecology. Nat Immunol 11:76–83PubMedCrossRefGoogle Scholar
  97. Sawamura D, Goto M, Shibaki A, Akiyama M, McMillan JR, Abiko Y, Shimizu H (2005) Beta defensin-3 engineered epidermis shows highly protective effect for bacterial infection. Gene Ther 12:857–861PubMedCrossRefGoogle Scholar
  98. Schauber J, Gallo RL (2008) The vitamin D pathway: a new target for control of the skin's immune response? Exp Dermatol 17:633–639PubMedCrossRefGoogle Scholar
  99. Schroder JM, Harder J (2006) Antimicrobial skin peptides and proteins. Cell Mol Life Sci 63:469–486PubMedCrossRefGoogle Scholar
  100. Shai Y (1999) Mechanism of the binding, insertion and destabilization of phospholipid bilayer membranes by alpha-helical antimicrobial and cell non-selective membrane-lytic peptides. Biochim Biophys Acta 1462:55–70PubMedCrossRefGoogle Scholar
  101. Shu Q, Shi Z, Zhao Z, Chen Z, Yao H, Chen Q, et al (2006) Protection against Pseudomonas aeruginosa pneumonia and sepsis-induced lung injury by overexpression of beta-defensin-2 in rats. Shock 26:365–371PubMedCrossRefGoogle Scholar
  102. Simpson AJ, Wallace WA, Marsden ME, Govan JR, Porteous DJ, Haslett C, Sallenave JM (2001) Adenoviral augmentation of elafin protects the lung against acute injury mediated by activated neutrophils and bacterial infection. J Immunol 167:1778–1786PubMedGoogle Scholar
  103. Sorensen OE, Gram L, Johnsen AH, Andersson E, Bangsbøll S, Tjabringa GS, et al (2003) Processing of seminal plasma hCAP-18 to ALL-38 by gastricsin: a novel mechanism of generating antimicrobial peptides in vagina. J Biol Chem 278:28540–28546PubMedCrossRefGoogle Scholar
  104. Starner TD, Agerberth B, Gudmundsson GH, McCray PB Jr (2005) Expression and activity of beta-defensins and LL-37 in the developing human lung. J Immunol 174:1608–1615PubMedGoogle Scholar
  105. Sumikawa Y, Asada H, Hoshino K, Azukizawa H, Katayama I, Akira S, Itami S (2006) Induction of beta-defensin 3 in keratinocytes stimulated by bacterial lipopeptides through toll-like receptor 2. Microbes Infect 8:1513–1521PubMedCrossRefGoogle Scholar
  106. Thomas-Virnig CL, Centanni JM, Johnston CE, He LK, Schlosser SJ, Van Winkle KF, et al (2009) Inhibition of multidrug-resistant Acinetobacter baumannii by nonviral expression of hCAP-18 in a bioengineered human skin tissue. Mol Ther 17:562–569PubMedCrossRefGoogle Scholar
  107. Tjabringa GS, Aarbiou J, Ninaber DK, Drijfhout JW, Sørensen OE, Borregaard N, et al (2003) The antimicrobial peptide LL-37 activates innate immunity at the airway epithelial surface by transactivation of the epidermal growth factor receptor. J Immunol 171:6690–6696PubMedGoogle Scholar
  108. Tokumaru S, Sayama K, Shirakata Y, Komatsuzawa H, Ouhara K, Hanakawa Y, et al (2005) Induction of keratinocyte migration via transactivation of the epidermal growth factor receptor by the antimicrobial peptide LL-37. J Immunol 175:4662–4668PubMedGoogle Scholar
  109. Valore EV, Park CH, Quayle AJ, Wiles KR, McCray PB Jr, Ganz T (1998) Human beta-defensin-1: an antimicrobial peptide of urogenital tissues. J Clin Invest 101:1633–1642PubMedCrossRefGoogle Scholar
  110. Vora P, Youdim A, Thomas LS, Fukata M, Tesfay SY, Lukasek K, et al (2004) Beta-defensin-2 expression is regulated by TLR signaling in intestinal epithelial cells. J Immunol 173:5398–5405PubMedGoogle Scholar
  111. Wang W, Owen SM, Rudolph DL, Cole AM, Hong T, Waring AJ, et al (2004) Activity of alpha- and theta-defensins against primary isolates of HIV-1. J Immunol 173:515–520PubMedGoogle Scholar
  112. Weber G, Chamorro CI, Granath F, Liljegren A, Zreika S, Saidak Z, et al (2009) Human antimicrobial protein hCAP18/LL-37 promotes a metastatic phenotype in breast cancer. Breast Cancer Res 11:R6PubMedCrossRefGoogle Scholar
  113. Wehkamp J, Harder J, Weichenthal M, Schwab M, Schäffeler E, Schlee M, et al (2004) NOD2 (CARD15) mutations in Crohn's disease are associated with diminished mucosal alpha-defensin expression. Gut 53:1658–1664PubMedCrossRefGoogle Scholar
  114. Wehkamp J, Salzman NH, Porter E, Nuding S, Weichenthal M, Petras RE, et al (2005) Reduced Paneth cell alpha-defensins in ileal Crohn's disease. Proc Natl Acad Sci USA 102:18129–18134PubMedCrossRefGoogle Scholar
  115. White SH, Wimley WC, Selsted ME (1995) Structure, function, and membrane integration of defensins. Curr Opin Struct Biol 5:521–527PubMedCrossRefGoogle Scholar
  116. Wilson CL, Ouellette AJ, Satchell DP, Ayabe T, López-Boado YS, Stratman JL, et al (1999) Regulation of intestinal alpha-defensin activation by the metalloproteinase matrilysin in innate host defense. Science 286:113–117PubMedCrossRefGoogle Scholar
  117. Wolfram JA, Diaconu D, Hatala DA, Rastegar J, Knutsen DA, Lowther A, et al (2009) Keratinocyte but not endothelial cell-specific overexpression of Tie2 leads to the development of psoriasis. Am J Pathol 174:1443–1458PubMedCrossRefGoogle Scholar
  118. Yamaguchi Y, Nagase T, Tomita T, Nakamura K, Fukuhara S, Amano T, et al (2007) Beta-defensin overexpression induces progressive muscle degeneration in mice. Am J Physiol Cell Physiol 292:C2141–C2149PubMedCrossRefGoogle Scholar
  119. Yamasaki K, Schauber J, Coda A, Lin H, Dorschner RA, Schechter NM, et al (2006) Kallikrein-mediated proteolysis regulates the antimicrobial effects of cathelicidins in skin. FASEB J 20:2068–2080PubMedCrossRefGoogle Scholar
  120. Yamasaki K, Di Nardo A, Bardan A, Murakami M, Ohtake T, Coda A, et al (2007) Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea. Nat Med 13:975–980PubMedCrossRefGoogle Scholar
  121. Yen C-C, Lin CY, Chong KY, Tsai TC, Shen CJ, Lin MF, et al (2009) Lactoferrin as a natural regimen for selective decontamination of the digestive tract: recombinant porcine lactoferrin expressed in the milk of transgenic mice protects neonates from pathogenic challenge in the gastrointestinal tract. J Infect Dis 199:590–598PubMedCrossRefGoogle Scholar
  122. Zanetti M (2004) Cathelicidins, multifunctional peptides of the innate immunity. J Leukoc Biol 75:39–48PubMedCrossRefGoogle Scholar
  123. Zasloff M (2002) Innate immunity, antimicrobial peptides, and protection of the oral cavity. Lancet 360:1116–1117PubMedCrossRefGoogle Scholar
  124. Zughaier SM, Shafer WM, Stephens DS (2005) Antimicrobial peptides and endotoxin inhibit cytokine and nitric oxide release but amplify respiratory burst response in human and murine macrophages. Cell Microbiol 7:1251–1262PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Tova Dybvig
    • 1
  • Marina Facci
    • 1
  • Volker Gerdts
    • 1
    • 2
  • Heather L. Wilson
    • 1
    • 3
  1. 1.Vaccine & Infectious Disease Organization (VIDO)University of SaskatchewanSaskatoonCanada
  2. 2.Department of Veterinary Microbiology, Western College of Veterinary MedicineUniversity of SaskatchewanSaskatoonCanada
  3. 3.Department of BiochemistryUniversity of SaskatchewanSaskatoonCanada

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