Advertisement

Antimicrobial Peptides as First-Line Effector Molecules of the Human Innate Immune System

  • Regine Gläser
  • Jürgen Harder
  • Jens-Michael Schröder
Part of the Nucleic Acids and Molecular Biology book series (NUCLEIC, volume 21)

Findings of the past two decades clearly document that epithelial cells have the capacity to mount a “chemical barrier” apart from the physical defense shield against invading microorganisms. This “chemical barrier” includes preformed antimicrobial proteins present at the uppermost layers of the epithelium as well as newly synthesized compounds that are produced upon stimulation after contact with pathogenic bacteria or bacterial products, endogenous proinflammatory cytokines and/or the disruption of the physical barrier by wounding with subsequently released growth factors. This chapter introduces the reader into the field by giving an overview of the most important human epithelial and phagocyte derived anti-microbial peptides. Furthermore, strategies for the putative action of antimicrobial peptides in the healthy human are presented. The third part of the review gives an overview of several diseases which are in connection with a decreased or impaired antimicrobial peptide expression: skin diseases and wound healing, diseases of the airway epithelia and the gastrointestinal tract as well as diseases associated with phagocyte dysfunction. Exogenous application of antimicrobial peptides could be a promising therapeutic option in the near future for the treatment of patients with epithelial infections and chronic wounds but a much more promising option would be the promotion of the endogenous expression of antimicrobial peptides.

Keywords

Atopic Dermatitis Stratum Corneum Antimicrobial Peptide Paneth Cell Secretory Leukocyte Protease Inhibitor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Abiko Y, Nishimura M, Kusano K, Yamazaki M, Arakawa T, Takuma T, Kaku T (2003) Upregulated expression of human beta defensin-1 and -3 mRNA during differentiation of keratinocyte immortalized cell lines, HaCaT and PHK16–0b. J Dermatol Sci 31:225–228PubMedCrossRefGoogle Scholar
  2. Agerberth B, Gunne H, Odeberg J, Kogner P, Boman HG, Gudmundsson GH (1995) FALL-39, a putative human peptide antibiotic, is cysteine-free and expressed in bone marrow and testis. Proc Natl Acad Sci USA 92:195–199PubMedCrossRefGoogle Scholar
  3. Ali RS, Falconer A, Ikram M, Bissett CE, Cerio R, Quinn AG (2001) Expression of the peptide antibiotics human beta defensin-1 and human beta defensin-2 in normal human skin. J Invest Dermatol 117:106–111PubMedCrossRefGoogle Scholar
  4. Alkemade JA, Molhuizen HO, Ponec M, Kempenaar JA, Zeeuwen PL, Jongh GJ de, Vlijmen-Willems IM van, Erp PE van, Kerkhof PC van de, Schalkwijk J (1994) SKALP/elafin is an inducible proteinase inhibitor in human epidermal keratinocytes. J Cell Sci 107:2335–2342PubMedGoogle Scholar
  5. Allaker RP, Kapas S (2003) Adrenomedullin expression by gastric epithelial cells in response to infection. Clin Diagn Lab Immunol 10:546–551PubMedGoogle Scholar
  6. Allaker RP, Zihni C, Kapas S (1999) An investigation into the antimicrobial effects of adrenomedullin on members of the skin, oral, respiratory tract and gut microflora. FEMS Immunol Med Microbiol 23:289–293PubMedGoogle Scholar
  7. Bals R, Wang X, Wu Z, Freeman T, Bafna V, Zasloff M, Wilson JM (1998) Human beta-defensin 2 is a salt-sensitive peptide antibiotic expressed in human lung. J Clin Invest 102:874–880PubMedCrossRefGoogle Scholar
  8. Bals R, Weiner DJ, Meegalla RL, Wilson JM (1999) Transfer of a cathelicidin peptide antibiotic gene restores bacterial killing in a cystic fibrosis xenograft model. J Clin Invest 103:1113–1117PubMedCrossRefGoogle Scholar
  9. Bensch KW, Raida M, Magert HJ, Schulz-Knappe P, Forssmann WG (1995) hBD-1: a novel beta-defensin from human plasma. FEBS Lett 368:331–335PubMedCrossRefGoogle Scholar
  10. Bevins CL (2006) Paneth cell defensins: key effector molecules of innate immunity. Biochem Soc Trans 34:263–266PubMedCrossRefGoogle Scholar
  11. Braff MH, Di Nardo A, Gallo RL (2005) Keratinocytes store the antimicrobial peptide cathelicidin in lamellar bodies. J Invest Dermatol 124:394–400PubMedCrossRefGoogle Scholar
  12. Butmarc J, Yufit T, Carson P, Falanga V (2004) Human beta-defensin-2 expression is increased in chronic wounds. Wound Repair Regen 12:439–443PubMedCrossRefGoogle Scholar
  13. Casewell MW, Desai N (1983) Survival of multiply-resistant Klebsiella aerogenes and other gram-negative bacilli on finger-tips. J Hosp Infect 4:350–360PubMedCrossRefGoogle Scholar
  14. Chronnell CM, Ghali LR, Ali RS, Quinn AG, Holland DB, Bull JJ, Cunliffe WJ, McKay IA, Philpott MP, Muller-Rover S (2001) Human beta defensin-1 and -2 expression in human pilosebaceous units: upregulation in acne vulgaris lesions. J Invest Dermatol 117:1120–1125PubMedCrossRefGoogle Scholar
  15. Chung WO, Dale BA (2004) Innate immune response of oral and foreskin keratinocytes: utilization of different signaling pathways by various bacterial species. Infect Immun 72:352–358PubMedCrossRefGoogle Scholar
  16. Clohessy PA, Golden BE (1995) Calprotectin-mediated zinc chelation as a biostatic mechanism in host defence. Scand J Immunol 42:551–556PubMedCrossRefGoogle Scholar
  17. Cole AM, Kim YH, Tahk S, Hong T, Weis P, Waring AJ, Ganz T (2001) Calcitermin, a novel antimicrobial peptide isolated from human airway secretions. FEBS Lett 504:5–10PubMedCrossRefGoogle Scholar
  18. 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 169:6985–6991PubMedGoogle Scholar
  19. Conner K, Nern K, Rudisill J, O’Grady T, Gallo RL (2002) The antimicrobial peptide LL-37 is expressed by keratinocytes in condyloma acuminatum and verruca vulgaris. J Am Acad Dermatol 47:347–350PubMedCrossRefGoogle Scholar
  20. Cunliffe RN (2003) Alpha-defensins in the gastrointestinal tract. Mol Immunol 40:463–467PubMedCrossRefGoogle Scholar
  21. Dale BA, Krisanaprakornkit S (2001) Defensin antimicrobial peptides in the oral cavity. J Oral Pathol Med 30:321–327PubMedCrossRefGoogle Scholar
  22. 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 192:1069–1074CrossRefGoogle Scholar
  23. Domachowske JB, Dyer KD, Adams AG, Leto TL, Rosenberg HF (1998) Eosinophil cationic protein/RNase 3 is another RNase A-family ribonuclease with direct antiviral activity. Nucleic Acids Res 26:3358–3363PubMedCrossRefGoogle Scholar
  24. Domachowske JB, Dyer KD, Bonville CA, Rosenberg HF (1998) Recombinant human eosinophil-derived neurotoxin/RNase 2 functions as an effective antiviral agent against respiratory syncytial virus. J Infect Dis 177:1458–1464PubMedCrossRefGoogle Scholar
  25. 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 117:91–97PubMedCrossRefGoogle Scholar
  26. Eckert RL, Broome AM, Ruse M, Robinson N, Ryan D, Lee K (2004) S100 proteins in the epidermis. J Invest Dermatol 123:23–33PubMedCrossRefGoogle Scholar
  27. Elias PM (2005) Stratum corneum defensive functions: an integrated view. J Invest Dermatol 125:183–200PubMedGoogle Scholar
  28. Ellison RT 3rd, Giehl TJ (1991) Killing of gram-negative bacteria by lactoferrin and lysozyme. J Clin Invest 88:1080–1091PubMedCrossRefGoogle Scholar
  29. Ericksen B, Wu Z, Lu W, Lehrer RI (2005) Antibacterial activity and specificity of the six human alpha-defensins. Antimicrob Agents Chemother 49:269–275PubMedCrossRefGoogle Scholar
  30. Ezoe K, Katsumata M (1990) Immunohistochemical study of lysozyme in human apocrine glands. J Dermatol 17:159–163PubMedGoogle Scholar
  31. 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 131:90–101PubMedCrossRefGoogle Scholar
  32. 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
  33. Fellermann K, Wehkamp J, Herrlinger KR, Stange EF (2003) Crohn’s disease: a defensin deficiency syndrome? Eur J Gastroenterol Hepatol 15:627–634PubMedCrossRefGoogle Scholar
  34. Fleming A (1922) On a remarkable bacteriolytic element found in tissues and secretions. Proc R Soc Lond 93:306–310CrossRefGoogle Scholar
  35. Fritz H (1988) Human mucus proteinase inhibitor (human MPI). Human seminal inhibitor I (HUSI-I), antileukoprotease (ALP), secretory leukocyte protease inhibitor (SLPI). Biol Chem Hoppe Seyler 369[Suppl]:79–82PubMedGoogle Scholar
  36. Frohm M, Agerberth B, Ahangari G, Stahle-Backdahl M, Liden S, Wigzell H, Gudmundsson GH (1997) The expression of the gene coding for the antibacterial peptide LL-37 is induced in human keratinocytes during inflammatory disorders. J Biol Chem 272:15258–15263PubMedCrossRefGoogle Scholar
  37. Frye M, Bargon J, Gropp R (2001) Expression of human beta-defensin-1 promotes differentiation of keratinocytes. J Mol Med 79:275–282PubMedCrossRefGoogle Scholar
  38. Fulton C, Anderson GM, Zasloff M, Bull R, Quinn AG (1997) Expression of natural peptide antibiotics in human skin. Lancet 350:1750–1751PubMedCrossRefGoogle Scholar
  39. Gadsby DC, Vergani P, Csanady L (2006) The ABC protein turned chloride channel whose failure causes cystic fibrosis. Nature 440:477–483PubMedCrossRefGoogle Scholar
  40. Ganz T (2004) Antimicrobial polypeptides. J Leukoc Biol 75:34–38PubMedCrossRefGoogle Scholar
  41. 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
  42. Garcia JR, Jaumann F, Schulz S, Krause A, Rodriguez-Jimenez J, Forssmann U, Adermann K, Kluver E, Vogelmeier C, Becker D, Hedrich R, Forssmann WG, Bals R (2001) Identification of a novel, multifunctional beta-defensin (human beta-defensin 3) with specific antimicrobial activity. Its interaction with plasma membranes of Xenopus oocytes and the induction of macrophage chemoattraction. Cell Tissue Res 306:257–264PubMedCrossRefGoogle Scholar
  43. Garcia JR, Krause A, Schulz S, Rodriguez-Jimenez FJ, Kluver E, Adermann K, Forssmann U, Frimpong-Boateng A, Bals R, Forssmann WG (2001) Human beta-defensin 4: a novel inducible peptide with a specific salt-sensitive spectrum of antimicrobial activity. FASEB J 15:1819–1821PubMedGoogle Scholar
  44. Gasior-Chrzan B, Bostad L, Falk ES (1994) An immunohistochemical study of lysozyme in the skin of psoriatic patients. Acta Derm Venereol 74:344–346PubMedGoogle Scholar
  45. Gearing AJ, Fincham NJ, Bird CR, Wadhwa M, Meager A, Cartwright JE, Camp RD (1990) Cytokines in skin lesions of psoriasis. Cytokine 2:68–75PubMedCrossRefGoogle Scholar
  46. Ghosh D, Porter E, Shen B, Lee SK, Wilk D, Drazba J, Yadav SP, Crabb JW, Ganz T, Bevins CL (2002) Paneth cell trypsin is the processing enzyme for human defensin-5. Nat Immunol 3:583–590PubMedCrossRefGoogle Scholar
  47. Gläser R, Harder J, Lange H, Bartels J, Christophers E, Schröder JM (2005) Antimicrobial psoriasin (S100A7) protects human skin from Escherichia coli infection. Nat Immunol 6:57–64PubMedCrossRefGoogle Scholar
  48. Goetz DH, Holmes MA, Borregaard N, Bluhm ME, Raymond KN, Strong RK (2002) The neutrophil lipocalin NGAL is a bacteriostatic agent that interferes with siderophore-mediated iron acquisition. Mol Cell 10:1033–1043PubMedCrossRefGoogle Scholar
  49. Gombart AF, Borregaard N, Koeffler HP (2005) Human cathelicidin antimicrobial peptide (CAMP) gene is a direct target of the vitamin D receptor and is strongly up-regulated in myeloid cells by 1, 25-dihydroxyvitamin D3. FASEB J 19:1067–1077PubMedCrossRefGoogle Scholar
  50. Gottsch JD, Eisinger SW, Liu SH, Scott AL (1999) Calgranulin C has filariacidal and filariastatic activity. Infect Immun 67:6631–6636PubMedGoogle Scholar
  51. Gudmundsson GH, Agerberth B, Odeberg J, Bergman T, Olsson B, Salcedo R (1996) The human gene FALL39 and processing of the cathelin precursor to the antibacterial peptide LL-37 in granulocytes. Eur J Biochem 238:325–332PubMedCrossRefGoogle Scholar
  52. Guggino WB (2001) Cystic fibrosis salt/fluid controversy: in the thick of it. Nat Med 7:888–889PubMedCrossRefGoogle Scholar
  53. Harder J, Bartels J, Christophers E, Schröder JM (1997) A peptide antibiotic from human skin. Nature 387:861PubMedCrossRefGoogle Scholar
  54. Harder J, Bartels J, Christophers E, Schröder JM (2001) Isolation and characterization of human beta -defensin-3, a novel human inducible peptide antibiotic. J Biol Chem 276:5707–5713PubMedCrossRefGoogle Scholar
  55. Harder J, Meyer-Hoffert U, Teran LM, Schwichtenberg L, Bartels J, Maune S, Schröder JM (2000) Mucoid Pseudomonas aeruginosa, TNF-alpha, and IL-1beta, but not IL-6, induce human beta-defensin-2 in respiratory epithelia. Am J Respir Cell Mol Biol 22:714–721PubMedGoogle Scholar
  56. Harder J, Meyer-Hoffert U, Wehkamp K, Schwichtenberg L, Schröder JM (2004) Differential gene induction of human beta-defensins (hBD-1, -2, -3, and -4) in keratinocytes is inhibited by retinoic acid. J Invest Dermatol 123:522–529PubMedCrossRefGoogle Scholar
  57. Harder J, Schröder JM (2002) RNase 7, a novel innate immune defense antimicrobial protein of healthy human skin. J Biol Chem 277:46779–46784PubMedCrossRefGoogle Scholar
  58. Harder J, Schröder JM (2005) Psoriatic scales: a promising source for the isolation of human skin-derived antimicrobial proteins. J Leukoc Biol 77:476–486PubMedCrossRefGoogle Scholar
  59. 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 120:379–389PubMedCrossRefGoogle Scholar
  60. Heizmann CW, Fritz G, Schafer BW (2002) S100 proteins: structure, functions and pathology. Front Biosci 7:d1356–d1368PubMedCrossRefGoogle Scholar
  61. Helmerhorst EJ, Van’t Hof W, Veerman EC, Simoons-Smit I, Nieuw Amerongen AV (1997) Synthetic histatin analogues with broad-spectrum antimicrobial activity. Biochem J 326:39–45PubMedGoogle Scholar
  62. Henseler T, Christophers E (1995) Disease concomitance in psoriasis. J Am Acad Dermatol 32:982–986PubMedCrossRefGoogle Scholar
  63. Hoover DM, Wu Z, Tucker K, Lu W, Lubkowski J (2003) Antimicrobial characterization of human beta-defensin 3 derivatives. Antimicrob Agents Chemother 47:2804–2809PubMedCrossRefGoogle Scholar
  64. Howell MD, Boguniewicz M, Pastore S, Novak N, Bieber T, Girolomoni G, Leung DY (2006) Mechanism of HBD-3 deficiency in atopic dermatitis. Clin Immunol 121:332–338PubMedCrossRefGoogle Scholar
  65. Huang GT, Zhang HB, Kim D, Liu L, Ganz T (2002) A model for antimicrobial gene therapy: demonstration of human beta-defensin 2 antimicrobial activities in vivo. Hum Gene Ther 13:2017–2025PubMedCrossRefGoogle Scholar
  66. Huh WK, Oono T, Shirafuji Y, Akiyama H, Arata J, Sakaguchi M, Huh NH, Iwatsuki K (2002) Dynamic alteration of human beta-defensin 2 localization from cytoplasm to intercellular space in psoriatic skin. J Mol Med 80:678–684PubMedCrossRefGoogle Scholar
  67. Jainkittivong A, Johnson DA, Yeh CK (1998) The relationship between salivary histatin levels and oral yeast carriage. Oral Microbiol Immunol 13:181–187PubMedCrossRefGoogle Scholar
  68. Jia HP, Schutte BC, Schudy A, Linzmeier R, Guthmiller JM, Johnson GK, Tack BF, Mitros JP, Rosenthal A, Ganz T, McCray PB Jr (2001) Discovery of new human beta-defensins using a genomics-based approach. Gene 263:211–218PubMedCrossRefGoogle Scholar
  69. Johansson J, Gudmundsson GH, Rottenberg ME, Berndt KD, Agerberth B (1998) Conformation-dependent antibacterial activity of the naturally occurring human peptide LL-37. J Biol Chem 273:3718–3724PubMedCrossRefGoogle Scholar
  70. Kao CY, Chen Y, Thai P, Wachi S, Huang F, Kim C, Harper RW, Wu R (2004) IL-17 markedly up-regulates beta-defensin-2 expression in human airway epithelium via JAK and NF-kappaB signaling pathways. J Immunol 173:3482–3491PubMedGoogle Scholar
  71. Kapas S, Bansal A, Bhargava V, Maher R, Malli D, Hagi-Pavli E, Allaker RP (2001) Adrenomedullin expression in pathogen-challenged oral epithelial cells. Peptides 22:1485–1489PubMedCrossRefGoogle Scholar
  72. Kavanagh K, Dowd S (2004) Histatins: antimicrobial peptides with therapeutic potential. J Pharm Pharmacol 56:285–289PubMedCrossRefGoogle Scholar
  73. Kawai M, Yamazaki M, Tsuboi R, Miyajima H, Ogawa H (2006) Human beta-defensin-2, an antimicrobial peptide, is elevated in scales collected from tinea pedis patients. Int J Dermatol 45:1389–1390PubMedCrossRefGoogle Scholar
  74. Kern RA, Kingkade MJ, Kern SF, Behrens OK (1951) Characterization of the action of lysozyme on Staphylococcus aureus and on Micrococcus lysodeikticus. J Bacteriol 61:171–178PubMedGoogle Scholar
  75. Kjeldsen L, Bainton DF, Sengelov H, Borregaard N (1994) Identification of neutrophil gelatinase-associated lipocalin as a novel matrix protein of specific granules in human neutrophils. Blood 83:799–807PubMedGoogle Scholar
  76. Kjeldsen L, Johnsen AH, Sengelov H, Borregaard N (1993) Isolation and primary structure of NGAL, a novel protein associated with human neutrophil gelatinase. J Biol Chem 268:10425–10432PubMedGoogle Scholar
  77. Klenha J, Krs V (1967) Lysozyme in mouse and human skin. J Invest Dermatol 49:396–399PubMedGoogle Scholar
  78. Lee KC, Eckert RL (2007) S100A7 (Psoriasin) – mechanism of antibacterial action in wounds. J Invest Dermatol 127:945–957PubMedCrossRefGoogle Scholar
  79. Lehrer RI, Szklarek D, Barton A, Ganz T, Hamann KJ, Gleich GJ (1989) Antibacterial properties of eosinophil major basic protein and eosinophil cationic protein. J Immunol 142:4428–4434PubMedGoogle Scholar
  80. Li X, Leeuw E de, Lu W (2005) Total chemical synthesis of human psoriasin by native chemical ligation. Biochemistry 44:14688–14694PubMedCrossRefGoogle Scholar
  81. Liang SC, Tan XY, Luxenberg DP, Karim R, Dunussi-Joannopoulos K, Collins M, Fouser LA (2006) Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J Exp Med 203:2271–2279PubMedCrossRefGoogle Scholar
  82. Liu AY, Destoumieux D, Wong AV, Park CH, Valore EV, Liu L, Ganz T (2002) Human beta-defensin-2 production in keratinocytes is regulated by interleukin-1, bacteria, and the state of differentiation. J Invest Dermatol 118:275–281PubMedCrossRefGoogle Scholar
  83. Liu L, Wang L, Jia HP, Zhao C, Heng HH, Schutte BC, McCray PB Jr, Ganz T (1998) Structure and mapping of the human beta-defensin HBD-2 gene and its expression at sites of inflammation. Gene 222:237–244PubMedCrossRefGoogle Scholar
  84. Mackewicz CE, Yuan J, Tran P, Diaz L, Mack E, Selsted ME, Levy JA (2003) alpha-Defensins can have anti-HIV activity but are not CD8 cell anti-HIV factors. Aids 17:F23–F32PubMedCrossRefGoogle Scholar
  85. Madsen P, Rasmussen HH, Leffers H, Honore B, Dejgaard K, Olsen E, Kiil J, Walbum E, Andersen AH, Basse B, et al (1991) Molecular cloning, occurrence, and expression of a novel partially secreted protein “psoriasin” that is highly up-regulated in psoriatic skin. J Invest Dermatol 97:701–712PubMedCrossRefGoogle Scholar
  86. Maisetta G, Batoni G, Esin S, Luperini F, Pardini M, Bottai D, Florio W, Giuca MR, Gabriele M, Campa M (2003) Activity of human beta-defensin 3 alone or combined with other antimicrobial agents against oral bacteria. Antimicrob Agents Chemother 47:3349–3351PubMedCrossRefGoogle Scholar
  87. Mallbris L, O’Brien KP, Hulthen A, Sandstedt B, Cowland JB, Borregaard N, Stahle-Backdahl M (2002) Neutrophil gelatinase-associated lipocalin is a marker for dysregulated keratinocyte differentiation in human skin. Exp Dermatol 11:584–591PubMedCrossRefGoogle Scholar
  88. Martin E, Ganz T, Lehrer RI (1995) Defensins and other endogenous peptide antibiotics of vertebrates. J Leukoc Biol 58:128–136PubMedGoogle Scholar
  89. Martinez A, Elsasser TH, Muro-Cacho C, Moody TW, Miller MJ, Macri CJ, Cuttitta F (1997) Expression of adrenomedullin and its receptor in normal and malignant human skin: a potential pluripotent role in the integument. Endocrinology 138:5597–5604PubMedCrossRefGoogle Scholar
  90. Mempel M, Voelcker V, Kollisch G, Plank C, Rad R, Gerhard M, Schnopp C, Fraunberger P, Walli AK, Ring J, Abeck D, Ollert M (2003) Toll-like receptor expression in human keratinocytes: nuclear factor kappaB controlled gene activation by Staphylococcus aureus is toll-like receptor 2 but not toll-like receptor 4 or platelet activating factor receptor dependent. J Invest Dermatol 121:1389–1396PubMedCrossRefGoogle Scholar
  91. Meyer-Hoffert U, Wichmann N, Schwichtenberg L, White PC, Wiedow O (2003) Supernatants of Pseudomonas aeruginosa induce the Pseudomonas-specific antibiotic elafin in human keratinocytes. Exp Dermatol 12:418–425PubMedCrossRefGoogle Scholar
  92. Midorikawa K, Ouhara K, Komatsuzawa H, Kawai T, Yamada S, Fujiwara T, Yamazaki K, Sayama K, Taubman MA, Kurihara H, Hashimoto K, Sugai M (2003) Staphylococcus aureus susceptibility to innate antimicrobial peptides, beta-defensins and CAP18, expressed by human keratinocytes. Infect Immun 71:3730–3739PubMedCrossRefGoogle Scholar
  93. Murakami M, Lopez-Garcia B, Braff M, Dorschner RA, Gallo RL (2004) Postsecretory processing generates multiple cathelicidins for enhanced topical antimicrobial defense. J Immunol 172:3070–3077PubMedGoogle Scholar
  94. Murakami M, Ohtake T, Dorschner RA, Schittek B, Garbe C, Gallo RL (2002) Cathelicidin anti-microbial peptide expression in sweat, an innate defense system for the skin. J Invest Dermatol 119:1090–1095PubMedCrossRefGoogle Scholar
  95. Murthy AR, Lehrer RI, Harwig SS, Miyasaki KT (1993) In vitro candidastatic properties of the human neutrophil calprotectin complex. J Immunol 151:6291–6301PubMedGoogle Scholar
  96. 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 from mast cells. Eur J Immunol 31:1066–1075PubMedCrossRefGoogle Scholar
  97. Niyonsaba F, Iwabuchi K, Someya A, Hirata M, Matsuda H, Ogawa H, Nagaoka I (2002) A cathelicidin family of human antibacterial peptide LL-37 induces mast cell chemotaxis. Immunology 106:20–26PubMedCrossRefGoogle Scholar
  98. Niyonsaba F, Ushio H, Nakano N, Ng W, Sayama K, Hashimoto K, Nagaoka I, Okumura K, Ogawa H (2007) Antimicrobial peptides human beta-defensins stimulate epidermal keratinocyte migration, proliferation and production of proinflammatory cytokines and chemokines. J Invest Dermatol 127:594–604PubMedCrossRefGoogle Scholar
  99. 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 414:454–457PubMedCrossRefGoogle Scholar
  100. Noble WC (1992) Other cutaneous bacteria. The skin microflora and microbial disease. Cambridge University Press, CambridgeGoogle Scholar
  101. 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 171:3262–3269PubMedGoogle Scholar
  102. Ogawa H, Miyazaki H, Kimura M (1971) Isolation and characterization of human skin lysozyme. J Invest Dermatol 57:111–116PubMedCrossRefGoogle Scholar
  103. 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 347:1151–1160PubMedCrossRefGoogle Scholar
  104. Oono T, Huh WK, Shirafuji Y, Akiyama H, Iwatsuki K (2003) Localization of human beta-defensin-2 and human neutrophil peptides in superficial folliculitis. Br J Dermatol 148:188–191PubMedCrossRefGoogle Scholar
  105. 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
  106. Ortega MR, Ganz T, Milner SM (2000) Human beta defensin is absent in burn blister fluid. Burns 26:724–726PubMedCrossRefGoogle Scholar
  107. Ouellette AJ (1997) Paneth cells and innate immunity in the crypt microenvironment. Gastroenterology 113:1779–1784PubMedCrossRefGoogle Scholar
  108. Papini M, Simonetti S, Franceschini S, Scaringi L, Binazzi M (1982) Lysozyme distribution in healthy human skin. Arch Dermatol Res 272:167–170PubMedCrossRefGoogle Scholar
  109. Pernet I, Reymermier C, Guezennec A, Branka JE, Guesnet J, Perrier E, Dezutter-Dambuyant C, Schmitt D, Viac J (2003) Calcium triggers beta-defensin (hBD-2 and hBD-3) and chemokine macrophage inflammatory protein-3 alpha (MIP-3alpha/CCL20) expression in monolayers of activated human keratinocytes. Exp Dermatol 12:755–760PubMedCrossRefGoogle Scholar
  110. Pfundt R, Wingens M, Bergers M, Zweers M, Frenken M, Schalkwijk J (2000) TNF-alpha and serum induce SKALP/elafin gene expression in human keratinocytes by a p38 MAP kinase-dependent pathway. Arch Dermatol Res 292:180–187PubMedCrossRefGoogle Scholar
  111. Podolsky DK (2002) Inflammatory bowel disease. N Engl J Med 347:417–429PubMedCrossRefGoogle Scholar
  112. Putsep 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
  113. Ritonja A, Kopitar M, Jerala R, Turk V (1989) Primary structure of a new cysteine proteinase inhibitor from pig leucocytes. FEBS Lett 255:211–214PubMedCrossRefGoogle Scholar
  114. Rudolph B, Podschun R, Sahly H, Schubert S, Schröder JM, Harder J (2006) Identification of RNase 8 as a novel human antimicrobial protein. Antimicrob Agents Chemother 50:3194–3196PubMedCrossRefGoogle Scholar
  115. Sahly H, Schubert S, Harder J, Rautenberg P, Ullmann U, Schroder J, Podschun R (2003) Burkholderia is highly resistant to human Beta-defensin 3. Antimicrob Agents Chemother 47:1739–1741PubMedCrossRefGoogle Scholar
  116. Salzman NH, Ghosh D, Huttner KM, Paterson Y, Bevins CL (2003) Protection against enteric salmonellosis in transgenic mice expressing a human intestinal defensin. Nature 422:522–526PubMedCrossRefGoogle Scholar
  117. Schittek B, Hipfel R, Sauer B, Bauer J, Kalbacher H, Stevanovic S, Schirle M, Schroeder K, Blin N, Meier F, Rassner G, Garbe C (2001) Dermcidin: a novel human antibiotic peptide secreted by sweat glands. Nat Immunol 2:1133–1137PubMedCrossRefGoogle Scholar
  118. Schmid M, Fellermann K, Fritz P, Wiedow O, Stange EF, Wehkamp J (2007) Attenuated induction of epithelial and leukocyte serine antiproteases elafin and secretory leukocyte protease inhibitor in Crohn’s disease. J Leukoc Biol 81:907–915PubMedCrossRefGoogle Scholar
  119. Schröder JM, Harder J (1999) Human beta-defensin-2. Int J Biochem Cell Biol 31:645–651PubMedCrossRefGoogle Scholar
  120. Shaykhiev R, Beisswenger C, Kandler K, Senske J, Puchner A, Damm T, Behr J, Bals R (2005) Human endogenous antibiotic LL-37 stimulates airway epithelial cell proliferation and wound closure. Am J Physiol Lung Cell Mol Physiol 289:L842–L848PubMedCrossRefGoogle Scholar
  121. Simpson AJ, Maxwell AI, Govan JR, Haslett C, Sallenave JM (1999) Elafin (elastase-specific inhibitor) has anti-microbial activity against gram-positive and gram-negative respiratory pathogens. FEBS Lett 452:309–313PubMedCrossRefGoogle Scholar
  122. 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
  123. 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 USA 95:14961–14966PubMedCrossRefGoogle Scholar
  124. Smith JJ, Travis SM, Greenberg EP, Welsh MJ (1996) Cystic fibrosis airway epithelia fail to kill bacteria because of abnormal airway surface fluid. Cell 85:229–236PubMedCrossRefGoogle Scholar
  125. Soferman R (2006) Immunopathophysiologic mechanisms of cystic fibrosis lung disease. Isr Med Assoc J 8:44–48PubMedGoogle Scholar
  126. Sohnle PG, Hunter MJ, Hahn B, Chazin WJ (2000) Zinc-reversible antimicrobial activity of recombinant calprotectin (migration inhibitory factor-related proteins 8 and 14). J Infect Dis 182:1272–1275PubMedCrossRefGoogle Scholar
  127. Sorensen OE, Cowland JB, Theilgaard-Monch K, Liu L, Ganz T, Borregaard N (2003) Wound healing and expression of antimicrobial peptides/polypeptides in human keratinocytes, a consequence of common growth factors. J Immunol 170:5583–5589PubMedGoogle Scholar
  128. 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 97:3951–3959PubMedCrossRefGoogle Scholar
  129. Sorensen OE, Thapa DR, Roupe KM, Valore EV, Sjobring U, Roberts AA, Schmidtchen A, Ganz T (2006) Injury-induced innate immune response in human skin mediated by transactivation of the epidermal growth factor receptor. J Clin Invest 116:1878–1885PubMedCrossRefGoogle Scholar
  130. Taggart CC, Greene CM, Smith SG, Levine RL, McCray PB Jr, O’Neill S, McElvaney NG (2003) Inactivation of human beta-defensins 2 and 3 by elastolytic cathepsins. J Immunol 171:931–937PubMedGoogle Scholar
  131. Tomita T, Hitomi S, Nagase T, Matsui H, Matsuse T, Kimura S, Ouchi Y (2000) Effect of ions on antibacterial activity of human beta defensin 2. Microbiol Immunol 44:749–754PubMedGoogle Scholar
  132. 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 42:2206–2214PubMedGoogle Scholar
  133. 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
  134. 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 273:33115–33118PubMedCrossRefGoogle Scholar
  135. Wehkamp J, Harder J, Wehkamp K, Wehkamp-von Meissner B, Schlee M, Enders C, Sonnenborn U, Nuding S, Bengmark S, Fellermann K, Schröder JM, Stange EF (2004) 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 72:5750–5758PubMedCrossRefGoogle Scholar
  136. Wehkamp J, Harder J, Weichenthal M, Mueller O, Herrlinger KR, Fellermann K, Schröder JM, Stange EF (2003) Inducible and constitutive beta-defensins are differentially expressed in Crohn’s disease and ulcerative colitis. Inflamm Bowel Dis 9:215–223PubMedCrossRefGoogle Scholar
  137. Wehkamp J, Harder J, Weichenthal M, Schwab M, Schaffeler E, Schlee M, Herrlinger KR, Stallmach A, Noack F, Fritz P, Schröder JM, Bevins CL, Fellermann K, Stange EF (2004) NOD2 (CARD15) mutations in Crohn’s disease are associated with diminished mucosal alpha-defensin expression. Gut 53:1658–1664PubMedCrossRefGoogle Scholar
  138. Wehkamp J, Salzman NH, Porter E, Nuding S, Weichenthal M, Petras RE, Shen B, Schaeffeler E, Schwab M, Linzmeier R, Feathers RW, Chu H, Lima H Jr, Fellermann K, Ganz T, Stange EF, Bevins CL (2005) Reduced Paneth cell alpha-defensins in ileal Crohn’s disease. Proc Natl Acad Sci USA 102:18129–18134PubMedCrossRefGoogle Scholar
  139. Wehkamp J, Schwind B, Herrlinger KR, Baxmann S, Schmidt K, Duchrow M, Wohlschlager C, Feller AC, Stange EF, Fellermann K (2002) Innate immunity and colonic inflammation: enhanced expression of epithelial alpha-defensins. Dig Dis Sci 47:1349–1355PubMedCrossRefGoogle Scholar
  140. Weinberg A, Krisanaprakornkit S, Dale BA (1998) Epithelial antimicrobial peptides: review and significance for oral applications. Crit Rev Oral Biol Med 9:399–414PubMedCrossRefGoogle Scholar
  141. Weinberg ED (2001) Human lactoferrin: a novel therapeutic with broad spectrum potential. J Pharm Pharmacol 53:1303–1310PubMedCrossRefGoogle Scholar
  142. Wiedow O, Harder J, Bartels J, Streit V, Christophers E (1998) Antileukoprotease in human skin: an antibiotic peptide constitutively produced by keratinocytes. Biochem Biophys Res Commun 248:904–909PubMedCrossRefGoogle Scholar
  143. Wiedow O, Schröder JM, Gregory H, Young JA, Christophers E (1990) Elafin: an elastase-specific inhibitor of human skin. Purification, characterization, and complete amino acid sequence. J Biol Chem 265:14791–14795PubMedGoogle Scholar
  144. Wilde CG, Griffith JE, Marra MN, Snable JL, Scott RW (1989) Purification and characterization of human neutrophil peptide 4, a novel member of the defensin family. J Biol Chem 264:11200–11203PubMedGoogle Scholar
  145. Wingens M, Bergen BH van, Hiemstra PS, Meis JF, Vlijmen-Willems IM van, Zeeuwen PL, Mulder J, Kramps HA, Ruissen F van, Schalkwijk J (1998) Induction of SLPI (ALP/HUSI-I) in epidermal keratinocytes. J Invest Dermatol 111:996–1002PubMedCrossRefGoogle Scholar
  146. Wolk K, Kunz S, Witte E, Friedrich M, Asadullah K, Sabat R (2004) IL-22 increases the innate immunity of tissues. Immunity 21:241–254PubMedCrossRefGoogle Scholar
  147. Wu Z, Hoover DM, Yang D, Boulegue C, Santamaria F, Oppenheim JJ, Lubkowski J, Lu W (2003) Engineering disulfide bridges to dissect antimicrobial and chemotactic activities of human beta-defensin 3. Proc Natl Acad Sci USA 100:8880–8885PubMedCrossRefGoogle Scholar
  148. 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 286:525–528PubMedCrossRefGoogle Scholar
  149. Zaiou M, Nizet V, Gallo RL (2003) Antimicrobial and protease inhibitory functions of the human cathelicidin (hCAP18/LL-37) prosequence. J Invest Dermatol 120:810–816PubMedCrossRefGoogle Scholar
  150. Zasloff M (1987) Magainins, a class of antimicrobial peptides from Xenopus skin: isolation, characterization of two active forms, and partial cDNA sequence of a precursor. Proc Natl Acad Sci USA 84:5449–5453PubMedCrossRefGoogle Scholar
  151. Zhang J, Dyer KD, Rosenberg HF (2002) RNase 8, a novel RNase A superfamily ribonuclease expressed uniquely in placenta. Nucleic Acids Res 30:1169–1175PubMedCrossRefGoogle Scholar
  152. Zhang L, Yu W, He T, Yu J, Caffrey RE, Dalmasso EA, Fu S, Pham T, Mei J, Ho JJ, Zhang W, Lopez P, Ho DD (2002) Contribution of human alpha-defensin 1, 2, and 3 to the anti-HIV-1 activity of CD8 antiviral factor. Science 298:995–1000PubMedCrossRefGoogle Scholar
  153. Zheng Y, Danilenko DM, Valdez P, Kasman I, Eastham-Anderson J, Wu J, Ouyang W (2006) Interleukin-22, a T(H) 17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature 445: 648–651PubMedCrossRefGoogle Scholar
  154. Zucht HD, Grabowsky J, Schrader M, Liepke C, Jurgens M, Schulz-Knappe P, Forssmann WG (1998) Human beta-defensin-1: a urinary peptide present in variant molecular forms and its putative functional implication. Eur J Med Res 3:315–323PubMedGoogle Scholar
  155. Zudaire E, Martinez A, Cuttitta F (2003) Adrenomedullin and cancer. Regul Pept 112:175–183PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2008

Authors and Affiliations

  • Regine Gläser
    • 1
  • Jürgen Harder
    • 1
  • Jens-Michael Schröder
    • 1
  1. 1.Department of Dermatology, Venerology and Allergology, Clinical Research UnitUniversity Hospital Schleswig-Holstein, Campus KielKielGermany

Personalised recommendations