Journal of Molecular Medicine

, Volume 85, Issue 4, pp 317–329 | Cite as

Multifunctional antimicrobial peptides: therapeutic targets in several human diseases

  • Mohamed ZaiouEmail author


Antimicrobial peptides have emerged as promising agents against antibiotic-resistant pathogens. They represent essential components of the innate immunity and permit humans to resist infection by microbes. These gene-encoded peptides are found mainly in phagocytes and epithelial cells, showing a direct activity against a wide range of microorganisms. Their role has now broadened from that of simply endogenous antibiotics to multifunctional mediators, and their antimicrobial activity is probably not the only primary function. Although antimicrobial peptide deficiency, dysregulation, or overproduction is not known to be a direct cause of any single human disease, numerous studies have now provided compelling evidence for their involvement in the complex network of immune responses and inflammatory diseases, thereby influencing diverse processes including cytokine release, chemotaxis, angiogenesis, wound repair, and adaptive immune induction. The purpose of this review is to highlight recent literature, showing that antimicrobial peptides are associated with several human conditions including infectious and inflammatory diseases, and to discuss current clinical development of peptide-based therapeutics for future use.


Antimicrobial peptides Inflammatory diseases Innate immune system Infection Host defense 


  1. 1.
    Zasloff M (2002) Antimicrobial peptides of multicellular organisms. Nature 415:389–395PubMedCrossRefGoogle Scholar
  2. 2.
    Brogden KA (2005) Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria? Nat Rev Microbiol 3:238–250PubMedCrossRefGoogle Scholar
  3. 3.
    Zaiou M, Gallo RL (2002) Cathelicidins, essential gene-encoded mammalian antibiotics. J Mol Med 80:549–561PubMedCrossRefGoogle Scholar
  4. 4.
    Hancock REW, Diamond G (2000) The role of cationic antimicrobial peptides in innate host defences. Trends Microbiol 8:402–410PubMedCrossRefGoogle Scholar
  5. 5.
    Bulet P, Stocklin R, Menin L (2004) Anti-microbial peptides: from invertebrates to vertebrates. Immunol Rev 198:169–184PubMedCrossRefGoogle Scholar
  6. 6.
    Gantz T (1999) Defensins and host defense. Science 286:420–421CrossRefGoogle Scholar
  7. 7.
    Boman HG (2000) Innate immunity and the normal microflora. Immunol Rev 173:5–16PubMedCrossRefGoogle Scholar
  8. 8.
    Gennaro R, Zanetti M (2000) Structural features and biological activities of the cathelicidin-derived antimicrobial peptides. Biopolymers 55:31–49PubMedCrossRefGoogle Scholar
  9. 9.
    Bardan A, Nizet V, Gallo RL (2004) Antimicrobial peptides and the skin. Expert Opin Biol Ther 4:543–549PubMedCrossRefGoogle Scholar
  10. 10.
    Bevins CL (2006) Paneth cell defensins: key effector molecules of innate immunity. Biochem Soc Trans 34:263–266PubMedCrossRefGoogle Scholar
  11. 11.
    Zhang L, Falla TJ (2006) Antimicrobial peptides: therapeutic potential. Expert Opin Pharmacother 7:653–663PubMedCrossRefGoogle Scholar
  12. 12.
    Epand RM, Vogel HJ (1999) Diversity of antimicrobial peptides and their mechanisms of action. Biochim Biophys Acta 1462:11–28PubMedCrossRefGoogle Scholar
  13. 13.
    Friedrich CL, Moyles D, Beveridge TJ, Hancock REW (2000) Antibacterial action of structurally diverse cationic peptides on gram-positive bacteria. Antimicrob Agents Chemother 44:2086–2092PubMedCrossRefGoogle Scholar
  14. 14.
    Cudic M, Otvos L Jr (2002) Intracellular targets of antibacterial peptides. Curr Drug Targets 3:101–106PubMedCrossRefGoogle Scholar
  15. 15.
    Park CB, Kim HS, Kim SC (1998) Mechanism of action of the antimicrobial peptide buforin II: buforin II kills microorganisms by penetrating the cell membrane and inhibiting cellular functions. Biochem Biophys Res Commun 244:253–257PubMedCrossRefGoogle Scholar
  16. 16.
    Carlsson A, Nystrom T, de Cock H, Bennich H (1998) Attacin—an insect immune protein—binds LPS and triggers the specific inhibition of bacterial outer-membrane protein synthesis. Microbiology 144:2179–2188PubMedCrossRefGoogle Scholar
  17. 17.
    Boman HG, Agerberth B, Boman A (1993) Mechanisms of action on Escherichia coli of cecropin P1 and PR-39, two antibacterial peptides from pig intestine. Infect Immun 61:2978–2984PubMedGoogle Scholar
  18. 18.
    Otvos L Jr, Insug O, Rogers ME, Consolvo PJ, Condie BA, Lovas S, Bulet P, Blaszczyk-Thurin M (2000) Interaction between heat shock proteins and antimicrobial peptides. Biochemistry 39:14150–14159PubMedCrossRefGoogle Scholar
  19. 19.
    Leikina E, Delanoe-Ayari H, Melikov K, Cho MS, Chen A, Waring AJ, Wang W, Xie Y, Loo JA, Lehrer RI, Chernomordik LV (2005) Carbohydrate-binding molecules inhibit viral fusion and entry by crosslinking membrane glycoproteins. Nat Immunol 6:995–1001PubMedCrossRefGoogle Scholar
  20. 20.
    Rosenfeld Y, Papo N, Shai Y (2006) Endotoxin (lipopolysaccharide) neutralization by innate immunity host-defense peptides. Peptide properties and plausible modes of action. J Biol Chem 281:1636–1643PubMedCrossRefGoogle Scholar
  21. 21.
    Hoover DM, Boulegue C, Yang D, Oppenheim JJ, Tucker KD, Lu W, Lubkowski J (2002) The structure of human MIP-3/CCL20: linking antimicrobial and CCR6 receptor binding activities with human β-defensins. J Biol Chem 277:37647–37654PubMedCrossRefGoogle Scholar
  22. 22.
    Yang D, Biragyn A, Kwak LW, Oppenheim JJ (2002) Mammalian defensins in immunity: more than just microbicidal. Trends Immunol 23:291–296PubMedCrossRefGoogle Scholar
  23. 23.
    Bals R, Wilson JM (2003) Cathelicidins-a family of multifunctional antimicrobial peptides. Cell Mol Life Sci 60:711–720PubMedCrossRefGoogle Scholar
  24. 24.
    Fernandez Guerrero ML, Ramos JM, Marrero J, Cuenca M, Fernandez Roblas R, de Gorgolas M (2003) Bacteremic pneumococcal infections in immunocompromised patients without AIDS: the impact of beta-lactam resistance on mortality. Int J Infect Dis 7:46–52PubMedCrossRefGoogle Scholar
  25. 25.
    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 82:552–556PubMedGoogle Scholar
  26. 26.
    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
  27. 27.
    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
  28. 28.
    Scott MS, Davidson DJ, Gold MR, Bowdish D, Hancock REW (2002) The human antimicrobial peptide LL-37 is a multifunctional modulator of innate immune responses. J Immunol 169:3883–3891PubMedGoogle Scholar
  29. 29.
    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 169:187–194PubMedCrossRefGoogle Scholar
  30. 30.
    Moser C, Weiner DJ, Lysenko E, Bals R, Weiser JN, Wilson JM (2002) β-Defensin 1 contributes to pulmonary innate immunity in mice. Infect Immun 70:3068–3072PubMedCrossRefGoogle Scholar
  31. 31.
    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
  32. 32.
    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
  33. 33.
    Goldstein BP, Wei J, Greenberg K, Novick RJ (1998) Activity of nisin against Streptococcus pneumoniae, in vitro, and in a mouse infection model. Antimicrob Chemother 42:277–278CrossRefGoogle Scholar
  34. 34.
    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
  35. 35.
    Mygind PH, Fischer RL, Schnorr KM, Hansen MT, Sonksen CP, Ludvigsen S, Raventos D, Buskov S, Christensen B, De Maria L, Taboureau O, Yaver D, Elvig-Jorgensen SG, Sorensen MV, Christensen BE, Kjaerulff S, Frimodt-Moller N, Lehrer RI, Zasloff M, Kristensen HH (2005) Plectasin is a peptide antibiotic with therapeutic potential from a saprophytic fungus. Nature 437:975–980PubMedCrossRefGoogle Scholar
  36. 36.
    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
  37. 37.
    Braff MH, Zaiou M, Fierer J, Nizet V, Gallo RL (2005) Keratinocyte production of cathelicidin provides direct activity against bacterial skin pathogens. Infect Immun 73:6771–6781PubMedCrossRefGoogle Scholar
  38. 38.
    Carretero M, Del Rio M, Garcia M, Escamez MJ, Mirones I, Rivas L, Balague C, Jorcano JL, Larcher F (2004) A cutaneous gene therapy approach to treat infection through keratinocyte-targeted overexpression of antimicrobial peptides. FASEB J 18:1931–1933PubMedGoogle Scholar
  39. 39.
    Jacobsen F, Mittler D, Hirsch T, Gerhards A, Lehnhardt M, Voss B, Steinau HU, Steinstraesser L (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
  40. 40.
    Peschel A (2002) How do bacteria resist human antimicrobial peptides? Trends Microbiol 10:179–186PubMedCrossRefGoogle Scholar
  41. 41.
    Peschel A, Sahl HG (2006) The co-evolution of host cationic antimicrobial peptides and microbial resistance. Nat Rev Microbiol 4:529–536PubMedCrossRefGoogle Scholar
  42. 42.
    Cole AM, Hong T, Boo LM, Nguyen T, Zhao C, Bristol G, Zack JA, Waring AJ, Yang OO, Lehrer RI (2002) Retrocyclin: a primate peptide that protects cells from infection by T- and M-tropic strains of HIV-1. Proc Natl Acad Sci USA 99:1813–1818PubMedCrossRefGoogle Scholar
  43. 43.
    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
  44. 44.
    Wang W, Owen SM, Rudolph DL, Cole AM, Hong T, Waring AJ, Lal RB, Lehrer RI (2004) Activity of alpha- and theta-defensins against primary isolates of HIV-1. J Immunol 173:515–520PubMedGoogle Scholar
  45. 45.
    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 323:437–444PubMedCrossRefGoogle Scholar
  46. 46.
    Buck CB, Day PM, Thompson CD, Lubkowski J, Lu W, Lowy DR, Schiller JT (2006) Human alpha-defensins block papillomavirus infection. Proc Natl Acad Sci USA 103:1516–1521PubMedCrossRefGoogle Scholar
  47. 47.
    Braida L, Boniotto M, Pontillo A, Tovo PA, Amoroso A, Crovella S (2004) A single-nucleotide polymorphism in the human beta-defensin 1 gene is associated with HIV-1 infection in Italian children. AIDS 18:1598–1600PubMedCrossRefGoogle Scholar
  48. 48.
    Steinstraesser L, Tippler B, Mertens J, Lamme E, Homann HH, Lehnhardt M, Wildner O, Steinau HU, Uberla K (2005) Inhibition of early steps in the lentiviral replication cycle by cathelicidin host defense peptides. Retrovirology 2:2PubMedCrossRefGoogle Scholar
  49. 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. 50.
    Lorin C, Saidi H, Belaid A, Zairi A, Baleux F, Hocini H, Belec L, Hani K, Tangy F (2005) The antimicrobial peptide dermaseptin S4 inhibits HIV-1 infectivity in vitro. Virology 334:264–275PubMedCrossRefGoogle Scholar
  51. 51.
    Maddon PJ, Dalgleish AG, McDougal JS, Clapham PR, Weiss RA, Axel R (1986) The T4 gene encodes the AIDS virus receptor and is expressed in the immune system and the brain. Cell 47:333–348PubMedCrossRefGoogle Scholar
  52. 52.
    Berger EA, Murphy PM, Farber JM (1999) Chemokine receptors as HIV-1 coreceptors: roles in viral entry, tropism, and disease. Annu Rev Immunol 17:657–700PubMedCrossRefGoogle Scholar
  53. 53.
    Gallo SA, Wang W, Rawat SS, Jung G, Waring AJ, Cole AM, Lu H, Yan X, Daly NL, Craik DJ, Jiang S, Lehrer RI, Blumenthal R (2006) {theta}-defensins prevent HIV-1 Env-mediated fusion by binding gp41 and blocking 6-helix bundle formation. J Biol Chem 281:18787–18792PubMedCrossRefGoogle Scholar
  54. 54.
    Feng Z, Dubyak GR, Lederman MM, Weinberg A (2006) Cutting edge: human beta defensin 3-a novel antagonist of the HIV-1 coreceptor CXCR4. J Immunol 177:782–786PubMedGoogle Scholar
  55. 55.
    Lupetti A, Danesi R, van ’t Wout JW, van Dissel JT, Senesi S, Nibbering PH (2002) Antimicrobial peptides: therapeutic potential for the treatment of Candida infections. Expert Opin Investig Drugs 11:309–318PubMedCrossRefGoogle Scholar
  56. 56.
    Lehrer R, Ganz T, Szklarek D, Selsted M (1988) Modulation of the in situ candidiacial activity of human neutrophil defensins by target cell metabolism and divalent cations. J Clin Invest 81:1829–1835PubMedGoogle Scholar
  57. 57.
    Selsted M, Szklarek D, Ganz T, Lehrer R (1985) Activity of rabbit leukocyte peptides against Candida albicans. Infect Immun 49:202–206PubMedGoogle Scholar
  58. 58.
    Xu T, Levitz SM, Diamond RD, Oppenheim FG (1991) Anticandidal activity of major human salivary histatins. Infect Immun 59:2549–2554PubMedGoogle Scholar
  59. 59.
    Mandel L, Fatehi J (1992) Minor salivary gland sialolithiasis. Review and case report. N Y State Dent J 58:31–33PubMedGoogle Scholar
  60. 60.
    Helmerhorst EJ, Venuleo C, Beri A, Oppenheim FG (2005) Candida glabrata is unusual with respect to its resistance to cationic antifungal proteins. Yeast 22:705–714PubMedCrossRefGoogle Scholar
  61. 61.
    Shai Y (1995) Molecular recognition between membrane-spanning polypeptides. TIBS 20:460–464PubMedGoogle Scholar
  62. 62.
    Hugosson M, Andreu D, Boman HG, Glaser E (1994) Antibacterial peptides and mitochondrial coupling, respiration and protein import. Eur J Biochem 223:1027–1033PubMedCrossRefGoogle Scholar
  63. 63.
    Gwadz RW, Kaslow D, Lee JY, Maloy WL, Zasloff M, Miller LH (1989) Effects of magainins and cecropins on the sporogonic development of malaria parasites in mosquitoes. Infect Immun 57:2628–2633PubMedGoogle Scholar
  64. 64.
    Huang CM, Chen HC, Zierdt CH (1990) Magainin analogs effective against pathogenic protozoa. Antimicrob Agents Chemother 34:1824–1826PubMedGoogle Scholar
  65. 65.
    McGwire BS, Olson CL, Tack BF (1993) Killing of African trypanosomes by antimicrobial peptides. J Infect Dis 188:146–152CrossRefGoogle Scholar
  66. 66.
    Zuyderduyn S, Ninaber DK, Hiemstra PS, Rabe KF (2006) The antimicrobial peptide LL-37 enhances IL-8 release by human airway smooth muscle cells. J Allergy Clin Immunol 117:1328–1335PubMedCrossRefGoogle Scholar
  67. 67.
    Braff MH, Hawkins MA, Di Nardo A, Lopez-Garcia B, Howell MD, Wong C, Lin K, Streib JE, Dorschner R, Leung DY, Gallo RL (2005) Structure–function relationships among human cathelicidin peptides: dissociation of antimicrobial properties from host immunostimulatory activities. J Immunol 174:4271–4278PubMedGoogle Scholar
  68. 68.
    Tjabringa GS, Aarbiou J, Ninaber DK, Drijfhout JW, Sorensen OE, Borregaard N, Rabe KF, Hiemstra PS (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
  69. 69.
    Scott MG, Hancock REW (2000) Cationic antimicrobial peptides and their multifunctional role in the immune system. Crit Rev Immunol 20:407–431PubMedGoogle Scholar
  70. 70.
    Gallo RL, Nizet V (2003) Endogenous production of antimicrobial peptides in innate immunity and human disease. Curr Allergy Asthma Rep 3:402–409PubMedGoogle Scholar
  71. 71.
    Harder J, Schroder JM (2005) Psoriatic scales: a promising source for the isolation of human skin-derived antimicrobial proteins. J Leukoc Biol 77:476–486PubMedCrossRefGoogle Scholar
  72. 72.
    Glaser R, Harder J, Lange H, Bartels J, Christophers E, Schroder JM (2005) Antimicrobial psoriasin (S100A7) protects human skin from Escherichia coli infection. Nat Immunol 6:57–64PubMedCrossRefGoogle Scholar
  73. 73.
    Rieg S, Steffen H, Seeber S, Humeny A, Kalbacher H, Dietz K, Garbe C, Schittek B (2005) Deficiency of dermcidin-derived antimicrobial peptides in sweat of patients with atopic dermatitis correlates with an impaired innate defense of human skin in vivo. J Immunol 174:8003–8010PubMedGoogle Scholar
  74. 74.
    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
  75. 75.
    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
  76. 76.
    Marta Guarna M, Coulson R, Rubinchik E (2006) Anti-inflammatory activity of cationic peptides: application to the treatment of acne vulgaris. FEMS Microbiol Lett 257:1–6PubMedCrossRefGoogle Scholar
  77. 77.
    McInturff JE, Wang SJ, Machleidt T, Lin TR, Oren A, Hertz CJ, Krutzik SR, Hart S, Zeh K, Anderson DH, Gallo RL, Modlin RL, Kim J (2005) Granulysin-derived peptides demonstrate antimicrobial and anti-inflammatory effects against Propionibacterium acnes. J Invest Dermatol 125:256–263PubMedCrossRefGoogle Scholar
  78. 78.
    Friedland HD, Sharp DD, Robinson JR (2003) Double-blind, randomized, vehicle-controlled study to asses the safety and efficacy of MBI 594AN in the treatment of acne vulgaris. Abstracts of the 61st annual meeting of American Academy of Dermatology 61:22Google Scholar
  79. 79.
    Bals R, Hiemstra PS (2006) Antimicrobial peptides in COPD-basic biology and therapeutic applications. Curr Drug Targets 7:743–750PubMedCrossRefGoogle Scholar
  80. 80.
    Beisswenger C, Bals R (2005) Antimicrobial peptides in lung inflammation. Chem Immunol Allergy 86:55–71PubMedCrossRefGoogle Scholar
  81. 81.
    Ashitani J, Mukae H, Nakazato M, Ihi T, Mashimoto H, Kadota J, Kohno S, Matsukura S (1998) Elevated concentrations of defensins in bronchoalveolar lavage fluid in diffuse panbronchiolitis. Eur Respir J 11:104–111PubMedCrossRefGoogle Scholar
  82. 82.
    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
  83. 83.
    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 102:874–880PubMedGoogle Scholar
  84. 84.
    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
  85. 85.
    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 103:1113–1117PubMedGoogle Scholar
  86. 86.
    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 12:691–700PubMedCrossRefGoogle Scholar
  87. 87.
    Oppenheim JJ, Biragyn A, Kwak LW, Yang D (2003) Roles of antimicrobial peptides such as defensins in innate and adaptive immunity. Ann Rheum Dis 62:17–21CrossRefGoogle Scholar
  88. 88.
    Lu Q, Jin L, Darveau RP, Samaranayake LP (2004) Expression of human beta-defensins-1 and -2 peptides in unresolved chronic periodontitis. J Periodontal Res 39:221–227PubMedCrossRefGoogle Scholar
  89. 89.
    Gusman H, Travis J, Helmerhorst EJ, Potempa J, Troxler RF, Oppenheim FG (2001) Salivary histatin 5 is an inhibitor of both host and bacterial enzymes implicated in periodontal disease. Infect Immun 69:1402–1408PubMedCrossRefGoogle Scholar
  90. 90.
    Yoshinari M, Kato T, Matsuzaka K, Hayakawa T, Inoue T, Oda Y, Okuda K, Shimono M (2006) Adsorption behavior of antimicrobial peptide histatin 5 on PMMA. J Biomed Mater Res B Appl Biomater 77:47–54PubMedGoogle Scholar
  91. 91.
    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
  92. 92.
    Bevins CL (2006) Paneth cell defensins: key effector molecules of innate immunity. Biochem Soc Trans 34:263–266PubMedCrossRefGoogle Scholar
  93. 93.
    Kobayashi KS, Chamaillard M, Ogura Y, Henegariu O, Inohara N, Nunez G, Flavell RA (2005) Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science 307:731–734PubMedCrossRefGoogle Scholar
  94. 94.
    Schauber J, Rieger D, Weiler F, Wehkamp J, Eck M, Fellermann K, Scheppach W, Gallo RL, Stange EF (2006) Heterogeneous expression of human cathelicidin hCAP18/LL-37 in inflammatory bowel diseases. Eur J Gastroenterol Hepatol 18:615–62PubMedCrossRefGoogle Scholar
  95. 95.
    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
  96. 96.
    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
  97. 97.
    Baker MA, Maloy WL, Zasloff M, Jacob LS (1993) Anticancer efficacy of magainin2 and analogue peptides. Cancer Res 53:3052–3057PubMedGoogle Scholar
  98. 98.
    Soballe PW, Maloy WL, Myrga ML, Jacob LS, Herlyn M (1995) Experimental local therapy of human melanoma with lytic magainin peptides. Int J Cancer 60:280–284PubMedGoogle Scholar
  99. 99.
    Lehmann J, Retz M, Sidhu SS, Suttmann H, Sell M, Paulsen F, Harder J, Unteregger G, Stockle M (2006) Antitumor activity of the antimicrobial peptide magainin II against bladder cancer cell lines. Eur Urol 50:141–147PubMedCrossRefGoogle Scholar
  100. 100.
    Moore AJ, Devine DA, Bibby MC (1994) Preliminary experimental anticancer activity of cecropins. Pept Res 7:265–269PubMedGoogle Scholar
  101. 101.
    Yoo YC, Watanabe S, Watanabe R, Hata K, Shimazaki K, Azuma I (1998) Bovine lactoferrin and lactoferricin inhibit tumor metastasis in mice. Adv Exp Med Biol 443:285–291PubMedGoogle Scholar
  102. 102.
    Mader JS, Salsman J, Conrad DM, Hoskin DW (2005) Bovine lactoferricin selectively induces apoptosis in human leukemia and carcinoma cell lines. Mol Cancer Ther 4:612–624PubMedCrossRefGoogle Scholar
  103. 103.
    Eliassen LT, Berge G, Leknessund A, Wikman M, Lindin I, Lokke C, Ponthan F, Johnsen JI, Sveinbjornsson B, Kogner P, Flaegstad T, Rekdal O (2006) The antimicrobial peptide, lactoferricin B, is cytotoxic to neuroblastoma cells in vitro and inhibits xenograft growth in vivo. Int J Cancer 119:493–500PubMedCrossRefGoogle Scholar
  104. 104.
    Eliassen LT, Berge G, Sveinbjornsson B, Svendsen JS, Vorland LH, Rekdal O (2002) Evidence for a direct antitumor mechanism of action of bovine lactoferricin. Anticancer Res 22:2703–2710PubMedGoogle Scholar
  105. 105.
    Bateman A, Singh A, Jothy S, Fraser R, Esch F, Solomon S (1992) The levels and biologic action of the human neutrophil granule peptide HP-1 in lung tumors. Peptides 13:133–139PubMedCrossRefGoogle Scholar
  106. 106.
    Mizukawa N, Sugiyama K, Kamio M, Yamachika E, Ueno T, Fukunaga J, Takagi S, Sugahara T (2000) Immunohistochemical staining of human alpha-defensin-1 (HNP-1), in the submandibular glands of patients with oral carcinomas. Anticancer Res 20:1125–1127PubMedGoogle Scholar
  107. 107.
    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 160:1311–1324PubMedGoogle Scholar
  108. 108.
    Holterman DA, Diaz JI, Blackmore PF, Davis JW, Schellhammer PF, Corica A, Semmes OJ, Vlahou A (2006) Overexpression of alpha-defensin is associated with bladder cancer invasiveness. Urol Oncol 24:97–108PubMedGoogle Scholar
  109. 109.
    Papo N, Shai Y (2005) Host defense peptides as new weapons in cancer treatment. Cell Mol Life Sci 62:784–90PubMedCrossRefGoogle Scholar
  110. 110.
    Glass CK, Witztum JL (2001) Atherosclerosis. the road ahead. Cell 104:503–516PubMedCrossRefGoogle Scholar
  111. 111.
    Higazi AA, Lavi E, Bdeir K, Ulrich AM, Jamieson DG, Rader DJ, Usher DC, Kane W, Ganz T, Cines DB (1997) Defensin stimulates the binding of lipoprotein (a) to human vascular endothelial and smooth muscle cells. Blood 89:4290–4298PubMedGoogle Scholar
  112. 112.
    Barnathan ES, Raghunath PN, Tomaszewski JE, Ganz T, Cines DB, Higazi AA (1997) Immunohistochemical localization of defensin in human coronary vessels. Am J Pathol 150:1009–1020PubMedGoogle Scholar
  113. 113.
    Higazi AA, Nassar T, Ganz T, Rader DJ, Udassin R, Bdeir K, Hiss E, Sachais BS, Williams KJ, Leitersdorf E, Cines DB (2000) The alpha-defensins stimulate proteoglycan-dependent catabolism of low-density lipoprotein by vascular cells: a new class of inflammatory apolipoprotein and a possible contributor to atherogenesis. Blood 96:1393–1398PubMedGoogle Scholar
  114. 114.
    Higazi AA, Ganz T, Kariko K, Cines DB (1996) Defensin modulates tissue-type plasminogen activator and plasminogen binding to fibrin and endothelial cells. J Biol Chem 271:1760–1765Google Scholar
  115. 115.
    Chavakis T, Cines DB, Rhee JS, Liang OD, Schubert U, Hammes HP, Higazi AA, Nawroth PP, Preissner KT, Bdeir K (2004) Regulation of neovascularization by human neutrophil peptides (alpha-defensins): a link between inflammation and angiogenesis. FASEB J 18:1306–1308PubMedGoogle Scholar
  116. 116.
    Hooper LV, Stappenbeck TS, Hong CV, Gordon JI (2003) Angiogenins: a new class of microbicidal proteins involved in innate immunity? Nat Immunol 4:269–273PubMedCrossRefGoogle Scholar
  117. 117.
    Kougias P, Chai H, Lin PH, Yao Q, Lumsden AB, Chen C (2006) Neutrophil antimicrobial peptide alpha-defensin causes endothelial dysfunction in porcine coronary arteries. J Vasc Surg 43:357–363PubMedCrossRefGoogle Scholar
  118. 118.
    Edfeldt K, Agerberth B, Rottenberg ME, Gudmundsson GH, Wang XB, Mandal K, Xu Q, Yan ZQ (2006) Involvement of the antimicrobial peptide LL-37 in human atherosclerosis. Arterioscler Thromb Vasc Biol 26:1551–1557PubMedCrossRefGoogle Scholar
  119. 119.
    Post MJ, Sato K, Murakami M, Bao J, Tirziu D, Pearlman JD, Simons M (2006) Adenoviral PR39 improves blood flow and myocardial function in a pig model of chronic myocardial ischemia by enhancing collateral formation. Am J Physiol Regul Integr Comp Physiol 290:R494–R500PubMedGoogle Scholar
  120. 120.
    Li YM, Tan AX, Vlassara H (1995) Antibacterial activity of lysozyme and lactoferrin is inhibited by binding of advanced glycation-modified proteins to a conserved motif. Nat Med 1:1057–1061PubMedCrossRefGoogle Scholar
  121. 121.
    Paulsen F, Pufe T, Petersen W, Tillmann B (2001) Expression of natural peptide antibiotics in human articular cartilage and synovial membrane. Clin Diagn Lab Immunol 8:1021–1023PubMedCrossRefGoogle Scholar
  122. 122.
    Paulsen F, Pufe T, Conradi L, Varoga D, Tsokos M, Papendieck J, Petersen W (2002) Antimicrobial peptides are expressed and produced in healthy and inflamed human synovial membranes. J Pathol 198:369–377PubMedCrossRefGoogle Scholar
  123. 123.
    Bals R, Wang X, Meegalla RL, Wattler S, Weiner DJ, Nehls MC, Wilson JM (1999) Mouse beta-defensin 3 is an inducible antimicrobial peptide expressed in the epithelia of multiple organs. Infect Immun 67:3542–3547PubMedGoogle Scholar
  124. 124.
    Varoga D, Pufe T, Mentlein R, Kohrs S, Grohmann S, Tillmann B, Hassenpflug J, Paulsen F (2005) Expression and regulation of antimicrobial peptides in articular joints. Ann Anat 187:499–508PubMedCrossRefGoogle Scholar
  125. 125.
    Varoga D, Pufe T, Harder J, Schroder JM, Mentlein R, Meyer-Hoffert U, Goldring MB, Tillmann B, Hassenpflug J, Paulsen F (2005) Human beta-defensin 3 mediates tissue remodeling processes in articular cartilage by increasing levels of metalloproteinases and reducing levels of their endogenous inhibitors. Arthritis Rheum 52:1736–1745PubMedCrossRefGoogle Scholar
  126. 126.
    Harder J, Bartels J, Christophers E, Schroder JM (1997) A peptide antibiotic from human skin. Nature 387:861PubMedCrossRefGoogle Scholar
  127. 127.
    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 95:1491–1496Google Scholar
  128. 128.
    Folkman J, D’Amore PA (1996) Blood vessel formation: what is its molecular basis? Cell 87:1153–1155PubMedCrossRefGoogle Scholar
  129. 129.
    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
  130. 130.
    Sorensen OE, Cowland JB, Theilgaard-Monch K, Liu L, Ganz T, Borregaard N (2003) Related wound healing and expression of antimicrobial peptides/polypeptides in human keratinocytes, a consequence of common growth factors. J Immunol 170:5583–5589PubMedGoogle Scholar
  131. 131.
    Ashcroft GS, Lei K, Jin W, Longenecker G, Kulkarni AB, Greenwell-Wild T, Hale-Donze H, McGrady G, Song XY, Wahl SM (2000) Secretory leukocyte protease inhibitor mediates non-redundant functions necessary for normal wound healing. Nat Med 6:1147–1153PubMedCrossRefGoogle Scholar
  132. 132.
    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
  133. 133.
    Milner SM, Ortega MR (1999) Reduced antimicrobial peptide expression in human burn wounds. Burns 25:411–413PubMedCrossRefGoogle Scholar
  134. 134.
    Ortega MR, Ganz T, Milner SM (2000) Human beta defensins is absent in burn blister fluid. Burns 26:724–726PubMedCrossRefGoogle Scholar
  135. 135.
    Steinstraesser L, Klein RD, Aminlari A, Fan MH, Khilanani V, Remick, DG, Su GL, Wang SC (2001) Protegrin-1 enhances bacterial killing in thermally injured skin. Crit Care Med 29:1431–1437PubMedCrossRefGoogle Scholar
  136. 136.
    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 111:1665–1672PubMedCrossRefGoogle Scholar
  137. 137.
    Li J, Post M, Volk R, Gao Y, Li M, Metais C, Sato K, Tsai J, Aird W, Rosenberg RD, Hampton TG, Sellke F, Carmeliet P, Simons M (2000) PR39, a peptide regulator of angiogenesis. Nat Med 6:49–55PubMedCrossRefGoogle Scholar
  138. 138.
    Paquette DW, Simpson DM, Friden P, Braman V, Williams RC (2002) Safety and clinical effects of topical histatin gels in humans with experimental gingivitis. J Clin Periodontol 29:1051–1058PubMedCrossRefGoogle Scholar
  139. 139.
    Isaacson RE (2003) MBI-226. Micrologix/Fujisawa. Curr Opin Investig Drugs 4:9991003Google Scholar
  140. 140.
    Goldman MJ, Anderson GM, Stolzenberg ED, Kari UP, Zasloff M, Wilson JM (1997) Human beta-defensin-1 is a salt-sensitive antibiotic in lung that is inactivated in cystic fibrosis. Cell 88:553–560PubMedCrossRefGoogle Scholar
  141. 141.
    Marr AK, Gooderham WJ, Hancock RE (2006) Antibacterial peptides for therapeutic use: obstacles and realistic outlook. Curr Opin Pharmacol 6:468–472PubMedCrossRefGoogle Scholar
  142. 142.
    Tanida T, Okamoto T, Okamoto A, Wang H, Hamada T, Ueta E, Osaki T (2003) Decreased excretion of antimicrobial proteins and peptides in saliva of patients with oral candidiasi. J Oral Pathol & Med 32:586–594CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  1. 1.INSERM 525 E4, Faculté de PharmacieUniversité Henri Poincaré Nancy INancyFrance

Personalised recommendations