The human beta-defensins (-1, -2, -3, -4) and cathelicidin LL-37 induce IL-18 secretion through p38 and ERK MAPK activation in primary human keratinocytes.
In addition to its physical barrier against invading microorganisms, the skin produces antimicrobial peptides, human beta-defensins (hBDs) and cathelicidin LL-37, that participate in the innate host defense. Because IL-18 is produced by keratinocytes and involved in skin diseases in which hBDs and LL-37 are highly expressed, we hypothesized that these peptides would activate keratinocytes to secrete IL-18. We found that hBD-2, -3, and -4 and LL-37, but not hBD-1, activated normal human keratinocytes to secrete IL-18; this secretion reached peak strength at 3 h. In addition, the combination of peptides resulted in a synergistic effect on IL-18 secretion. We also revealed that hBD-2, -3, and -4 and LL-37 increased IL-18 mRNA expression, and that IL-18 secretion was more enhanced in keratinocytes differentiated in vitro with high Ca2+-containing medium. Furthermore, because IL-18 secretion induced by hBDs and LL-37 could not be suppressed by caspase-1 or caspase family inhibitors, and because these peptides failed to increase caspase-1 activity, we suggest that hBD- and LL-37-induced IL-18 secretion is probably via a caspase-1-independent pathway. To determine the molecular mechanism involved, we demonstrated that IL-18 secretion was through p38 and ERK1/2 MAPK pathways, because the inhibitors of p38 and ERK1/2, but not JNK, almost completely nullified IL-18 secretion. Moreover, hBD-2, -3, and -4 and LL-37 could induce the phosphorylation of p38 and ERK1/2, but not JNK. Thus, the ability of hBDs and LL-37 to induce IL-18 secretion by keratinocytes provides a new mechanism for these peptides in innate immunity and an understanding of their role in the pathogenesis of skin disorders.
Niyonsaba
François
F
Atopy (Allergy) Research Center, Juntendo University School of Medicine, Hongo, Tokyo, Japan. francois@med.juntendo.ac.jp
Ushio
Hiroko
H
Nagaoka
Isao
I
Okumura
Ko
K
Ogawa
Hideoki
H
D000595:Amino Acid Sequence; D023181:Antimicrobial Cationic Peptides / Q000502:physiology*; D020170:Caspase 1 / Q000502:physiology; D054804:Cathelicidins; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D004357:Drug Synergism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D020382:Interleukin-18 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000276:immunology; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000096:biosynthesis; D023083:beta-Defensins / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism* / Q000502:physiology
D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; C406407:DEFB1 protein, human; C422950:DEFB103A protein, human; C106641:DEFB4A protein, human; D020382:Interleukin-18; D012333:RNA, Messenger; D023083:beta-Defensins; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020170:Caspase 1