The activity of caspase-1 is increased in lesional psoriatic epidermis.
Caspase-1 belongs to the group of inflammatory caspases and is the activating enzyme for the proinflammatory cytokine IL-18, a cytokine known to play an important role in the pathogenesis of psoriasis. The purpose of this study was to determine the expression of caspase-1 in psoriatic skin and the signaling mechanisms involved in stress-induced activation of caspase-1 and IL-18. Interestingly, increased caspase-1 activity in lesional compared with non-lesional psoriatic skin was seen. In vitro experiments in cultured human keratinocytes demonstrated anisomycin-induced, p38 mitogen-activated protein kinase (p38 MAPK)-dependent increased secretion of procaspase-1 and active caspase-1. Furthermore, anisomycin increased the mRNA expression of IL-18 through a p38 MAPK-dependent but caspase-1-independent mechanism, reaching a maximum level after 12 hours of stimulation. Finally, anisomycin caused a rapid (4 hours) increase in the secretion of proIL-18 and active IL-18. Secretion of active IL-18 was mediated through a p38 MAPK/caspase-1-dependent mechanism, whereas secretion of proIL-18 was mediated by a p38 MAPK-dependent but caspase-1-independent mechanism. These data demonstrate that the activity of caspase-1 is increased in psoriatic skin and that IL-18 secretion is regulated by a p38 MAPK/caspase-1-dependent mechanism, making caspase-1 a potential target in the treatment of psoriasis.
Johansen
Claus
C
Department of Dermatology, Aarhus University Hospital, Aarhus C, Denmark. claus.johansen@ki.au.dk
Moeller
Kristine
K
Kragballe
Knud
K
Iversen
Lars
L
D000841:Anisomycin / Q000494:pharmacology; D001706:Biopsy; D020170:Caspase 1 / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D004789:Enzyme Activation; D004817:Epidermis / Q000378:metabolism*; D006801:Humans; D020382:Interleukin-18 / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D011565:Psoriasis / Q000378:metabolism* / Q000628:therapy; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D020382:Interleukin-18; D012333:RNA, Messenger; D012313:RNA; D000841:Anisomycin; D007770:L-Lactate Dehydrogenase; D048051:p38 Mitogen-Activated Protein Kinases; D020170:Caspase 1