Skin-specific caspase-1-transgenic mice show cutaneous apoptosis and pre-endotoxin shock condition with a high serum level of IL-18

To study the pathophysiological roles of overexpressed caspase-1 (CASP1), o riginally designated as IL-1 beta-converting enzyme, we generated transgeni c mice in which human CASP1 is overexpressed in their keratinocytes. The tr ansgenic mice spontaneously developed recalcitrant dermatitis and skin ulce rs, characterized by the presence of massive keratinocyte apoptosis, The sk in of the mice contained the active form of human CASP1 and expressed mRNA for caspase-activated DNase, an effector endonuclease responsible for DNA f ragmentation. Their skin and sera showed elevated levels of mature IL-18 an d IL-1 beta, but not of IFN-gamma. The plasma from these animals induced IF N-gamma production by IL-ls-responsive NK cells. Administration of heat-kil led Propionibacterium acnes, a potent in vivo type 1 cell inducer, caused I FN-gamma-mediated lethal liver injury in the transgenic mice, which was com pletely inhibited by treatment with neutralizing anti-IL-18 Ab, These resul ts indicated that in vivo overexpression of CASP1 caused spontaneous apopto tic tissue injury and rendered mice highly susceptible to exogenous type 1 cell-inducing condition in collaboration with endogenously accumulated proi nflammatory cytokines.