INDUCTION OF BIOLOGICALLY-ACTIVE IL-1-BETA-CONVERTING ENZYME AND MATURE IL-1-BETA IN HUMAN KERATINOCYTES BY INFLAMMATORY AND IMMUNOLOGICAL STIMULI

IL-1 beta, a major mediator of inflammatory and immunologic skin disea se, undergoes post-translational site-specific cleavage by a novel cys teine protease termed IL-1 beta-converting enzyme (ICE). Although in h uman skin keratinocytes produce significant amounts of the 31-kDa IL-1 beta precursor protein, they fail under nonpathologic conditions to c onvert it to the 17.5-kDa bioactive form. In this study, we examined w hether haptens and inflammatory agents might serve as stimuli for ICE activity in human keratinocytes, and, if so, whether ICE activity migh t precipitate enzymatic processing of IL-1 beta to its 17.5-kDa form. Baseline levels of ICE mRNA were detected in keratinocyte cultures dev oid of Langerhans cells and were up-regulated by nontoxic concentratio ns of the reactive hapten urushiol and by the irritant chemicals sodiu m lauryl sulfate and PMA. Although untreated keratinocytes expressed t he 31-kDa form of the protein, 17.5-kDa IL-1 beta was easily detected in keratinocytes and keratinocyte supernatants treated with either uru shiol or the irritant chemicals. Enzymatic conversion from the 31-kDa to the 17.5-kDa form of IL-1 beta was blocked by addition of a highly specific aldehyde inhibitor that contained a tetrapeptide recognition sequence specific for ICE, but not by an aldehyde inhibitor of a relat ed ICE-like cysteine protease. Induction of IL-1 beta-converting enzym e by immunologic and inflammatory stimuli may be one of the key regula tory elements in the pathogenesis of allergic and irritant contact hyp ersensitivity.