Interleukin 1 beta (IL-1 beta) is produced as a biologically inactive 31 kD precursor, which is converted to the active 18 kD form by proteolytic processing. Keratinocytes express IL-1 beta but not the active form of the specific IL-1 beta converting enzyme (ICE). We have recently presented evidence that IL-1 beta activation in human epidermis occurs via an alternative mechanism involving hitherto unknown proteases. We asked whether stratum corneum chymotryptic enzyme (SCCE), which is a serine protease specifically expressed in keratinizing squamous epithelia, can act as an IL-1 beta activator in vitro. Recombinant human pro-IL-1 beta was incubated with recombinant SCCE, and the reaction products were characterized as regards molecular size and ability to induce expression of E-Selectin in human umbilical cord endothelial cells. SCCE caused degradation of pro-IL-1 beta and the accumulation of a component with electrophoretic mobility slightly lower than recombination mature IL-1 beta. Whereas incubation mixtures with pro-IL-1 beta which had been incubated in the absence of SCCE, or with SCCE, which had been incubated in the absence of pro-Il-1 beta, did not induce expression above baseline levels of E-Selectin, pro-Il1 beta which had been incubated with SCCE induced a significant increase in E-Selectin expression. This effect could be abolished by neutralizing antibodies to IL-1 beta, but not by antibodies to IL-1 alpha. In addition to IL-1 beta activation, SCCE also prepared to be able to catalyze a further degradation of IL-1 beta, leading to a loss of biological activity. We conclude that SCCE is a potential candidate for being responsible for IL-1 beta activation in human epidermis.