Human vascular smooth muscle cells express interleukin-1β-converting enzyme (ICE), but inhibit processing of the interleukin-1β precursor by ICE

Abstract

Local immunoregulatory processes during normal vascular biology or pathogenesis are mediated in part by the production of and response to cytokines by vessel wall cells. Among these cytokines interleukin (IL)-1 is considered to be of major importance. Although vascular smooth muscle (SMC) and endothelial cells (EC) expressed both IL-1α and IL-1β as cell- associated, 33-kilodalton (kD) precursors, SMC neither contained detectable mature IL-1β, nor processed recombinant IL-1β precursor into its mature 17- kD form. Thus, we investigated the expression and function of IL-1β- converting enzyme (ICE) in vascular cells. We demonstrate in processing experiments with recombinant IL-1 precursor molecules that EC processed IL- 1β, in contrast to SMC. Despite the failure of SMC to process IL-1β, these cells expressed ICE mRNA, immunoreactive ICE protein, and the expected IL- 1β nucleotide sequence. The lack of processing was explained by our finding that extracts of SMC specifically and concentration dependently blocked processing of IL-1β precursor by recombinant or native ICE. The initial biochemical characterization of the inhibitory activity showed that it is heat-labile, has a molecular size of 50-100 kD, and is associated to the cell membrane compartment. Inhibition of processing, i.e., activation of IL-1β precursor by SMC may constitute a novel regulatory mechanism during normal vascular biology or pathogenesis of vascular diseases.