ENDOGENOUS INTERLEUKIN-1-ALPHA IS ASSOCIATED WITH SKIN IRRITATION INDUCED BY TRIBUTYLTIN

Tributyltin (TBT) salts are well-known skin irritants in both human an d rodents, This study investigated the role of interleukin-1 alpha (IL -1 alpha) in the process in mice and in murine keratinocytes. The ears of Balb/c mice were painted with different amounts of TBT (67-536 nmo l in acetone) or with acetone alone, Two hours later there was dose-re lated production of IL-1 alpha along with ear swelling and accumulatio n of skin water, all of which were partially prevented by intraperiton eal injection of antibody against murine IL-1 alpha. By reverse transc ription-polymerase chain reaction we were able to show that the neutra lizing antibody also partially prevented TBT-induced in vivo IL-6 expr ession but no TBT-induced TNF-alpha expression, suggesting a paracrine effect of IL-1 alpha on IL-6 production but not TNF-alpha expression and indicating that other inflammatory mediators are involved, TBT ind uced both intracellular production of IL-1 alpha and its release into culture medium in a murine keratinocyte cell line (HEL30). IL-1 alpha production was inhibited by addition of a neutralizing antibody agains t IL-1 alpha, which suggests an autocrine effect of IL-1 alpha on its own production. The intracellular production of IL-1 alpha could be si gnificantly inhibited by prior treatment with antioxidants, which stro ngly suggests a role for oxidative species in rite mechanism of action of TBT in IL-1 alpha induction. The complex-1 inhibitor rotenone also significantly inhibits IL-1 alpha production. Since TBT causes distur bances in the respiratory chain in mitochondria, the mechanism of its action may be the production of reactive oxygen intermediates at the u biquinone site, which activate transcription factors and promote IL-1 alpha synthesis. (C) 1996 Academic Press, Inc.