Endogenous interleukin-1 alpha is associated with skin irritation induced by tributyltin

Tributyltin (TBT) salts are well-known skin irritants in both human and 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 nmol in acetone) or with acetone alone, Two hours later there was dose-related production of IL-1 alpha along with ear swelling and accumulation of skin water, all of which were partially prevented by intraperitoneal injection of antibody against murine IL-1 alpha. By reverse transcription-polymerase chain reaction we were able to show that the neutralizing antibody also partially prevented TBT-induced in vivo IL-6 expression 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 induced 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 against 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 significantly inhibited by prior treatment with antioxidants, which strongly 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 disturbances in the respiratory chain in mitochondria, the mechanism of its action may be the production of reactive oxygen intermediates at the ubiquinone site, which activate transcription factors and promote IL-1 alpha synthesis. (C) 1996 Academic Press, Inc.