Endogenous interleukin-1 alpha 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-1alpha (IL-1alpha) 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-1alpha along with ear swelling and accumulation of skin water, all of which were partially prevented by intraperitoneal injection of antibody against murine IL-1alpha. 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-1alpha on IL-6 production but not TNF-alpha expression and indicating that other inflammatory mediators are involved. TBT induced both intracellular production of IL-1alpha and its release into culture medium in a murine keratinocyte cell line (HEL30). IL-1alpha production was inhibited by addition of a neutralizing antibody against IL-1alpha, which suggests an autocrine effect of IL-1alpha on its own production. The intracellular production of IL-1alpha could he significantly inhibited by prior treatment with antioxidants, which strongly suggests a role for oxidative species in the mechanism of action of TBT in IL-1alpha induction. The complex-1 inhibitor rotenone also significantly inhibits IL-1alpha 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-1alpha synthesis.