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