Induction of tumor necrosis factor-alpha in vivo by a skin irritant, tributyltin, through activation of transcription factors: Its pharmacological modulation by anti-inflammatory drugs

Skin irritant reactions are under the control of a network of cytokines and lipid mediators, This study characterized the production of tumor necrosis factor-alpha (TNF) induced by a skin irritant treatment, tributyltin (TBT), in mice through transcription factor activation and its pharmacologic modulation by anti-inflammatory agents. The ears of BALB/c mice were painted with different amounts of TBT (67-536 nmol in acetone) or with acetone alone, At different times thereafter, TNF production was analyzed both at the mRNA and protein level, by semiquantitative RT-PCR and L929 cytotoxicity assay, respectively, TBT induced rapid (1 h) TNF gene expression and protein synthesis, Maximal TNF production was observed 2 h after treatment, The production of TNF was paralleled by accumulation of skin water; this was partially prevented by intraperitoneal injection of antibody against murine TNF, These data indicate that skin irritation induced by TBT is attributable, in addition to the actions of other inflammatory mediators, to the action of keratinocyte-derived TNF, TNF production was preceded by a rapid (5 min) activation of nuclear factor-kappa B (NF-kappa B), which was also maximal 30 min after treatment, TBT-induced accumulation of skin water and TNF production were significantly reduced by topical treatment with dexamethasone and pentamidine, two anti-inflammatory agents, Interestingly, dexamethasone, but not pentamidine, decreased TBT-induced NF-kappa B activation, confirming in vivo that the glucocorticoid receptor interacts functionally within the nucleus with other transcription factors opposing one another's activity.