INDUCTION OF TUMOR-NECROSIS-FACTOR-ALPHA IN-VIVO BY A SKIN IRRITANT, TRIBUTYLTIN, THROUGH ACTIVATION OF TRANSCRIPTION FACTORS - ITS PHARMACOLOGICAL MODULATION BY ANTIINFLAMMATORY DRUGS

Skin irritant reactions are under the control of a network of cytokine s and lipid mediators, This study characterized the production of tumo r necrosis factor-alpha (TNF) induced by a skin irritant treatment, tr ibutyltin (TBT), in mice through transcription factor activation and i ts pharmacologic modulation by anti-inflammatory agents. The ears of B ALB/c mice were painted with different amounts of TBT (67-536 nmol in acetone) or with acetone alone, At different times thereafter, TNF pro duction was analyzed both at the mRNA and protein level, by semiquanti tative RT-PCR and L929 cytotoxicity assay, respectively, TBT induced r apid (1 h) TNF gene expression and protein synthesis, Maximal TNF prod uction was observed 2 h after treatment, The production of TNF was par alleled 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 addit ion to the actions of other inflammatory mediators, to the action of k eratinocyte-derived TNF, TNF production was preceded by a rapid (5 min ) activation of nuclear factor-kappa B (NF-kappa B), which was also ma ximal 30 min after treatment, TBT-induced accumulation of skin water a nd TNF production were significantly reduced by topical treatment with dexamethasone and pentamidine, two anti-inflammatory agents, Interest ingly, dexamethasone, but not pentamidine, decreased TBT-induced NF-ka ppa B activation, confirming in vivo that the glucocorticoid receptor interacts functionally within the nucleus with other transcription fac tors opposing one another's activity.