INDUCTION OF TUMOR-NECROSIS-FACTOR-ALPHA IN-VIVO BY A SKIN IRRITANT, TRIBUTYLTIN, THROUGH ACTIVATION OF TRANSCRIPTION FACTORS - ITS PHARMACOLOGICAL MODULATION BY ANTIINFLAMMATORY DRUGS
E. Corsini et al., INDUCTION OF TUMOR-NECROSIS-FACTOR-ALPHA IN-VIVO BY A SKIN IRRITANT, TRIBUTYLTIN, THROUGH ACTIVATION OF TRANSCRIPTION FACTORS - ITS PHARMACOLOGICAL MODULATION BY ANTIINFLAMMATORY DRUGS, Journal of investigative dermatology, 108(6), 1997, pp. 892-896
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.