Endogenous glucocorticoids released during acute toxic liver injury enhance hepatic IL-10 synthesis and release

Endogenous glucocorticoids are known to play a role in the regulation of th e inflammatory response possibly by modulating pro- and anti-inflammatory c ytokine expression. We examined endogenous glucocorticoid secretion, hepati c damage, tumor necrosis factor-alpha (TNF-alpha), and interleukin-10 (IL-1 0) mRNA expression and release in rats treated with carbon tetrachloride (C Cl4) after treatment with vehicle or a glucocorticoid receptor antagonist ( RU-486). Rats treated with CCl4 demonstrated striking elevations of plasma corticosterone levels. Inhibition of endogenous glucocorticoid activity by pretreatment with the glucocorticoid receptor antagonist RU-486 resulted in augmented CCl4-mediated hepatotoxicity, as reflected by histology and seru m transaminase levels, which were independent of alterations in serum TNF-a lpha levels or hepatic mRNA expression. CCl4 treatment resulted in enhanced hepatic IL-10 mRNA expression and elevated serum IL-10 levels, which were markedly attenuated by glucocorticoid receptor blockade. In summary, signif icant endogenous glucocorticoid release occurs during acute toxic liver inj ury in the rat and suppresses the inflammatory response independent of effe cts on TNF-alpha but possibly by upregulating hepatic IL-10 production.