INTERLEUKIN-1 AND TUMOR-NECROSIS-FACTOR INDUCE HEPATIC HEME OXYGENASE - FEEDBACK-REGULATION BY GLUCOCORTICOIDS

During the acute-phase response to bacterial endotoxins [lipopolysaccharide (LPS)] in mice, the hepatic activity of haem oxygenase (HO) is increased. We investigated the effects of the potential humoral mediators of inflammation, interleukin-1 (IL-1) and tumour necrosis factor (TNF), on hepatic HO activity. In mice, IL-1 or TNF (5-mu-g) caused an elevation of HO activity comparable with that after LPS exposure (20-mu-g). The induction of HO by both cytokines was more pronounced in adrenalectomized mice. In the intact mice induction of HO activity by cytokines was observed earlier than depression of 7-ethoxycoumarin O-de-ethylase, a cytochrome P-450-dependent enzyme activity. Pretreatment with dexamethasone of the intact mice (3 mg/kg) or of the adrenalectomized mice (0.4 mg/kg) prevented the induction of HO activity caused by LPS and IL-1 respectively. These results suggest that: (1) HO activity is increased during an IL-1- or TNF-mediated acute-phase response, so haem metabolism might be a potential target of inflammation, and (2) HO induction by IL-1 and TNF does not require glucocorticoids, which in fact act as antagonists of this cytokine-induced effect.