Interleukin-1 and tumour necrosis factor induce hepatic haem 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 micrograms) caused an elevation of HO activity comparable with that after LPS exposure (20 micrograms). 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.
Cantoni
L
L
Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Rossi
C
C
Rizzardini
M
M
Gadina
M
M
Ghezzi
P
P
D015660:7-Alkoxycoumarin O-Dealkylase / Q000378:metabolism; D000210:Acute-Phase Reaction / Q000378:metabolism*; D000818:Animals; D003907:Dexamethasone / Q000494:pharmacology; D004790:Enzyme Induction; D005938:Glucocorticoids / Q000494:pharmacology*; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis*; D007375:Interleukin-1 / Q000378:metabolism / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000502:physiology; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D051379:Mice; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000378:metabolism; D017472:Receptors, Interleukin-1; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D005938:Glucocorticoids; D007375:Interleukin-1; D008070:Lipopolysaccharides; D011971:Receptors, Immunologic; D017472:Receptors, Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone; D015660:7-Alkoxycoumarin O-Dealkylase; D006419:Heme Oxygenase (Decyclizing)