Interleukin-1 and tumour necrosis factor induce hepatic haem oxygenase. Feedback regulation by glucocorticoids

Abstract

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.

Induction of heme oxygenase-1 inhibits the monocyte transmigration induced by mildly oxidized LDL.

“…Studies of the promoter region of HO-1 revealed transcriptional responsive elements including AP-1 (55-57), AP-2 (57), NF-B (57), and IL-6 responsive elements (8). These transcriptional factors are known to be activated in inflammatory processes and by oxidative stress.…”

“…HO-1 is transcriptionally activated through several regulatory mechanisms by a variety of physical and chemical stresses (2,5,6,(8)(9)(10)(11). Studies of the promoter region of HO-1 revealed transcriptional responsive elements including AP-1 (55-57), AP-2 (57), NF-B (57), and IL-6 responsive elements (8).…”

“…Two isoforms of HO have been identified, which exhibit differences in regulation and tissue localization (2)(3)(4). HO-1 is an inducible form that is transcriptionally upregulated by a variety of chemical or physical stress-inducing factors such as heavy metals (5), certain organic compounds (5), hydrogen peroxide (6), heat shock (2), ultraviolet (UV) irradiation (6), cytokines (7,8), hypoxia (9), hyperoxia (10), as well as its substrate, heme (11). Many of these stresses are not directly involved in heme metabolism, raising the question of why HO-1 responds to these factors and conditions.…”

Heme oxygenase 1 is required for mammalian iron reutilization

“…Hmox1 activity is normally strongly up-regulated by inflammatory cytokines (27)(28)(29), and the enzyme appears to be important in preserving serum iron levels and reducing inflammation in mice. Therefore, it is conceivable that an iron release pathway involving Hmox1 is down-regulated in the course of chronic inflammatory illnesses.…”

Cooperative effect of biliverdin and carbon monoxide on survival of mice in immune-mediated liver injury

“…HO-1, in contrast to the second isoform HO-2, is inducible by various stimuli. 1,2 To investigate HO effects in vitro as well as in vivo, HO-1 can be induced by application of cobalt-protoporphyrin-IX (CoPP), for example, while tin-protoporphyrin-IX (SnPP) suppresses HO activity. 3,4 In the liver, administration of CoPP to mice results in HO-1 expression in hepatocytes as well as in Kupffer cells.…”