Cytokine induction of haem oxygenase mRNA in mouse liver. Interleukin 1 transcriptionally activates the haem oxygenase gene

Abstract

Accumulation of the mRNA coding for haem oxygenase (HO, EC 1.14.99.3) was stimulated by treating mice with endotoxin (lipopolysaccharide, LPS; 20 micrograms/mouse intraperitoneally), suggesting that haem catabolism is a target of infection and inflammation in vivo. Therefore various cytokines, possible mediators for the biological responses to LPS, were administered intraperitoneally to mice, and the levels of HO mRNA were measured by Northern-blotting analysis using the rat HO cDNA as a probe [Shibahara, Müller, Taguchi and Yoshida (1985) Proc. Natl. Acad. Sci. U.S.A. 82, 7865-7869]. Marked induction of HO mRNA was observed 2 h after administration of interleukin 1 (IL-1) (34-fold) and tumour necrosis factor (19.5-fold) (5 micrograms/mouse), whereas interleukin 6 (6.2 micrograms/mouse) was much less active (3.5-fold) and interleukin 2 (25 micrograms/mouse) and interferon-gamma (3 micrograms/mouse) were ineffective. HO mRNA induced by the cytokines of LPS accumulated rapidly (maximum at 1-2 h after administration), preceding the elevation of HO enzymic activity. Treatment of mice with IL-1 stimulated the transcription of the HO gene by 4-fold, as assessed by in vitro nuclear-run-on assay. These results indicate that enzymic haem catabolism in the liver is a process inducible in vivo by inflammatory cytokines, which up-regulate HO synthesis at the transcriptional level. Increased removal of haem might be part of the protective mechanisms elicited by the acute-phase response, possibly to reduce the pro-oxidant state of the cell.

Induction of nitric oxide synthase and heme oxygenase activities by endotoxin in the rat adrenal cortex: involvement of both signaling systems in the modulation of ACTH-dependent steroid production

“…Comparable results were obtained in mice liver (Rizzardini et al 1993), rat Kuppfer cells (Immenschuh et al 1999), macrophages (Srisook & Cha 2004), and rat glial cells (Kitamura et al 1998). As was also demonstrated in other tissues or cell types, the induction of this enzymatic activity is probably involved in the development of cytoprotective mechanisms triggered by both injury and infection (Ryter & Tyrrell 2000).…”

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.…”

Heme Oxygenase-1 Induction in Islet Cells Results in Protection From Apoptosis and Improved In Vivo Function After Transplantation

“…RNA extraction was performed using the RNA NOW-LM kit (Biogentex, Seabrook, TX). Synthesis of first-strand cDNA was performed from DNase-treated RNA (DNase I; Gibco-BRL), using the SuperScript II RT kit (Gibco-BRL), with 25 ng/l oligo(dT) [12][13][14][15][16][17][18] as primer. The RT product was amplified by PCR in the LightCycler, which allows real-time quantification of the PCR product, based on the incorporation of a fluorescent dye in the neosynthesized DNA and its measurement at the end of each PCR cycle.…”

“…Inflammation can not only functionally impair or reduce the mass of implanted islets but can also result in the amplification of the subsequent immune response in a transplantation setting. In the transplanted islets, the induction of cytoprotective genes that are capable of scavenging oxygen radicals and preventing the toxic effects of proinflammatory cytokines might therefore promote early function (12-16).Heme oxygenase-1 (HO-1) has been identified as a ubiquitous stress protein induced in many cell types by various stimulants, such as hemolysis, inflammatory cytokines, oxidative stress, heat shock, heavy metals, and endotoxin (17)(18)(19)(20)(21)(22). HO-1 is the rate-limiting enzyme in the heme degradative pathway that catalyzes the oxidation of heme into biliverdin, carbon monoxide (CO), and free iron (23).…”

“…Heme oxygenase-1 (HO-1) has been identified as a ubiquitous stress protein induced in many cell types by various stimulants, such as hemolysis, inflammatory cytokines, oxidative stress, heat shock, heavy metals, and endotoxin (17)(18)(19)(20)(21)(22). HO-1 is the rate-limiting enzyme in the heme degradative pathway that catalyzes the oxidation of heme into biliverdin, carbon monoxide (CO), and free iron (23).…”