A beneficial role of bile pigments as an endogenous tissue protector: Anti-complement effects of biliverdin and conjugated bilirubin

Nakagami, Tatsuyoshi; Toyomura, Keigo; Kinoshita, Tsuguki; Morisawa, Seiji

doi:10.1016/0304-4165(93)90013-x

Cited by 243 publications

(162 citation statements)

References 18 publications

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“…1,2 For example, the induction of ferritin by free iron has been shown to inhibit leukocyte migration, 27 proliferation of T cells 28 and to promote the development of DCs capable of inhibiting MLRs. 29 Bilirubin and biliverdin have been demonstrated to inhibit complement activation 30 and bilirubin has been described as a potent antioxidant, 31 as well as been shown to inhibit lymphocyte proliferation, IL-2 production and cytotoxicity. 32,33 Recently, CO has been shown to have antiinflammatory and protective roles in xenograft 34 and allograft rejection.…”

Section: Discussionmentioning

confidence: 99%

Induction of long-term cardiac allograft survival by heme oxygenase-1 gene transfer

et al. 2004

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Elevated expression of heme oxygenase-1 (HO-1), an intracellular enzyme that degrades heme into carbon monoxide (CO), biliverdine and free iron, has anti-inflammatory and antiapoptotic effects in diverse models. Here, we analyzed the effects of specific overexpression of HO-1 following adenovirus-mediated (AdHO-1) gene transfer in an acute cardiac allograft rejection model. The intragraft (i.g.) injection of AdHO-1 into cardiac allografts, as well as intramuscular (i.m.) or intravenous (i.v.) administration, prolonged allograft survival with, respectively, 13.3, 62.5 and 80% of the grafts surviving long term (4100 days), whereas control grafts were rejected with acute kinetics. HO-1 overexpression was associated with inhibited allogeneic responses in MLRs using graft-infiltrating leukocytes and splenocytes, but not with lymph node cells. The inhibition of splenocyte proliferation was mediated by soluble factors and was dependent on the presence of APCs, since purified T cells proliferated normally. i.v. but not i.g. AdHO-1 administration decreased the number of graft-infiltrating leukocytes, cytokine mRNA accumulation and apoptosis in transplanted hearts, whereas i.v. and i.g. AdHO-1 did not modify normal immune responses against cognate antigens, indicating that there was no general immunosuppression. These results indicate that HO-1 overexpression prolongs the survival of vascularized allografts by promoting tolerogenic mechanisms acting on allogeneic cellular immune responses.

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Section: Discussionmentioning

confidence: 99%

Induction of long-term cardiac allograft survival by heme oxygenase-1 gene transfer

et al. 2004

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“…9,34 -36 The cytoprotective properties of bilirubin may be explained by its inhibition of protein kinase C (PKC). 10,11,37 Haeme oxygenase activity is related to a faster resolution of inflammation, whereas the inhibition of this enzyme seems to increase the inflammatory response. 38 Familial aggregation and linkage analysis for high bilirubin levels Familial aggregation of bilirubin levels was supported by recent segregation analysis on 1240 adults in 84 Utah pedigrees suggesting a major gene controlling bilirubin levels.…”

Section: Discussionmentioning

confidence: 99%

A genome scan for loci influencing anti-atherogenic serum bilirubin levels

et al. 2002

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Epidemiological studies have shown an association of decreased serum bilirubin levels with coronary artery disease. Two segregation analyses in large pedigrees have suggested a major gene responsible for high bilirubin levels occurring in about 12% of the population. Based on a recessive model from a previous segregation analysis, we performed a genome scan using 587 markers genotyped in 862 individuals from 48 Utah pedigrees to detect loci linked to high bilirubin levels. As a complementary approach, non-parametric linkage (NPL) analysis was performed. These two methods identified four regions showing evidence for linkage. The first region is on chromosome 2q34 -37 with multipoint LOD and NPL scores of 3.01 and 3.22, respectively, for marker D2S1363. This region contains a previously described gene, uridine diphosphate glycosyltransferase 1, which has been associated with high bilirubin levels. A polymorphism in the promoter of this gene was recently shown to be responsible for Gilbert syndrome which is associated with mild hyperbilirubinemia. The other regions were found on chromosomes 9q21, 10q25 -26, and 18q12 with maximum NPL scores of 2.39, 1.55, and 2.79, respectively. Furthermore, we investigated in these pedigrees the association between bilirubin levels and coronary artery disease. One-hundred and sixty-one male and 41 female subjects had already suffered a coronary artery disease event. Male patients showed significantly lower bilirubin concentrations than age-matched controls. This association, however, was not observed in females. These results provide evidence that loci influencing bilirubin variation exist on chromosomes 2q34 -37, 9q21, 10q25 -26, and 18q12 and confirms the association of low bilirubin levels with coronary artery disease in males.

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“…69 Biliverdin has also been shown to inhibit human complement system in vitro. 70 Bilirubin had a protective effect on the transplanted liver grafts via inhibition of lipid peroxidation in hepatocytes. 71 Although reduced iron (Fe 2 þ ) released by HO-1 from the core of the heme molecule is a potent prooxidant, the potential catalysis of oxidative reactions by this compound is limited through its chelation by iron-sequestering protein ferritin as well as via its active removal from the cell by the specific Fe-ATPase pump.…”

Section: Expression Of Il-6 After To Administration and Its Possible mentioning

confidence: 99%

Upregulation of heme oxygenase-1 gene by turpentine oil-induced localized inflammation: involvement of interleukin-6

Tron¹,

Novosyadlyy²,

Dudás³

et al. 2005

Laboratory Investigation

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Heme oxygenase-1 (HO-1) is the inducible isoform of an enzyme family responsible for heme degradation and was suggested to be involved in the acute phase response in the liver. However, the mechanisms of the HO-1 regulation under inflammatory conditions are poorly understood. Therefore, the purpose of the current work was to study the expression of HO-1 in the liver and other organs of rats with a localized inflammation after intramuscular injection of turpentine oil (TO). Since interleukin-6 (IL-6) is known to be a principal mediator of inflammation, the levels of this cytokine were also estimated in the animal model used. HO-1 and IL-6 expression was evaluated by Northern blot, in situ hybridization, Western blot, immunohistochemistry and enzyme-linked immunosorbent assay. In the liver and injured muscle, the HO-1 mRNA levels were dramatically increased 4-6 h after TO administration. HO-1 protein levels in the liver were elevated starting from 6-12 h after the treatment. In other internal organs such as the heart, kidney and large intestine, only a slight induction of HO-1 mRNA was observed. IL-6-specific transcripts appeared only in the injured muscle and were in accordance with serum levels of IL-6. In turn, temporal expression of IL-6 in the muscle and circulatory IL-6 levels correlated well with HO-1 expression in the liver and injured muscle. In the liver of control rats HO-1 protein was detected in Kupffer cells, while in TO-injected rats also hepatocytes became strongly HO-1 positive. Conversely, in the injured muscle, HO-1 immunoreactivity was attributed only to macrophages. Our data demonstrate that during localized inflammation HO-1 expression was rapidly and strongly induced in macrophages of injured muscle and in hepatocytes, and IL-6 derived from injured muscle seems to be responsible for the HO-1 induction in the liver.

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A beneficial role of bile pigments as an endogenous tissue protector: Anti-complement effects of biliverdin and conjugated bilirubin

Cited by 243 publications

References 18 publications

Induction of long-term cardiac allograft survival by heme oxygenase-1 gene transfer

Induction of long-term cardiac allograft survival by heme oxygenase-1 gene transfer

A genome scan for loci influencing anti-atherogenic serum bilirubin levels

Upregulation of heme oxygenase-1 gene by turpentine oil-induced localized inflammation: involvement of interleukin-6

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