Bilirubin derived from heme degradation suppresses MHC class II expression in endothelial cells.
The enzymatic action of heme oxygenase (HO) is mediated by the cleavage of heme into carbon monoxide, ferrous iron, and biliverdin/bilirubin. Here, we show that induction of HO-1 expression, an inducible form of HO, down-regulates IFN-gamma-induced MHC class II expression in endothelial cells. Among three catalytic products of HO, bilirubin, but not carbon monoxide or ferrous iron, mediated the suppressive effects of HO through the reduction of mRNA levels of Stat-1-dependent class II transactivator. Expression of HO-1 could suppress the levels of IFN-gamma-induced Stat-1 phosphorylation. This effect could be mimicked by exposing the cells to one of its catalytic products, bilirubin. In addition, HO-1 or bilirubin could modulate the transcript activities of Stat-1-driven gene expression in luciferase reporter assays. These findings suggest an important role of HO-1 in the modulation of immune responses through suppression of MHC-II expression in antigen presenting cells. Our data provide a new line of evidence supporting HO-1-targeted therapy for immune modulation.
Wu
Jian
J
Department of Surgery, Queen Mary Hospital, University of Hong Kong Medical Centre, Pokfulam, Hong Kong.
Ma
Jian
J
Fan
Sheung-Tat
ST
Schlitt
Hans J
HJ
Tsui
Tung-Yu
TY
D000818:Animals; D001663:Bilirubin / Q000008:administration & dosage* / Q000737:chemistry*; D001673:Biodegradation, Environmental; D002460:Cell Line; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006418:Heme / Q000737:chemistry*; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D000949:Histocompatibility Antigens Class II / Q000378:metabolism*; D007371:Interferon-gamma / Q000008:administration & dosage*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice
D000949:Histocompatibility Antigens Class II; D008565:Membrane Proteins; D006418:Heme; D007371:Interferon-gamma; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D001663:Bilirubin