Bilirubin derived from heme degradation suppresses MHC class II expression in endothelial cells

• Published in: Biochemical and biophysical research communications Vol. 338; no. 2; pp. 890 - 896
• Main Authors: Wu, Jian, Ma, Jian, Fan, Sheung-Tat, Schlitt, Hans J., Tsui, Tung-Yu
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16-12-2005
• Subjects: Animals; Bilirubin; Bilirubin - administration & dosage; Bilirubin - chemistry; Biodegradation, Environmental; Cell Line; Endothelial cells; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Gene Expression Regulation - drug effects; Gene Expression Regulation - physiology; Heme - chemistry; Heme oxygenase-1; Heme Oxygenase-1 - metabolism; Histocompatibility Antigens Class II - metabolism; Interferon-gamma - administration & dosage; Interferon-γ; Major histocompatibility complex class II; Membrane Proteins - metabolism; Mice; Bilirubin; Interferon-γ; Major histocompatibility complex class II; Endothelial cells; Heme oxygenase-1
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2005.10.021

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-γ-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-γ-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.