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Bilirubin Possesses Powerful Immunomodulatory Activity and Suppresses Experimental Autoimmune Encephalomyelitis¹

Yingru Liu^2,3,*,¶, Ping Li^2,, Jie Lu^*, Wei Xiong^*, Joel Oger, Wolfram Tetzlaff and Max Cynader^*

^* Brain Research Center, Department of Psychiatry, Neuroimmunology Laboratories, and Collaboration on Repair Discoveries, University of British Columbia, Vancouver, British Columbia, Canada; and ^¶ Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115

Bilirubin, an abundant bile pigment in mammalian serum, was once considered a toxic waste product and has more recently been recognized as a potent antioxidant of physiological importance. However, its potential biological functions in other fields are not well understood. Herein we show that bilirubin is also a powerful immunomodulatory agent. Bilirubin significantly inhibited Ag-specific and polyclonal T cell responses, while other similar antioxidants completely lacked this effect. Bilirubin suppressed CD4⁺ T cell responses at multiple steps. High levels of bilirubin could induce apoptosis in reactive CD4⁺ T cells. Bilirubin at nonapoptotic concentrations suppressed CD4⁺ T cell reactivity through a wide range of actions, including inhibition of costimulator activities, suppression of immune transcription factor activation, and down-regulation of inducible MHC class II expression. Further studies suggest that bilirubin actions were direct, rather than via induction of immune deviation or regulatory T cells. In vivo, treatment with bilirubin effectively suppressed experimental autoimmune encephalomyelitis in SJL/J mice. In contrast, depletion of endogenous bilirubin dramatically exacerbated this disease. In summary, our results identify bilirubin as an important immunomodulator that may protect mammals against autoimmune diseases, thereby indicating its potential in the treatment of multiple sclerosis and other immune disorders.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by funds from Canadian Institutes of Health Research and the Multiple Sclerosis Society of Canada.

² Y.L. and P.L. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Yingru Li, Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Room 710, Boston, MA 02115. E-mail address: yliu{at}rics.bwh.harvard.edu

⁴ Abbreviations used in this paper: HO, heme oxygenase; BVR, biliverdin reductase; EAE, experimental autoimmune encephalomyelitis; PLP, proteolipid protein peptide; GSH, glutathione; DAI, days after immunization; ZnPP, zinc protoporphyrin; TCPOBOP, 1,4 bis[2-(3,5-dichloropyridyloxy)]benzene; PI, propidium iodide; DC, dendritic cell; β-APP, β-amyloid precursor protein; ROS, reactive oxygen species; Treg, regulatory T.