Bilirubin possesses powerful immunomodulatory activity and suppresses experimental autoimmune encephalomyelitis.
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.
Liu
Yingru
Y
Brain Research Center, University of British Columbia, Vancouver, British Columbia, Canada. yliu@rics.bwh.harvard.edu
Li
Ping
P
Lu
Jie
J
Xiong
Wei
W
Oger
Joel
J
Tetzlaff
Wolfram
W
Cynader
Max
M
D000818:Animals; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology; D001663:Bilirubin / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000473:pathology*; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects
D000949:Histocompatibility Antigens Class II; D007166:Immunosuppressive Agents; D016328:NF-kappa B; D001663:Bilirubin