{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:23:38Z","timestamp":1790036618117,"version":"4.0.1"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2008,8,1]],"date-time":"2008-08-01T00:00:00Z","timestamp":1217548800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2008,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>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.<\/jats:p>","DOI":"10.4049\/jimmunol.181.3.1887","type":"journal-article","created":{"date-parts":[[2014,4,18]],"date-time":"2014-04-18T19:00:52Z","timestamp":1397847652000},"page":"1887-1897","source":"Crossref","is-referenced-by-count":197,"title":["Bilirubin Possesses Powerful Immunomodulatory Activity and Suppresses Experimental Autoimmune Encephalomyelitis"],"prefix":"10.1093","volume":"181","author":[{"given":"Yingru","family":"Liu","sequence":"first","affiliation":[{"name":"Brain Research Center"},{"name":"Center for Neurologic Diseases, Brigham and Women\u2019s Hospital, Harvard Medical School , Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Psychiatry"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Lu","sequence":"additional","affiliation":[{"name":"Brain Research Center"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Xiong","sequence":"additional","affiliation":[{"name":"Brain Research Center"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joel","family":"Oger","sequence":"additional","affiliation":[{"name":"Neuroimmunology Laboratories"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfram","family":"Tetzlaff","sequence":"additional","affiliation":[{"name":"Collaboration on Repair Discoveries, University of British Columbia , Vancouver, British Columbia,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Max","family":"Cynader","sequence":"additional","affiliation":[{"name":"Brain Research Center"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2008,8,1]]},"reference":[{"key":"2025032608194650400_R1","first-page":"748","article-title":"The enzymatic conversion of heme to bilirubin by microsomal heme oxygenase","volume-title":"Proc. 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