Bilirubin Possesses Powerful Immunomodulatory Activity and Suppresses Experimental Autoimmune Encephalomyelitis

Abstract

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.

Bilirubin suppresses Th17 immunity in colitis by upregulating CD39

“…Previous evidence had shown that UCB has immunomodulatory properties in inflammatory conditions in vivo (2,6). We tested the effect of UCB administration on DSS-induced colitis during the induction and recovery phases of the disease, when the DSS treatment was replaced with standard drinking water.…”

“…High systemic concentrations of UCB in certain disease states are potentially injurious to the basal ganglia and neurons (1). However, physiological concentrations of this metabolite have immunomodulatory effects on antigen-presenting cells (2,3) and effector cells (2,4), ultimately favoring the expansion of FOXP3 + Tregs (5,6). UCB immunomodulatory properties have been confirmed by in vivo experimental studies, as in the setting of islet cell transplantation (6,7), experimental autoimmune encephalomyelitis (2), and in acute colitis induced by dextran sodium sulfate (DSS) (8).…”

Peptides in Low Molecular Weight Fraction of Serum Associated with Hepatocellular Carcinoma

“…Several authors pointed out that bilirubin is likely to play important physiological functions because biliverdin is water soluble and could be directly excreted. It was already shown that bilirubin has antioxidant [51] and immunomodulatory [52] functions. Bilirubin diglucuronide is a sign of liver injury; biliverdin diglucuronide is possibly an oxidation product of bilirubin diglucuronide reflective of liver injury [53].…”

Evaluation of Methanolic and Ethanolic Extracts of Azadirachta Indica Seed Oil for Hypoglycaemic Properties and Effects on Some Biochemical Parameters in Diabetic Mice

“…The rapid release of bilirubin into the blood may also be as a result of obstruction of bile ducts or damage to the liver cells, so that even the usual amounts of bilirubin cannot be excreted into the gastrointestinal tracts. The elevated level observed may indicate liver damage or disease (22).…”