Bilirubin as a potent antioxidant suppresses experimental autoimmune encephalomyelitis: implications for the role of oxidative stress in the development of multiple sclerosis

Liu, Yingru; Zhu, Bing; Wang, Xuefeng; Luo, Laihui; Li, Ping; Paty, Donald W.; Cynader, Max S.

doi:10.1016/s0165-5728(03)00132-2

Cited by 116 publications

(73 citation statements)

References 30 publications

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“…However, the inflammatory grade in ␣-tocopherol-treated mice was only slightly decreased when compared with control animals (2.8 Ϯ 0.7) ( p Ͻ 0.05). Overall, bilirubin delayed the onset and alleviated the severity of EAE much more efficiently than treatment with ␣-tocopherol, although many previous studies, including ours, have demonstrated that they are similarly potent antioxidants (10,27). Therefore, the results herein suggest that bilirubin's efficacy in vivo is not solely due to its antioxidant effect.…”

Section: Bilirubin Suppresses Eae In Sjl/j Micementioning

confidence: 43%

“…It halted disease progression even when administered after the onset of clinical EAE. More importantly, in contrast to the traditional immunosuppressive agents such as dexamethasone (10), the therapeutic effect of bilirubin was long-lasting after treatment ceased, and it improved the long-term course of chronic EAE successfully. Analyses of animals with EAE showed that the clinical protection afforded by bilirubin was associated with changes in the PLP-specific autoimmune response.…”

Section: Discussionmentioning

confidence: 97%

“…The sections were stained with H&E to assess inflammation. The severity of inflammation in the lumbosacral, thoracic, and cervical spinal cord was each graded on a scale of 0 -4 as detailed previously (10), and the total inflammation score was obtained by adding these three scores. Luxol fast blue staining and immunostaining were performed following the established protocols (11).…”

Section: Morphological Techniques and Histopathological Studiesmentioning

confidence: 99%

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Bilirubin Possesses Powerful Immunomodulatory Activity and Suppresses Experimental Autoimmune Encephalomyelitis

Liu

Li²,

et al. 2008

The Journal of Immunology

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165

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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.

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Section: Bilirubin Suppresses Eae In Sjl/j Micementioning

confidence: 43%

Section: Discussionmentioning

confidence: 97%

Section: Morphological Techniques and Histopathological Studiesmentioning

confidence: 99%

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Bilirubin Possesses Powerful Immunomodulatory Activity and Suppresses Experimental Autoimmune Encephalomyelitis

Liu

Li²,

et al. 2008

The Journal of Immunology

Self Cite

190

165

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“…We assume that it is the effect of increased bilirubin/biliverdin, as in Gunn rats or rats carotid arteries treated with biliverdin, on VSMC cell cycle progression that suppresses neointimal proliferation after balloon injury, as reagents inhibiting cell cycle progression in VSMCs do have antiatherosclerotic properties. 1,2 We cannot rule out that at least in part the anti-inflammatory 32,33 and/or immunosuppressive 34,35 properties that have been attributed to bilirubin/biliverdin may contribute to our observations.…”

Section: Discussionmentioning

confidence: 84%

Bilirubin and Biliverdin Treatment of Atherosclerotic Diseases

Öllinger¹,

Yamashita²,

Bilban³

et al. 2007

Cell Cycle

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We have recently shown that the natural bile pigment bilirubin has antiproliferative effects on vascular smooth muscle cells (VSMCs). Bilirubin is the end product of heme catabolism mediated by heme oxygenases and has for decades been considered a toxic waste product of our bodies. However, 14 separate studies and a meta-analysis have documented an inverse correlation between atherosclerosis and the levels of bilirubin in normal individuals. Having high normal or supranormal levels of bilirubin is associated with less atherosclerotic-type disease as compared with that in individuals with low normal levels of bilirubin. This combined with experimental data showing anti-atherosclerotic properties of the enzyme heme oxygenase-1 encouraged us to hypothesize that bilirubin and its precursor biliverdin, would act to ameliorate components of atherosclerosis, in a manner similar to what has been shown with HO-1. Both did so in an animal model of restenosis in which vascular smooth muscle cell proliferation leads to intimal proliferation and causes narrowing of the vessels. We also analyzed the antiproliferative effects of the bile pigments in an in vitro system where bilirubin/biliverdin caused p53 dependent cell cycle arrest by hypophosphorylation of the retinoblastoma tumor suppressor protein in growth factor stimulated VSMCs.

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“…It has been reported that bilirubin has a strong antioxidative activity (Liu et al, 2003;Sedlak et al, 2004), and inhibits NOS expression and NO production in response to endotoxin in rats (Wang et al, 2004). The iNOS-NO system plays an important role in acute and severe hypoxic injury in pancreatic β cells (Ko et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Bilirubin protects grafts against nonspecific inflammation-induced injury in syngeneic intraportal islet transplantation

et al. 2010

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Nonspecific inflammatory response is the major cause for failure of islet grafts at the early phase of intraportal islet transplantation (IPIT). Bilirubin, a natural product of heme catabolism, has displayed anti-oxidative and anti-inflammatory activities. The present study has demonstrated that bilirubin protected islet grafts by inhibiting nonspecific inflammatory response in a syngeneic rat model of IPIT. The inflammation-induced cell injury was mimicked by exposing cultured rat insulinoma INS-1 cells to cytokines (IL-1β, TNF-α and IFN-γ) in in vitro assays. At appropriate lower concentrations, bilirubin significantly attenuated the reduced cell viability and enhanced cell apoptosis induced by cytokines, and protected the insulin secretory function of INS-1 cells. Diabetic inbred male Lewis rats induced by streptozotocin underwent IPIT at different islet equivalents (IEQs) (optimal dose of 1000, and suboptimal doses of 750 or 500), and bilirubin was administered to the recipients every 12 h, starting from one day before transplantation until 5 days after transplantation. Administration of bilirubin improved glucose control and enhanced glucose tolerance in diabetic recipients, and reduced the serum levels of inflammatory mediators including IL-1β, TNF-α, soluble intercellular adhesion molecule 1, monocyte chemoattractant protein-1 and NO, and inhibited the infiltration of Kupffer cells into the islet grafts, and restored insulin-producing ability of transplanted islets.

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Bilirubin as a potent antioxidant suppresses experimental autoimmune encephalomyelitis: implications for the role of oxidative stress in the development of multiple sclerosis

Cited by 116 publications

References 30 publications

Bilirubin Possesses Powerful Immunomodulatory Activity and Suppresses Experimental Autoimmune Encephalomyelitis

Bilirubin Possesses Powerful Immunomodulatory Activity and Suppresses Experimental Autoimmune Encephalomyelitis

Bilirubin and Biliverdin Treatment of Atherosclerotic Diseases

Bilirubin protects grafts against nonspecific inflammation-induced injury in syngeneic intraportal islet transplantation

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