Rethinking the immune properties of bilirubin in viral hepatitis: from bench to bedside

Abstract

Communication between the immune system and metabolic components can be exemplified by the process of heme catabolism. The immunomodulatory functions of the enzymes, substrates and active products related to catabolism of the heme group have been extensively studied. Bilirubin (BR), the final breakdown product of heme, is primarily considered to be a toxic waste product but has recently been considered to be an immunomodulatory metabolite. Through mechanisms that include intracellular signaling and transcriptional control, BR affects those immune cell functions that regulate cell proliferation, differentiation and apoptosis. During the pathogenesis of viral hepatitis, the heme degradation pathway is disrupted, resulting in changes to normal BR concentrations. These alterations have been previously studied mainly as a consequence of the infection. However, little is known about the potential immunomodulatory role played by BR in the development of infectious hepatocellular diseases. Differences in BR levels in the context of viral hepatitis are likely to provide important insights into the metabolite-mediated mechanisms controlling the immune responses underlying both the long-term persistence of hepatitis C virus (HCV) infection and the resolution of hepatitis A virus (HAV) infection during the acute phase. In this review, the cross-talk between heme catabolism and immune function is described in detail. Special emphasis is given to discoveries that hold promise for identifying immunologic features of metabolic products in the resolution of viral diseases.

Conjugated Bilirubin Differentially Regulates CD4+ T Effector Cells and T Regulatory Cell Function through Outside-In and Inside-Out Mechanisms: The Effects of HAV Cell Surface Receptor and Intracellular Signaling

“…Moreover, in vitro models reveal that BR concentrations >25 μ M modulate CD4+ T cell and neutrophil apoptosis [ 3 , 4 ]. The induction of tolerance reported after the administration of BR to transplant recipients, which results from the de novo generation of T regulatory cells (Tregs) in murine models [ 5 , 6 ], is in agreement with the ability of BR to inhibit T cell proliferation and to decrease IL-2 production in human lymphocytes [ 1 ]. Furthermore, a BR-conferred protection against autoimmune diseases has been described [ 3 , 7 , 8 ], presumably as a result of the capacity of BR to bind to the peptide binding groove of human leukocyte antigen (HLA) molecules, blocking the antigenic peptide presentation to T cell receptor (TCR) and hence suppressing autoimmune responses [ 9 ].…”

“…Bilirubin (BR), long considered to be exclusively a toxic waste product, has recently been recognized as an immune-modulatory metabolite able to modulate CD4+ T lymphocyte (TL) function [ 1 – 3 ]. Particularly, we recently reported an immune-modulatory role of conjugated BR (CB) in hepatitis A virus (HAV) infection [ 1 ].…”

“…Bilirubin (BR), long considered to be exclusively a toxic waste product, has recently been recognized as an immune-modulatory metabolite able to modulate CD4+ T lymphocyte (TL) function [ 1 – 3 ]. Particularly, we recently reported an immune-modulatory role of conjugated BR (CB) in hepatitis A virus (HAV) infection [ 1 ]. BR can suppress inflammation and increase antioxidant enzyme generation in activated neonatal neutrophils by downregulating the lipopolysaccharide- (LPS-) induced generation of IL-8 [ 4 ].…”

“…Infections with hepatotropic viruses cause an elevation of serum aminotransferase activity and of serum-associated BR [ 1 , 10 , 11 ]. Viral hepatitis A is a major health concern worldwide, with a higher incidence in developing countries.…”

Network Pharmacology-Based Analysis on the Potential Biological Mechanisms of Yinzhihuang Oral Liquid in Treating Neonatal Hyperbilirubinemia

“…CD4+ T cells are crucial in the whole-body resistance to HAV infection, and they produce a large number of cytokines in the early stages of infection, including IFN- γ , TNF- α , IL-2, and IL-21. However, it has been reported that high levels of BR induce apoptosis in reactive CD4+ T cells [ 39 ]. The finding that the absence of an effective CD4+ T-cell response during HCV infection results in the development of an exhausted CD8+ T-cell pool has been attributed to chronic antigen-specific stimulation [ 40 ].…”