Lymphtoxin β Receptor-Ig Protects from T-Cell-Mediated Liver Injury in Mice through Blocking LIGHT/HVEM Signaling

抄録

LIGHT is a member of the TNF superfamily, which is transiently expressed on the surface of activated T lymphocytes and immature dendritic cells. Its known receptors are herpesvirus entry mediator (HVEM) prominently in T lymphocytes, and lymphtoxin β receptor (LTβR) in stromal cells or nonlymphoid hematopoietic cells.Previous studies have shown that overexpression of LIGHT on T cells could lead to autoimmune reaction including lymphocytes activation, inflammation, and tissue destruction. To address the role of LIGHT/HVEM signaling in autoimmune hepatitis, an experimental colitis model induced by intravenous administration of concanavalin A (ConA) was given a soluble LTβR-Ig fusion protein as a competitive inhibitor of LIGHT/HVEM pathway. Marked elevation of LIGHT expression was detected in isolate intrahepatic leukocytes (IHLs) of the experimental animal. Treatment with LTβR-Ig significantly attenuated the progression and histological manifestations of the hepatic inflammation and reduced the production of inflammatory cytokines including TNF-α, IFN-γ. Moreover, LTβR-Ig treatment significantly down-regulated LIGHT expression, leading to reduced lymphocytes (particularly CD4⁺ T cells), infiltrating into the hepatic inflammation and inhibited NF-κB activation and expression. We postulated that blockade of LIGHT/HVEM signaling by LTβR-Ig may ameliorate hepatitis by down-regulating LIGHT expression, and therefore we envision that LTβR-Ig would prove to a promising strategy for the clinical treatment of human autoimmune hepatitis.