Lymphtoxin beta receptor-Ig protects from T-cell-mediated liver injury in mice through blocking LIGHT/HVEM signaling.
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 beta receptor (LTbetaR) 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 LTbetaR-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 LTbetaR-Ig significantly attenuated the progression and histological manifestations of the hepatic inflammation and reduced the production of inflammatory cytokines including TNF-alpha, IFN-gamma. Moreover, LTbetaR-Ig treatment significantly down-regulated LIGHT expression, leading to reduced lymphocytes (particularly CD4+ T cells), infiltrating into the hepatic inflammation and inhibited NF-kappaB activation and expression. We postulated that blockade of LIGHT/HVEM signaling by LTbetaR-Ig may ameliorate hepatitis by down-regulating LIGHT expression, and therefore we envision that LTbetaR-Ig would prove to a promising strategy for the clinical treatment of human autoimmune hepatitis.
An
Mao-Mao
MM
Department of Pharmacology, College of Pharmacy, Second Military Medical University, Shanghai, P R China.
Fan
Ke-Xing
KX
Cao
Yong-Bing
YB
Shen
Hui
H
Zhang
Jun-Dong
JD
Lu
Lei
L
Gao
Ping-Hui
PH
Jiang
Yuan-Ying
YY
D000818:Animals; D003208:Concanavalin A / Q000633:toxicity; D006505:Hepatitis / Q000517:prevention & control; D007136:Immunoglobulins / Q000494:pharmacology*; D007371:Interferon-gamma / Q000097:blood; D008099:Liver / Q000473:pathology*; D053259:Lymphotoxin beta Receptor / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology*; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14 / Q000037:antagonists & inhibitors*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D007136:Immunoglobulins; D053259:Lymphotoxin beta Receptor; D016328:NF-kappa B; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D014409:Tumor Necrosis Factor-alpha; D003208:Concanavalin A; D007371:Interferon-gamma