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- Title
Essential role of TNF family molecule LIGHT as a cytokine in the pathogenesis of hepatitis.
- Authors
Anand, Sudarshan; Pu Wang; Yoshimura, Kiyoshi; In-Hak Choi; Hilliard, Anja; Chen, Youhai H.; Chyung-Ru Wang; Schulick, Richard; Flies, Andrew S.; Flies, Dallas B.; Gefeng Zhu; Yanhui Xu; Pardoll, Drew M.; Lieping Chen; Tamada, Koji; Wang, Pu; Choi, In-Hak; Wang, Chyung-Ru; Zhu, Gefeng; Xu, Yanhui
- Abstract
LIGHT is an important costimulatory molecule for T cell immunity. Recent studies have further implicated its role in innate immunity and inflammatory diseases, but its cellular and molecular mechanisms remain elusive. We report here that LIGHT is upregulated and functions as a proinflammatory cytokine in 2 independent experimental hepatitis models, induced by concanavalin A and Listeria monocytogenes. Molecular mutagenesis studies suggest that soluble LIGHT protein produced by cleavage from the cell membrane plays an important role in this effect through the interaction with the lymphotoxin-beta receptor (LTbetaR) but not herpes virus entry mediator. NK1.1+ T cells contribute to the production, but not the cleavage or effector functions, of soluble LIGHT. Importantly, treatment with a mAb that specifically interferes with the LIGHT-LTbetaR interaction protects mice from lethal hepatitis. Our studies thus identify a what we believe to be a novel function of soluble LIGHT in vivo and offer a potential target for therapeutic interventions in hepatic inflammatory diseases.
- Subjects
CYTOKINES; T cells; TUMOR necrosis factors; CELLULAR immunity; LISTERIA monocytogenes; MUTAGENESIS; CELL membranes; PROTEIN metabolism; PLANT protein metabolism; ANIMALS; ANTIGENS; CELL receptors; HEPATITIS; INFLAMMATION; LISTERIA; MEMBRANE proteins; MICE; PLANT proteins; RESEARCH funding; SOLUBILITY
- Publication
Journal of Clinical Investigation, 2006, Vol 116, Issue 4, p1045
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI27083