Essential role of TNF family molecule LIGHT as a cytokine in the pathogenesis of hepatitis

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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-β receptor (LTβR) 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-LTβR 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.

Authors

Sudarshan Anand, Pu Wang, Kiyoshi Yoshimura, In-Hak Choi, Anja Hilliard, Youhai H. Chen, Chyung-Ru Wang, Richard Schulick, Andrew S. Flies, Dallas B. Flies, Gefeng Zhu, Yanhui Xu, Drew M. Pardoll, Lieping Chen, Koji Tamada