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

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

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56 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1045-1051
Number of pages7
JournalJournal of Clinical Investigation
Volume116
Issue number4
DOIs
StatePublished - Apr 1 2006

ASJC Scopus subject areas

  • Medicine(all)

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    Anand, S., Wang, P., Yoshimura, K., Choi, I. H., Hilliard, A., Chen, Y. H., Wang, C. R., Schulick, R., Flies, A. S., Flies, D. B., Zhu, G., Xu, Y., Pardoll, D. M., Chen, L., & Tamada, K. (2006). Essential role of TNF family molecule LIGHT as a cytokine in the pathogenesis of hepatitis. Journal of Clinical Investigation, 116(4), 1045-1051. https://doi.org/10.1172/JCI27083