Essential role of TNF family molecule LIGHT as a cytokine in the pathogenesis of hepatitis
Sudarshan Anand, … , Lieping Chen, Koji Tamada
Sudarshan Anand, … , Lieping Chen, Koji Tamada
Published April 3, 2006
Citation Information: J Clin Invest. 2006;116(4):1045-1051. https://doi.org/10.1172/JCI27083.
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Research Article Hepatology

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

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

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Figure 3

LTβR is necessary and sufficient for LIGHT-mediated hepatitis.

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LTβR is necessary and sufficient for LIGHT-mediated hepatitis. (A) B6 mi...
(A) B6 mice were injected with either empty vector or plasmid DNA encoding wild-type LIGHT or Y173F mutant by hydrodynamic method in combination with a sublethal dose of ConA (12.5 mg/kg). ALT levels were measured 18 hours after injection. One representative result from 2 independent experiments is shown as mean ± SD of 5 mice per group. (B) B6 mice were injected i.v. with 30 mg/kg of ConA together with 100 μg of control rat Ig (open circles, n = 12), anti-LTβR (filled circles, n = 10), or anti-HVEM mAb (filled squares, n = 9). The survival was monitored thereafter. (C) B6 mice were injected with either empty vector or plasmid DNA encoding LIGHT by hydrodynamic method in combination with a sublethal dose of ConA (12.5 mg/kg). The mice were treated i.p. with 100 μg of the indicated Abs 2 hours before the plasmid injections. After 18 hours, serum ALT levels were measured. One representative result from 2 independent experiments is shown as mean ± SD of 5 mice per group. hIg, control hamster Ig; rIg, control rat Ig.