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
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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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 2

Essential role of the soluble form of LIGHT in liver inflammation.

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Essential role of the soluble form of LIGHT in liver inflammation. (A) B...
(A) B6 mice were injected i.v. with 30 mg/kg of ConA. At the indicated time points, serum was collected from the recipient mice and measured for soluble LIGHT concentration by LIGHT-specific ELISA. (B and C) B6 mice were injected with a sublethal dose of ConA (12.5 mg/kg) alone (filled circles, n = 13) or together with 20 μg plasmids encoding control pcDNA3.1 (open circles, n = 13), wild-type LIGHT (filled squares, n = 11), or LIGHTΔL (open squares, n = 10) by hydrodynamic injection technique. Survival of mice (B) and liver sections stained with H&E 18 hours after injection (C) were examined. N, necrotic area. *P = 0.3, **P = 0.033 between the groups by log-rank test. (D) BALB/c mice were injected i.p. with 50 μg of soluble LIGHT-flag fusion protein or control protein. One hour later, the mice were injected i.v. with 25 mg/kg ConA, and serum ALT levels were measured 6 hours later. One representative result from 3 independent experiments is shown as mean ± SD.