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 4

Essential role of NKT cells in the production of soluble LIGHT in ConA-induced hepatitis.

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Essential role of NKT cells in the production of soluble LIGHT in ConA-i...
(A and B) B6 mice were treated i.p. with 500 μg of either control mouse IgG or anti-NK1.1 mAb (PK136) on days 0 and 3 (A). Similarly, B6 mice were treated i.p. with 30 μg of control rabbit IgG or anti–asialo GM1 (ASGM1) on days 0 and 3 (B). On day 4, each group was injected i.v. with 30 mg/kg of ConA, and mouse sera were collected 1 hour later. The amounts of soluble LIGHT were measured by ELISA. *P = 0.02. (C) CD1d-deficient mice were injected with 20 μg of control vector or LIGHT-encoding plasmid by hydrodynamic injection in combination with a sublethal dose of ConA (12.5 mg/kg). Mouse sera were collected 18 hours later, and ALT levels were measured. **P = 0.002.