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
View: Text | PDF
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

×

Figure 1

Pathogenic role of upregulated LIGHT in hepatitis.

Options: View larger image (or click on image) Download as PowerPoint
Pathogenic role of upregulated LIGHT in hepatitis. (A) BALB/c mice were ...
(A) BALB/c mice were injected i.v. with 25 mg/kg ConA. At the indicated time points, the mice were sacrificed, and total RNA was extracted from liver and spleen. LIGHT, HVEM, LTβR, and GAPDH expression was examined by Northern blot analysis. (B and C) Wild-type (open circles) and LIGHT-deficient (filled circles) mice were injected i.v. with 30 mg/kg ConA. The survival (B) and serum ALT levels (C) of recipient mice were monitored. Sera were collected 18 hours after ConA injection, and the ALT levels were measured as described in Methods. SF, Sigma-Frankel. *p = 0.003.