Essential role of TNF family molecule LIGHT as a cytokine in the pathogenesis of hepatitis.
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-beta receptor (LTbetaR) 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-LTbetaR 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.
Immunology Graduate Program, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Sudarshan
S
Anand
Pu
P
Wang
Kiyoshi
K
Yoshimura
In-Hak
IH
Choi
Anja
A
Hilliard
Youhai H
YH
Chen
Chyung-Ru
CR
Wang
Richard
R
Schulick
Andrew S
AS
Flies
Dallas B
DB
Flies
Gefeng
G
Zhu
Yanhui
Y
Xu
Drew M
DM
Pardoll
Lieping
L
Chen
Koji
K
Tamada
D000818:Animals; D000950:Antigens, Ly; D000954:Antigens, Surface / Q000378:metabolism; D003208:Concanavalin A / Q000378:metabolism / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism*; D006505:Hepatitis / Q000209:etiology* / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism; D037181:Lectins, C-Type / Q000378:metabolism; D008089:Listeria monocytogenes / Q000378:metabolism / Q000472:pathogenicity; D053259:Lymphotoxin beta Receptor; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D055651:NK Cell Lectin-Like Receptor Subfamily B; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology / Q000378:metabolism; D053240:Receptors, Tumor Necrosis Factor, Member 14; D011991:Receptors, Virus / Q000276:immunology / Q000378:metabolism; D012995:Solubility; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
D000950:Antigens, Ly; D000954:Antigens, Surface; D016207:Cytokines; C527211:Klrb1c protein, mouse; D037181:Lectins, C-Type; C505699:Ltbr protein, mouse; D053259:Lymphotoxin beta Receptor; D008565:Membrane Proteins; D055651:NK Cell Lectin-Like Receptor Subfamily B; D018124:Receptors, Tumor Necrosis Factor; D053240:Receptors, Tumor Necrosis Factor, Member 14; D011991:Receptors, Virus; C506029:Tnfrsf14 protein, mouse; C505915:Tnfsf14 protein, mouse; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D014409:Tumor Necrosis Factor-alpha; D003208:Concanavalin A