Lymphtoxin beta receptor-Ig ameliorates TNBS-induced colitis via blocking LIGHT/HVEM signaling.

LIGHT is a member of the TNF superfamily, which is transiently expressed on the surface of activated T lymphocytes and immature dendritic cells. Its known receptors are herpesvirus entry mediator (HVEM) prominently in T lymphocytes, and lymphtoxin beta receptor (LTbetaR) in stromal cells or nonlymphoid hematopoietic cells. Previous studies have shown that overexpression of LIGHT on T cells could lead to lymphocytes activation, inflammation, and tissue destruction focused on intestinal mucosal tissues. To address the role of LIGHT/HVEM signaling in colonic inflammation, an experimental colitis model induced by rectal administration of trinitrobenzene sulfonic acid (TNBS) was given a soluble LTbetaR-Ig fusion protein as a competitive inhibitor of LIGHT/HVEM pathway. Marked elevation of LIGHT expression was detected in colonic tissue of the experimental colitis. Treatment with LTbetaR-Ig significantly attenuated the progression and histological manifestations of the colonic inflammation and reduced the production of inflammatory cytokines including TNF-alpha, IL-1beta and IL-8. Moreover, LTbetaR-Ig treatment significantly down-regulated LIGHT expression, leading to reduced lymphocytes, particularly CD4+ T cells, infiltrating into the colonic inflammation tissue as shown by histological analysis. In addition, comparison of the therapeutic effects on TNBS-induced colitis between LTbetaR-Ig and mesalazine showed that both treatments were equally efficacious. We postulated that blockade of LIGHT/HVEM signaling by LTbetaR-Ig may ameliorate TNBS-induced colitis by down-regulating LIGHT expression, and therefore we envision that LTbetaR-Ig would prove to a promising strategy for the clinical treatment of inflammatory bowel disease.