Ameliorate Inflammatory Bowel Disease Via Blocking LIGHT/HVEM Costimulatory Signaling

Multiple factors including genetic susceptibility, immune, and the environment, most notably the bacterial flora, are believed to be involved in the etiology of inflammatory bowel disease (IBD), mainly referring to Crohn's disease and ulcerative colitis. There is increasing evidence that immune factor plays crucial role in the pathogenesis of IBD, and therefore viewed as a good candidate for immunomodulatory treatment. CD4+ T cells are key in immune response and several studies established it as key mediators of the aberrant inflammatory response underlying IBD.LIGHT is a member of the TNF superfamily. Its known receptors are herpesvirus entry mediator (HVEM) and lymphtoxin β receptor (LTβR). Evidence is accumulating that LIGHT signaling through HVEM may function as a costimulatory molecule for T cells, including the enhancement of T cells proliferation .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 LTβR-Ig fusion protein as a competitive inhibitor of LIGHT/HVEM pathway.In this study we found: The experimental colitis model induced by rectal administration of trinitrobenzene sulfonic acid (TNBS) developed the symptom resemble to human IBD such as weight loss, stool consistency and stool hemoccult and colonic inflammation, furthermore, marked elevation of LIGHT expression was detected in their colonic tissue. Treatment with LTβR-Ig at a dose of 1600 μg kg-1 on alternative days for 7days significantly ameliorates colitic symptom including weight loss, stool consistency and stool hemoccult, attenuated the progression and histological manifestations of the colonic inflammation including degree, extent and crypt damage, reduced the inflammatory infiltration of granulocytes (MPO level) andthe production of inflammatory cytokines including TNF-a, IL-16 and IL-8. Moreover, LTBR-Ig treatment significantly down-regulated LIGHT expression, leading to reduced lymphocytes, particularly CD4+ T cells, infiltrates into the colonic inflammation tissue as shown by histological analysis.Our study suggests that LIGHT/HVEM signaling was involved in the development and/or progression of TNBS-induced colitis. Lymphtoxin 8 receptor-Ig ameliorates TNBS induced colitis via blocking LIGHT/HVEM signaling and LIGHT maybe potent target for IBD treatment through immunomodulation.Blocking LIGHT/HVEM signaling by LTBR-Ig would prove to be a promising strategy for treatment of IBD.