Lymphtoxin [beta] receptor-Ig ameliorates TNBS-induced colitis via blocking LIGHT/HVEM signaling.
An, Mao-Mao a,1,2; Fan, Ke-Xing b,1; Zhang, Jun-Dong a; Li, Hai-Jun c; Song, Shui-Chuan b; Liu, Bin-Guo a; Gao, Ping-Hui a; Zhou, Qian b; Jiang, Yuan-Ying a,*
[Article]
Pharmacological Research.
52(3):234-244, September 2005.
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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 (LT[beta]R) 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 LT[beta]R-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 LT[beta]R-Ig significantly attenuated the progression and histological manifestations of the colonic inflammation and reduced the production of inflammatory cytokines including TNF-[alpha], IL-1[beta] and IL-8. Moreover, LT[beta]R-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 LT[beta]R-Ig and mesalazine showed that both treatments were equally efficacious. We postulated that blockade of LIGHT/HVEM signaling by LT[beta]R-Ig may ameliorate TNBS-induced colitis by down-regulating LIGHT expression, and therefore we envision that LT[beta]R-Ig would prove to a promising strategy for the clinical treatment of inflammatory bowel disease.
(C) 2005Elsevier, Inc.