title: Lymphtoxin beta receptor-Ig ameliorates TNBS-induced colitis via blocking LIGHT/HVEM signaling.
abstract: 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.
authors.affiliation: Department of Pharmacology, College of Pharmacy, Second Military Medical University, 325 Guo He Road, Shanghai 200433, PR China. maoan168@yahoo.com.cn
authors.forename: Mao-Mao
authors.initials: MM
authors.lastname: An
authors.forename: Ke-Xing
authors.initials: KX
authors.lastname: Fan
authors.forename: Jun-Dong
authors.initials: JD
authors.lastname: Zhang
authors.forename: Hai-Jun
authors.initials: HJ
authors.lastname: Li
authors.forename: Shui-Chuan
authors.initials: SC
authors.lastname: Song
authors.forename: Bin-Guo
authors.initials: BG
authors.lastname: Liu
authors.forename: Ping-Hui
authors.initials: PH
authors.lastname: Gao
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhou
authors.forename: Yuan-Ying
authors.initials: YY
authors.lastname: Jiang
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D007136:Immunoglobulins / Q000494:pharmacology*; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D053259:Lymphotoxin beta Receptor; D008233:Lymphotoxin-alpha; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D019804:Mesalamine / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism*; D053240:Receptors, Tumor Necrosis Factor, Member 14; D011991:Receptors, Virus / Q000378:metabolism*; D014302:Trinitrobenzenesulfonic Acid; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D007136:Immunoglobulins; D007375:Interleukin-1; D016209:Interleukin-8; D053259:Lymphotoxin beta Receptor; D008233:Lymphotoxin-alpha; D008565:Membrane Proteins; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D053240:Receptors, Tumor Necrosis Factor, Member 14; D011991:Receptors, Virus; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D014409:Tumor Necrosis Factor-alpha; D019804:Mesalamine; D014302:Trinitrobenzenesulfonic Acid