title: Lymphotoxin-alphabeta heterotrimers are cleaved by metalloproteinases and contribute to synovitis in rheumatoid arthritis.
abstract: Tumor necrosis factor-superfamily (TNF-SF) members, lymphotoxin (LT)-alpha and LTbeta, are proinflammatory cytokines associated with pathology in rheumatoid arthritis. LTalpha3 homotrimers are secreted, whereas LTalpha(1)beta(2) heterotrimers are expressed on the surface of activated lymphocytes. As many TNF-SF members are actively cleaved from cell membranes, we determined whether LTalphabeta heterotrimers are also cleaved, and are biologically active in rheumatoid arthritis (RA) patients. LTalphabeta heterotrimers were detected in culture supernatants from activated human T-helper (Th) 0, Th1, and Th17 cells, together with LTalpha3 and TNFalpha. The heterotimers were actively cleaved from the cell surface by ADAM17 metalloproteinase (MMP) and MMP-8, and cleavage was inhibited by TAPI-1, a TNF-alpha converting enzyme (TACE) inhibitor. Soluble LTalphabeta was detected in serum from both normal donors and RA patients, and was elevated in synovial fluid from RA patients compared to osteoarthritis (OA) patients. Levels of LTalphabeta in RA patient synovial fluid correlated with increased TNFalpha, IL-8, IL-12, IL-1beta, IFN-gamma, and IL-6 cytokines. Moreover, recombinant LTalpha1beta2-induced CXCL1, CXCL2, IL-6, IL-8, VCAM-1, and ICAM-1 from primary synovial fibroblasts isolated from RA patients. Therefore, soluble LTalphabeta in synovial fluid is associated with a proinflammatory cytokine milieu that contributes to synovitis in RA.
authors.affiliation: Department of Assay and Automation Technology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Judy
authors.initials: J
authors.lastname: Young
authors.forename: Xin
authors.initials: X
authors.lastname: Yu
authors.forename: Kristen
authors.initials: K
authors.lastname: Wolslegel
authors.forename: Allen
authors.initials: A
authors.lastname: Nguyen
authors.forename: Catherine
authors.initials: C
authors.lastname: Kung
authors.forename: Eugene
authors.initials: E
authors.lastname: Chiang
authors.forename: Ganesh
authors.initials: G
authors.lastname: Kolumam
authors.forename: Nathan
authors.initials: N
authors.lastname: Wei
authors.forename: Wai Lee
authors.initials: WL
authors.lastname: Wong
authors.forename: Laura
authors.initials: L
authors.lastname: DeForge
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Townsend
authors.forename: Jane L
authors.initials: JL
authors.lastname: Grogan
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000150:complications* / Q000201:enzymology*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism; D003710:Demography; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D053361:Lymphotoxin alpha1, beta2 Heterotrimer / Q000097:blood / Q000378:metabolism*; D008297:Male; D045726:Metalloproteases / Q000378:metabolism*; D008875:Middle Aged; D012995:Solubility; D013582:Synovial Fluid / Q000378:metabolism; D013585:Synovitis / Q000150:complications* / Q000201:enzymology* / Q000473:pathology; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology
chemical_list: D015815:Cell Adhesion Molecules; D018925:Chemokines; D053361:Lymphotoxin alpha1, beta2 Heterotrimer; D045726:Metalloproteases