Lymphotoxin-alphabeta heterotrimers are cleaved by metalloproteinases and contribute to synovitis in rheumatoid arthritis.
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.
Young
Judy
J
Department of Assay and Automation Technology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Yu
Xin
X
Wolslegel
Kristen
K
Nguyen
Allen
A
Kung
Catherine
C
Chiang
Eugene
E
Kolumam
Ganesh
G
Wei
Nathan
N
Wong
Wai Lee
WL
DeForge
Laura
L
Townsend
Michael J
MJ
Grogan
Jane L
JL
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
D015815:Cell Adhesion Molecules; D018925:Chemokines; D053361:Lymphotoxin alpha1, beta2 Heterotrimer; D045726:Metalloproteases