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.