Lymphotoxin-αβ heterotrimers are cleaved by metalloproteinases and contribute to synovitis in rheumatoid arthritis

Abstract Tumor necrosis factor-superfamily (TNF-SF) members, lymphotoxin (LT)-α and LTβ, are proinflammatory cytokines associated with pathology in rheumatoid arthritis. LTα3 homotrimers are secreted, whereas LTα 1 β 2 heterotrimers are expressed on the surface of activated lymphocytes. As many TNF-SF members are actively cleaved from cell membranes, we determined whether LTαβ heterotrimers are also cleaved, and are biologically active in rheumatoid arthritis (RA) patients. LTαβ heterotrimers were detected in culture supernatants from activated human T-helper (Th) 0, Th1, and Th17 cells, together with LTα3 and TNFα. 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-α converting enzyme (TACE) inhibitor. Soluble LTαβ 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 LTαβ in RA patient synovial fluid correlated with increased TNFα, IL-8, IL-12, IL-1β, IFN-γ, and IL-6 cytokines. Moreover, recombinant LTα1β2-induced CXCL1, CXCL2, IL-6, IL-8, VCAM-1, and ICAM-1 from primary synovial fibroblasts isolated from RA patients. Therefore, soluble LTαβ in synovial fluid is associated with a proinflammatory cytokine milieu that contributes to synovitis in RA.