Lymphotoxin β–mediated stimulation of synoviocytes in rheumatoid arthritis

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Abstract
Objective Lymphotoxin β (LTβ), a cytokine produced by T cells and B cells, plays a central role in the normal development of lymph nodes and is critical in the formation of ectopic germinal center reactions in rheumatoid synovitis. Because resident fibroblast‐like synoviocytes (FLS) express receptors for LTβ, we examined the consequences of FLS activation by LTβ. Methods FLS from patients with rheumatoid arthritis were isolated and examined for the expression of LTβ receptor. FLS were incubated with LTα1β2 and assayed for the production of cytokines and chemokines and the up‐regulation of adhesion molecules. Results Exposure of FLS to recombinant LTα1β2 resulted in the production of multiple inflammatory cytokines and metalloproteinases, implicating FLS as amplifiers of the inflammatory process in the inflamed joint. Additionally, LTα1β2 was found to up‐regulate the expression of cell adhesion molecules, rendering FLS to efficient adhesion substrates for T cells. LTα1β2 also induced production of the chemokines CCL2 and CCL5, which elicited transmigration activity of T cells. Upon stimulation with LTα1β2, FLS did not acquire characteristics of follicular dendritic cells. Conclusion These data document that FLS are involved in multiple stages of the inflammatory process, including the recruitment and retention of lymphocytes in the synovial microenvironment. We propose that the heterotypic interaction between LTβ‐producing lymphocytes and responding FLS contributes to the establishment of complex lymphoid microstructures, and that this may be one element that defines susceptibility of the synovial membrane to lymphoid organogenesis.