Fibroblast-Like Synoviocytes of Mesenchymal Origin Express Functional B Cell-Activating Factor of the TNF Family in Response to Proinflammatory Cytokines

Abstract

Immunohistochemical analysis revealed that the intimal lining cells of synovial tissue of inflamed joints of patients with rheumatoid arthritis differed from that of normal joints or of diseased joints in osteoarthritis in that they stained with mAb specific for the B cell-activating factor of the TNF family (BAFF; also called BLyS). We generated fibroblast-like synoviocytes (FLS) cell lines that were bereft of myelomonocytic cells to examine whether mesenchymal-derived FLS could express this critical B cell survival factor. We found that FLS expressed low amounts of BAFF mRNA relative to that of myelomonocytic cells. However, when various cytokines/factors were added to such FLS cell lines, we found that IFN-γ or TNF-α were unique in that they could induce significant increases in BAFF mRNA and protein. Even minute amounts of IFN-γ primed FLS for TNF-α, allowing the latter to stimulate significantly higher levels of BAFF mRNA and protein than could TNF-α alone. Consistent with this, B cells cocultured with IFN-γ and/or TNF-α-treated FLS had a significantly greater viability than B cells cocultured with nontreated FLS. The enhanced protection of B cells afforded by IFN-γ/TNF-α-treated FLS was inhibited by the addition of BAFF-R:Fc fusion protein. We conclude that the proinflammatory cytokines IFN-γ and TNF-α can induce mesenchymal-derived FLS to express functional BAFF in vitro. The induced expression of BAFF on FLS by proinflammatory cytokines may enhance the capacity of such cells to protect B cells from apoptosis in inflammatory microenvironments in vivo.