gms | German Medical Science

Background: Rheumatoid arthritis (RA) synovial fibroblasts (SF) show an activated, invasive phenotype which is accompanied by copious production of pro-inflammatory cytokines. In addition, RASF have been shown to stimulate B cell survival by the production of BAFF (CD257). While the role for TNF family member receptors CD267-CD269 has been extensively studied on B lymphocytes, less is known about their expression and function on RASF. In this study, we investigated the impact of TNF, IFN-γ and a combination of both on cell surface levels of CD154, CD257 and CD266-CD269 and the effect of specific ligands for CD266-269 on pro-inflammatory cytokine production by RASF.

Methods: CD154, CD257 and CD266-CD269 were detected by flow cytometry. IL-6, IL-8 and MMP-3 were quantified by ELISA.

Results: RASF showed surface expression of CD154 (CD40L), CD257 (membrane BAFF), CD266 (Fn14), CD267 (TACI), CD268 (BAFF-R) and CD269 (BCMA) under unstimulated conditions. While TNF and IFN-γ alone (10 ng/ml each) up-regulated CD266, CD267 and CD269 moderately (~20%), the combination of both demonstrated synergistic effects on surface levels of all receptors/ligands investigated. Membrane BAFF was increased to 185% (±80%; p=0.03), CD40L to 175% (±71%; p=0.002), Fn14 to 246% (±71%; p=0.002), TACI to 190% (±108%; p=0.07), BAFF-R to 196% (±105%; p=0.017) and BCMA to 163% (±30%; p=0.001) of control values. Incubation of TNF/IFN-γ stimulated RASF with either BAFF (ligand for CD267 and CD268), APRIL (ligand for CD267 and CD269) or TWEAK (ligand for CD266) demonstrated reduced IL-6, IL-8 and MMP-3 production.

Conclusion: Up-regulation of CD266-269 might be a compensatory mechanism of RASF in response to pro-inflammatory challenges to reduce excessive cytokine production and tissue damage. In contrast, increased expression of membrane BAFF and CD40L might support the expansion of autoreactive B lymphocytes even in the absence of T cell help.