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Fractalkine mediates T cell-dependent proliferation of synovial fibroblasts in rheumatoid arthritis ARTHRITIS AND RHEUMATISM Sawai, H., Park, Y. W., He, X., Goronzy, J. J., Weyand, C. M. 2007; 56 (10): 3215-3225

Abstract

In rheumatoid arthritis (RA), synovial fibroblasts proliferate excessively, eventually eroding bone and cartilage. The aim of this study was to examine the mechanisms through which CD4 T cells, the dominant lymphocyte population in patients with rheumatoid synovitis, regulate synoviocyte proliferation.Fibroblast-like synoviocyte (FLS) lines were established from rheumatoid synovium. CD4 T cells from patients with RA and age-matched control subjects were cultured on FLS monolayers. FLS proliferation was quantified by cytometry, using carboxyfluorescein succinimidyl ester staining or microscopic enumeration of PKH26-stained FLS. Surface expression of the fractalkine (FKN) receptor CX(3)CR1 was monitored by fluorescence-activated cell sorting. The induction of CX(3)CR1 and its ligand FKN in FLS was quantified by real-time polymerase chain reaction.The proliferation of FLS was significantly increased in the presence of CD4 T cells from patients with RA compared with control T cells. CD4+,CD28- T cells were particularly effective in supporting FLS growth, inducing a 25-fold expansion compared with a 5-fold expansion induced by CD4+,CD28+ T cells. The growth-promoting activity of CD4+,CD28- T cells was mediated through CX(3)CR1, a chemokine receptor expressed on both T cells and FLS. Anti-CX(3)CR1 antibodies inhibited T cell production of tumor necrosis factor alpha (TNFalpha) and suppressed FLS proliferation. TNFalpha amplified the expansion of FLS by enhancing their expression of CX(3)CR1 and FKN.FKN-CX(3)CR1 receptor-ligand interactions regulate FLS growth and FLS-dependent T cell function. FLS stimulate autocrine growth by releasing FKN and triggering the activity of their own CX(3)CR1. This growth-promotion loop is amplified by TNFalpha produced by CX(3)CR1-expressing T cells upon stimulation by FKN-expressing FLS. These data assign a critical role to FKN and its receptor in fibroblast proliferation and pannus formation in RA.

View details for DOI 10.1002/art.22919

View details for Web of Science ID 000250264800008

View details for PubMedID 17907166