Fractalkine mediates T cell-dependent proliferation of synovial fibroblasts in rheumatoid arthritis

Hirokazu Sawai, Yong W. Park, Xiaowen He, Jörg J. Goronzy, Cornelia M. Weyand

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

Objective. 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. Methods. 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 CX3CR1 was monitored by fluorescence-activated cell sorting. The induction of CX3CR1 and its ligand FKN in FLS was quantified by real-time polymerase chain reaction. Results. 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 3CR1, a chemokine receptor expressed on both T cells and FLS. Anti-CX3CR1 antibodies inhibited T cell production of tumor necrosis factor α (TNFα) and suppressed FLS proliferation. TNFα amplified the expansion of FLS by enhancing their expression of CX 3CR1 and FKN. Conclusion. FKN-CX3CR1 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 CX3CR1. This growth-promotion loop is amplified by TNFα produced by CX3CR1-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.

Original languageEnglish (US)
Pages (from-to)3215-3225
Number of pages11
JournalArthritis and rheumatism
Volume56
Issue number10
DOIs
StatePublished - Oct 2007

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Pharmacology (medical)

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