Detection of transforming growth factor-beta in rheumatoid arthritis synovial tissue: lack of effect on spontaneous cytokine production in joint cell cultures

Abstract

SUMMARY The presence of transforming growth factor-beta (TGF-β) in inflammatory joint disease was investigated. Synovial fluid from patients with rheumatoid arthritis (RA) and patients with other non-autoimmune inflammatory joint diseases contained high levels of both active and latent TGF-β. Levels of active TGF-β did not correlate with drug regimen in either patient group or with the recovery period in the individuals with non-RA joint disease. Freshly isolated synovial cells from individuals with RA were shown by Northern blotting to express the mRNA for TGF-β1 and to secrete latent TGF-β protein which could be neutralized by antibodies to TGF-β1 and TGF-β2. Lipopolysaccharide-stimulated peripheral blood mononuclear cells from normal donors produced interleukin-l (IL-1) and tumour necrosis factor-alpha (TNF-α) which was inhibited by pretreatment of these cells with recombinant TGF-β. Cytokine production was not inhibited if the addition of TGF-β was used after the inducing stimulus, suggesting that in activated cells cytokine production cannot be inhibited. This was confirmed by the observation that neither TGF-β1 or TGF-β2 inhibited spontaneous IL-1 or TNF-α production by rheumatoid synovial mononuclear cells in culture. These findings show that despite the presence of active TGF-β in RA synovial joints and the spontaneous production of latent (potentially active) TGF-β by RA cells in culture, additional TGF-β did not inhibit ongoing cytokine synthesis in vitro. This suggests that TGF-β may not inhibit cytokine production in the rheumatoid joint although it cannot be ruled out that in rivo TGF-β already has an immunosuppressive effect which cannot be further increased in vitro by exogenous protein.