Detection of transforming growth factor-beta in rheumatoid arthritis synovial tissue: lack of effect on spontaneous cytokine production in joint cell cultures.
The presence of transforming growth factor-beta (TGF-beta) 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-beta. Levels of active TGF-beta 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-beta 1 and to secrete latent TGF-beta protein which could be neutralized by antibodies to TGF-beta 1 and TGF-beta 2. Lipopolysaccharide-stimulated peripheral blood mononuclear cells from normal donors produced interleukin-1 (IL-1) and tumour necrosis factor-alpha (TNF-alpha) which was inhibited by pretreatment of these cells with recombinant TGF-beta. Cytokine production was not inhibited if the addition of TGF-beta 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-beta 1 or TGF-beta 2 inhibited spontaneous IL-1 or TNF-alpha production by rheumatoid synovial mononuclear cells in culture. These findings show that despite the presence of active TGF-beta in RA synovial joints and the spontaneous production of latent (potentially active) TGF-beta by RA cells in culture, additional TGF-beta did not inhibit ongoing cytokine synthesis in vitro. This suggests that TGF-beta may not inhibit cytokine production in the rheumatoid joint although it cannot be ruled out that in vivo TGF-beta already has an immunosuppressive effect which cannot be further increased in vitro by exogenous protein.
Charing Cross-Sunley Research Centre, London, England.
F M
FM
Brennan
D
D
Chantry
M
M
Turner
B
B
Foxwell
R
R
Maini
M
M
Feldmann
D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000276:immunology*; D001685:Biological Factors / Q000096:biosynthesis*; D015152:Blotting, Northern; D002478:Cells, Cultured; D016207:Cytokines; D015870:Gene Expression; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis; D011994:Recombinant Proteins; D013582:Synovial Fluid / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D013583:Synovial Membrane / Q000166:cytology / Q000187:drug effects; D015291:Transforming Growth Factors / Q000378:metabolism* / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D001685:Biological Factors; D016207:Cytokines; D007375:Interleukin-1; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D015291:Transforming Growth Factors