Regulation of synovial cell proliferation and prostaglandin E2 production by combined action of cytokines.
To study the causes of synovitis in rheumatoid arthritis (RA), we have analyzed the effect of several cytokines known to be secreted in RA joints, on synovial cell proliferation and prostaglandin E2 (PGE2) production. Recombinant interleukin-1-beta (IL-1-beta) and tumor necrosis factor-alpha (TNF-alpha) stimulated moderately the DNA synthesis and markedly the production of PGE2. Interferon-gamma (IFN-gamma) was often mitogenic but never induced PGE2 secretion. The association of IL-1-beta and TNF-alpha showed an additive effect on both parameters, whereas addition of IFN-gamma to either monokine reduced the proliferation and increased PGE2 release. Incubation with a crude T cell supernatant or a mixture of cytokines including IL-1-beta, TNF-alpha and IFN-gamma enhanced synovial cell growth and PGE2 production as compared to the effect elicited by each single cytokine. In contrast, interleukin-2 (IL-2) down regulated the synovial cell activation induced by the combined action of the three other cytokines. Taken together, our findings indicate that synovial cell proliferation is weakly stimulated, reaching a two-fold increase over background levels, whatever cytokines are used. Furthermore, proliferation can vary independently of PGE2 production. Nevertheless, the monokines IL-1-beta and TNF-alpha both exert agonistic effects on synovial cell activation, thus contributing to cartilage damage in RA, whereas IFN-gamma, IL-6 or IL-2 may rather play a regulatory role.
Jorgensen
C
C
INSERM U. 283, Hôpital Cochin, France.
Angel
J
J
Fournier
C
C
D001172:Arthritis, Rheumatoid / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D004261:DNA Replication / Q000187:drug effects; D015232:Dinoprostone / Q000096:biosynthesis*; D004347:Drug Interactions; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D015846:Monokines / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D013583:Synovial Membrane / Q000378:metabolism / Q000473:pathology*
D016207:Cytokines; D007376:Interleukin-2; D015846:Monokines; D011994:Recombinant Proteins; D015232:Dinoprostone