EXPRESSION OF INTERLEUKIN-12 IN SYNOVIAL TISSUE FROM PATIENTS WITH RHEUMATOID-ARTHRITIS

Objective. To examine the importance of interleukin-12 (IL-12) as a fa ctor in the interferon-gamma (IFN gamma)-dominant T cell cytokine resp onse in the synovial tissue of patients with rheumatoid arthritis (RA) . Methods. The expression of IL-12 in synovial tissue samples from pat ients with chronic RA (greater than or equal to 2 years) was compared with that in samples from osteoarthritis (OA) patients by detection of IL-12 p40 messenger RNA (mRNA) using reverse transcriptase-polymerase chain reaction, measurement of IL-12 p70 protein in culture supernata nts of tissue cells by immunoassay, and immunostaining of tissue secti ons with anti-IL-12 p70. The production of IFN gamma by RA synovial ti ssue cells cultured with or without IL-12 was determined, In addition, T cells were obtained 14 days after culturing RA synovial tissue cell s with IL-2 alone or with IL-2 plus IL-12, neutralizing anti-IL-12, or IL-4, and cytokine patterns (i.e., IFN gamma and IL-1 levels) were de termined by stimulating cells for 24 hours with anti-CD3 plus phorbol myristate acetate. Results. Synovial tissues from Ri patients more str ongly expressed IL-12 p40 mRNA than did OA tissues. Dissociated tissue cells from 21 of 37 RA patients spontaneously released detectable amo unts of IL-12 p70 (greater than or equal to 12.5 pg/ml) in culture, wh ereas production of IL-12 by OA tissues was limited. By immunohistoche mical analysis, IL-12-producing cells were localized mainly in the sub lining layer of RA synovium, and mostly expressed the CD68 antigen. Le vels of IFN gamma production by RA synovial tissue cells were potently and selectively enhanced by IL-12. The ability of IL-2-expanding syno vial T cells to produce IFN gamma was augmented by costimulation with IL-12 and diminished by anti-IL-12, while it was not affected by IL-4. Conclusion. These data suggest that IL-12, produced mainly by macroph age-lineage cells, may be involved in IFN gamma-dominant cytokine prod uction by infiltrating T cells in joints with chronic RA.