CONTRIBUTION OF IL-1, CD14, AND CD13 IN THE INCREASED IL-6 PRODUCTIONINDUCED BY IN-VITRO MONOCYTE-SYNOVIOCYTE INTERACTIONS

Rheumatoid synovitis is characterized by an infiltration of mononuclea r cells and by the proliferation of synoviocytes. Monocytes and synovi ocytes are major producers of cytokines, growth factors, and enzymes t hat contribute to the rheumatoid arthritis (RA) process. Since they ar e in close contact in vivo, we engaged in an in vitro study of the fun ctional consequences of their interactions. Coculture of unstimulated elutriated normal blood monocytes over RA synoviocytes resulted in a s ynergistic increase of the production of IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), leukemia inhibitory factor (LIF), and IL-8, when compared with their respective production in culture al one. In contrast, cytokines such as IL-10, IL-1 beta, IL-1 alpha, and TNF-alpha could not be detected. The IL-6 production in coculture was further increased by the addition of IL-1 beta, GM-CSF, IFN-gamma, or TNF-alpha, but was inhibited by the addition of IL-10, IL-4, IL-13, or IL-1Ra, an effect reverted by the addition of IL-1 beta. Moreover, an inhibition was also observed with anti-CD14 mAb and newly raised mAbs directed against RA synoviocytes. Under reducing conditions, the mAb SY12 precipitated a 150-kDa surface membrane protein, identified as am inopeptidase N (CD13/AP-N). Collectively, these results indicate that 1) monocytes and synoviocytes interact with each other to produce proi nflammatory cytokines, 2) pro- and antiinflammatory cytokines have opp osite effects on IL-6 production, and 3) molecules such as IL-1, CD14, and CD13 are involved.