Contribution of IL-1, CD14, and CD13 in the increased IL-6 production induced by in vitro monocyte-synoviocyte interactions

Rheumatoid synovitis is characterized by an infiltration of mononuclear cells and by the proliferation of synoviocytes. Monocytes and synoviocytes are major producers of cytokines, growth factors, and enzymes that contribute to the rheumatoid arthritis (RA) process. Since they are in close contact in vivo, we engaged in an in vitro study of the functional consequences of their interactions. Coculture of unstimulated elutriated normal blood monocytes over RA synoviocytes resulted in a synergistic 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 alone. 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 amino-peptidase N (CD13/AP-N). Collectively, these results indicate that 1) monocytes and synoviocytes interact with each other to produce proinflammatory cytokines, 2) pro- and antiinflammatory cytokines have opposite effects on IL-6 production, and 3) molecules such as IL-1, CD14, and CD13 are involved.