Cytokine and nitric oxide production in inflammatory arthritis
Rheumatoid arthritis (RA) is a chronic disease characterised by inflammatory infiltration of the synovial membrane, with concomitant destruction of adjacent cartilage and bone. Elucidation of immunoregulatory networks within the synovium offers the potential for therapeutic intervention. Two such pathways were investigated in the present study. Interleukin-15 (IL-15) is a novel pleiotropic cytokine produced by macrophages and fibroblasts, which induces T cell migration and activation and B cell maturation and immunoglobulin production. IL-15 was identified in RA synovial fluids and synovial membrane cultures and, using immunohistochemistry, its expression was localised in the RA synovial membrane to the lining layer and T lymphocyte aggregates. Enhanced proliferation and cytokine production to IL-15 was observed in RA synovial fluid (SF) T cells in comparison to matched peripheral blood (PB) T lymphocytes, which in turn, were more sensitive to IL-15 induced proliferation than PBT cells from normal controls. Following IL-15 mediated activation, PBT cells were capable of inducing TNF production from a macrophage cell line, from syngeneic PB monocytes, and from synovial macrophage/synoviocyte co-cultures, through a cell-contact dependent mechanism, which required no T cell cytokine synthesis. RASFT cells exhibited similar properties, which were IL-15 dependent . IL-15 upregulated CD69 expression on CD45ROT cells and neutralisation studies determined that such CD69 expression, in combination with LFA-1 and ICAM-1, was partly responsible for cell-contact mediated macrophage activation by T cells. Finally, in a murine model, IL-15 injection induced significant local tissue T cell invasion, confirming previous observations of its chemotactic properties. IL-15 expression in RA synovial membrane therefore provides a mechanism whereby polyclonal T cell recruitment and activation can lead to macrophage activation and TNF production, without T cell cytokine synthesis.