Role of interleukin-15 and nitric oxide expression in chronic inflammatory disease

Interleukin-15 (IL-15) is a pleiotropic cytokine produced by macrophages and fibroblasts, which mediates biological activities primarily through binding to the beta and gamma components of the IL-2 receptor, together with its own unique a chain. IL-15 induces T cell migration and activation, NK cell activation, B cell maturation and antibody production and monocyte activation. IL-15 mRNA is widely expressed in both immune and non-immune tissues and cells lines. However, the role of IL-15 in the context of any pathological situation remains unclear. Therefore, the role of IL-15 in a T helper-1 (Th1) disease prototype, rheumatoid arthritis (RA), and a Th2 disease prototype, asthma, was investigated in the present study. IL-15 was identified in RA synovial fluids. Following IL-15-mediated activation, peripheral blood (PB) T cells were capable of inducing TNF-alpha 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. RA synovial fluid (SF) T cells exhibited similar properties, which were IL-15-dependent in vitro. IL-15 up-regulated CD69 expression on CD45RO+ T 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. Furthermore, a similar mechanism operated in regulating cell-contact-induced IL-15 production by monocytes. Thus, activated T cells appeared to be effective costimulators of TNF-alpha and IL-15 production by monocytes via cell-cell contact, thereby generating a positive feedback loop. IL-15 also modulated cytokine production and adhesion molecule expression by RA neutrophils. Finally, in a murine model, IL-15 blockade profoundly suppressed the development of collagen-induced arthritis (CIA). This was accompanied in vitro by marked reductions in antigen-specific proliferation and interferon-gamma (IFN-y) synthesis by spleen cells from treated compared with control mice and in vivo by 4 significant reduction in serum anti-collagen antibody levels. Taken together, these data clearly demonstrated an important role for IL-15 in the development of inflammatory arthritis. Parallel studies established that epithelial cells and inflammatory leukocytes from the respiratory tract of asthma patients expressed IL-15. Moreover, such cells also expressed high levels of inducible nitric oxide synthase and produced NO in vitro. Expression of both IL-15 and iNOS was significantly suppressed in patients receiving inhaled corticosteroid therapy. In vitro studies demonstrated synergistic upregulation of TNF-alpha by IL-15 and NO providing evidence for interactions between radical inflammatory mediators and cytokines in chronic inflammatory responses