Role of the p38 MAPK pathway in induction of iNOS expression in human leukocytes

Inducible nitric oxide synthase (iNOS) is one of the enzymes responsible for NO production in neutrophils (PMN) and in peripheral blood mononuclear cells (PBMC). Several studies have demonstrated that iNOS expression is controlled by a wide group of cytokines which achieve their biological effect through, among others, the activation of the p38 MAPK pathway. The aim of the present study was to define the participation of the p38 MAPK pathway in the induction of iNOS expression and NO production by PMN and PBMC of healthy persons after stimulation of rhIL-15 and rhIL-18. We also estimated the influence of rhIL-15 and rhIL-18 on cGMP production by both population cells and the production of superoxide anion radicals by neutrophils. The results show that rhIL-15 and rhIL-18 induced an increase in the expression of iNOS and phospho-p38 MAPK in PMN and PBMC. We also found that PMN and PBMC, stimulated by these cytokines, released larger amounts of NO and cGMP in comparison with non-stimulated cells. Additionally, PMN showed a more pronounced ability to produce superoxide anions. The results suggest that iNOS activation in neutrophils and in peripheral blood mononuclear cells stimulated with rhIL-15 and rhIL-18 may be achieved through the assistance of the p38 MAPK pathway.