Extracellular signal-related kinase (ERK) and p38 mitogen-activated protein (MAP) kinases differentially regulate the lipopolysaccharide-mediated induction of inducible nitric oxide synthase and IL-12 in macrophages: Leishmania phosphoglycans subvert macrophage IL-12 production by targeting ERK MAPkinase

Macrophage activation by cytokines or microbial products such as LPS result s in the induction and release of several key immune effector molecules inc luding NO and IL-12, These have been shown to play crucial roles in the dev elopment of immunity to intracellular pathogens such as Leishmania, The mol ecular mechanisms underlying the induction of these effector molecules are not fully understood. We now show that the extracellular signal-related kin ase (ERK) and p38 mitogen-activated protein (MAP) kinases play differential roles in the regulation of LPS-stimulated inducible NO synthase and IL-12 gene expression. In macrophages, LPS stimulates the simultaneous activation of all three classes of MAP kinases, ERK, c-jun N-terminal kinase, and p38 , albeit with differential activation kinetics. However, studies using inhi bitors selective for ERK (PD98059) and p38 (SB203580) show that while p38 p lays an essential role in the induction of inducible NO synthase, ERK MAP k inases play only a minor role in promoting NO generation. In contrast, whil e p38 promotes induction of IL-12 (p40) mRNA, ERK activation suppresses LPS -mediated IL-12 transcription. The biological relevance of these regulatory signals is demonstrated by our finding that Leishmania lipophosphoglycans, which promote parasite survival, act by stimulating ERK MAP kinase to inhi bit macrophage IL-12 production. Thus, as ERK and p38 MAP kinases different ially regulate the induction of the macrophage effector molecules, inducibl e NO synthase and IL-12, these kinases are potential targets not only for t he development of novel strategies to combat intracellular pathogens hut al so for therapeutic immunomodulation.