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*
Department of Immunology, University of Glasgow, Glasgow, United Kingdom; and
Department of Chemistry, University of Dundee, Dundee, United Kingdom
Macrophage activation by cytokines or microbial products such as LPS results in the induction and release of several key immune effector molecules including NO and IL-12. These have been shown to play crucial roles in the development of immunity to intracellular pathogens such as Leishmania. The molecular mechanisms underlying the induction of these effector molecules are not fully understood. We now show that the extracellular signal-related kinase (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 inhibitors selective for ERK (PD98059) and p38 (SB203580) show that while p38 plays an essential role in the induction of inducible NO synthase, ERK MAP kinases play only a minor role in promoting NO generation. In contrast, while 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 inhibit macrophage IL-12 production. Thus, as ERK and p38 MAP kinases differentially regulate the induction of the macrophage effector molecules, inducible NO synthase and IL-12, these kinases are potential targets not only for the development of novel strategies to combat intracellular pathogens but also for therapeutic immunomodulation.
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C. Ropert, I. C. Almeida, M. Closel, L. R. Travassos, M. A. J. Ferguson, P. Cohen, and R. T. Gazzinelli Requirement of Mitogen-Activated Protein Kinases and I{{kappa}}B Phosphorylation for Induction of Proinflammatory Cytokines Synthesis by Macrophages Indicates Functional Similarity of Receptors Triggered by Glycosylphosphatidylinositol Anchors from Parasitic Protozoa and Bacterial Lipopolysaccharide J. Immunol., March 1, 2001; 166(5): 3423 - 3431. [Abstract] [Full Text] [PDF]
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T. Matsuguchi, T. Musikacharoen, T. Ogawa, and Y. Yoshikai Gene Expressions of Toll-Like Receptor 2, But Not Toll-Like Receptor 4, Is Induced by LPS and Inflammatory Cytokines in Mouse Macrophages J. Immunol., November 15, 2000; 165(10): 5767 - 5772. [Abstract] [Full Text] [PDF]
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A. B. Carter and G. W. Hunninghake A Constitutive Active MEK right-arrow ERK Pathway Negatively Regulates NF-kappa B-dependent Gene Expression by Modulating TATA-binding Protein Phosphorylation J. Biol. Chem., September 1, 2000; 275(36): 27858 - 27864. [Abstract] [Full Text] [PDF]
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A. S. Kristof, J. Marks-Konczalik, and J. Moss Mitogen-activated Protein Kinases Mediate Activator Protein-1-dependent Human Inducible Nitric-oxide Synthase Promoter Activation J. Biol. Chem., March 9, 2001; 276(11): 8445 - 8452. [Abstract] [Full Text] [PDF]
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C. Zhu, K. Gagnidze, J. H. M. Gemberling, and S. E. Plevy Characterization of an Activation Protein-1-binding Site in the Murine Interleukin-12 p40 Promoter. DEMONSTRATION OF NOVEL FUNCTIONAL ELEMENTS BY A REDUCTIONIST APPROACH J. Biol. Chem., May 18, 2001; 276(21): 18519 - 18528. [Abstract] [Full Text] [PDF]
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