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Activation of the MAPK, ERK, following Leishmania amazonensis Infection of Macrophages¹

Laboratory of Macrophage Biology, Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742

IL-10 is a critical cytokine in determining host susceptibility to Leishmania spp. We previously demonstrated that macrophage-derived IL-10 could contribute to disease exacerbation, but the mechanisms whereby Leishmania infections led to IL-10 induction were not fully understood. In this study, we demonstrated that infection of macrophages with Leishmania amazonensis amastigotes led to the activation of the MAPK, ERK1/2. This activation was required, but not sufficient for IL-10 induction. In addition to ERK activation, an inflammatory stimulus, such as low m.w. hyaluronic acid from the extracellular matrix, must also be present. The combination of these two signals resulted in the superinduction of IL-10. We also demonstrated that IgG on the surface of Leishmania amastigotes was required to achieve maximal IL-10 production from infected macrophages. Surface IgG engages macrophage FcR to induce ERK activation. Macrophages lacking FcR, or macrophages treated with an inhibitor of spleen tyrosine kinase, the tyrosine kinase that signals via FcR, failed to activate ERK and consequently failed to produce IL-10 following infection with Leishmania amastigotes. We confirmed that ERK1/2 activation led to the phosphorylation of histone H3 at the IL-10 promoter, and this phosphorylation allowed for the binding of the transcription factor, Sp1, to the IL-10 promoter. Finally, the administration of U0126, an inhibitor of ERK activation, to infected mice resulted in decreased lesion progression with reduced numbers of parasites in them. Thus, our findings reveal an important role of MAPK, ERK signaling in the pathogenesis of Leishmania infection.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by National Institutes of Health Grant AI55576.

² Address correspondence and reprint requests to Dr. David M. Mosser, 1103 Microbiology Building, University of Maryland, College Park, MD 20742. E-mail address: dmosser{at}umd.edu

³ Abbreviations used in this paper: BMM, bone marrow-derived macrophage; ChIP, chromatin immunoprecipitation; C_T, cycle threshold; Fp., footpad-derived; HA, hyaluronic acid; LA, Leishmania amazonensis; LMW-HA, low m.w. HA; MOI, multiplicity of infection; PI, propidium iodide; Syk, spleen tyrosine kinase; Qrt-PCR, quantitative real-time PCR.

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