Journal
JOURNAL OF IMMUNOLOGY
Volume 178, Issue 2, Pages 1077-1085Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.178.2.1077
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Funding
- NIAID NIH HHS [R01 AI055576, R01 AI055576-04, R21 AI055576, AI 55576] Funding Source: Medline
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IL-10 is a critical cytokine in determining host susceptibility to Leishmania spp. We previously demonstrated that macrophagederived 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 Fc gamma R to induce ERK activation. Macrophages lacking Fc gamma R, or macrophages treated with an inhibitor of spleen tyrosine kinase, the tyrosine kinase that signals via Fc gamma R, 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.
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