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

Abstract

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 FcγR to induce ERK activation. Macrophages lacking FcγR, or macrophages treated with an inhibitor of spleen tyrosine kinase, the tyrosine kinase that signals via FcγR, 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.

Down-regulation of dendritic cell signaling pathways by Leishmania amazonensis amastigotes

“…Of relevance to this study is the finding that lesion-derived La amastigotes can activate MAPK/ERK1/2 via the superinduction of IL-10 in MΦs (Yang et al, 2007), apparently through the prominent effects of FcγR signaling because these amastigotes are known to be coated with anti-Leishmania IgG Abs (Wanasen et al, 2008). In this study, we have provided strong evidence that alteration in DC signaling pathways during infection with Ab-free amastigotes is not due to endogenous IL-10.…”

SHP-1–Pyk2–Src Protein Complex and p38 MAPK Pathways Independently Regulate IL-10 Production in Lipopolysaccharide-Stimulated Macrophages

“…5) and human macrophages (13). However, we and others have shown that Erk1/2 MAPKs play a role in the regulation of IL-10 production in different model systems (58)(59)(60)62), such as following activation of macrophages with Leishmania amazonesis amastigotes (59,60). Likewise, dendritic cells from Erk 2/ 2 mice displayed a bias toward Th1 response manifested by enhanced IL-12p40 and reduced IL-10 production (58).…”

“…p38 MAPK regulates IL-10 production in both control and SHP-1-null splenic macrophages ERK has been shown to regulate IL-10 production in murine Th1 cells and macrophages (58)(59)(60)(61)(62). p38 MAPK also plays a critical ) were treated with PP2 (0.1-1 mM) for 2 h prior to LPS (10 mg/ml) stimulation for 24 h and IL-10 production was determined by ELISA.…”

Mechanisms of Immune Evasion in Leishmaniasis

“…This complex signaling pathway could either be activated or suppressed leading to the induction of gene products that favor parasite survival. While L. donovani inhibits EKR1/2, p38MAPK, and JNK activation in naïve macrophages leading to the suppression of pro-inflammatory cytokine production (Privé & Descoteaux, 2000), L. amazonensis activates ERK1/2 leading to the production of IL-10, a cytokine that contributes to parasite growth (Yang, Mosser, & Zhang, 2007). Mechanisms behind MAPK inactivation by Leishmania have been extensively studied.…”