Author: ["Ram Kumar Mathur","Amit Awasthi","Pallavi Wadhone","B Ramanamurthy","Bhaskar Saha"]
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Abstract
Macrophages play host to Leishmania major, a parasite that causes leishmaniasis in 500,000 people annually. Macrophage-expressed CD40, a costimulatory molecule1, induces interleukin-12 (IL-12)-dependent and interferon-γ (IFN-γ)-dependent host-protective immune responses to Leishmania and other intracellular pathogens2,3,4,5,6. Paradoxically, IL-10, another CD40-induced cytokine in macrophages7, promotes Leishmania infection8. How CD40 signaling regulates the secretion of these two counteractive cytokines remains unknown. Here we show that weak CD40 signals induce extracellular stress–related kinase-1/2 (ERK-1/2)-dependent IL-10 expression, whereas stronger signals induce p38 mitogen-activated protein kinase (p38MAPK)-dependent IL-12 production. p38MAPK and ERK-1/2 therefore have counter-regulatory actions. Leishmania skews CD40 signaling toward ERK-1/2, inducing IL-10, which inhibits activation of CD40-induced p38MAPK and expression of inducible nitric oxide synthase-2 (iNOS-2) and IL-12. ERK-1/2 inhibition or IL-10 neutralization restores CD40-induced p38MAPK activation and parasite killing in macrophages and the BALB/c mouse, a susceptible host. These data uncover a new immune evasion strategy, whereby Leishmania differentially modulates CD40-engaged, reciprocally functioning signaling modules, and provide a new conceptual framework for immune homeostasis.Cite this article
Mathur, R., Awasthi, A., Wadhone, P. et al. Reciprocal CD40 signals through p38MAPK and ERK-1/2 induce counteracting immune responses. Nat Med 10, 540–544 (2004). https://doi.org/10.1038/nm1045 