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Reciprocal CD40 signals through p38MAPK and ERK-1/2 induce counteracting immune responses

An Erratum to this article was published on 01 July 2004


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.

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Figure 1: Leishmania regulates CD40 signaling through p38MAPK- and CD40-induced effector functions in macrophages.
Figure 2: CD40-induced p38MAPK and ERK-1/2 regulate each other reciprocally, affecting their respective effector functions.
Figure 3: IL-10 neutralization and ERK-1/2 inhibition restore CD40-induced p38MAPK phosphorylation and restrict parasite growth in vitro.
Figure 4: In a susceptible host, ERK-1/2 inhibition ameliorates Leishmania infection and reinstates TH1 response.


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This work was supported by grants from the Department of Science and Technology, Department of Biotechnology, Indian Council of Medical Research, Council of Scientific and Industrial Research and Life Science Research Board, Government of India.

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Correspondence to Bhaskar Saha.

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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).

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