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

Mathur, Ram Kumar ; Awasthi, Amit ; Wadhone, Pallavi ; Ramanamurthy, B. ; Saha, Bhaskar (2004) Reciprocal CD40 signals through p38MAPK and ERK-1/2 induce counteracting immune responses Nature Medicine, 10 . pp. 540-544. ISSN 1078-8956

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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.

Item Type:Article
Source:Copyright of this article belongs to Nature Publishing Group.
ID Code:83120
Deposited On:16 Feb 2012 12:37
Last Modified:16 Feb 2012 12:37

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