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Cell Commun Signal. 2016 Jul 28;14(1):14. doi: 10.1186/s12964-016-0137-y.

Role of PKCtheta in macrophage-mediated immune response to Salmonella typhimurium infection in mice.

Author information

1
Department for Pharmacology and Genetics, Division of Translational Cell Genetics, Peter Mayr Straße 1a, 6020, Innsbruck, Austria.
2
Department of Internal Medicine VI/Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University Innsbruck, Anichstraße 35, 6020, Innsbruck, Austria.
3
Department for Pharmacology and Genetics, Division of Translational Cell Genetics, Peter Mayr Straße 1a, 6020, Innsbruck, Austria. gottfried.baier@i-med.ac.at.

Abstract

BACKGROUND:

The serine/threonine protein kinase C (PKC) theta has been firmly implicated in T cell-mediated immunity. Because its role in macrophages has remained undefined, we employed PKCtheta-deficient (PKCtheta (-/-)) mice in order to investigate if PKCtheta plays a role in macrophage-mediated immune responses during bacterial infections.

RESULTS:

Our results demonstrate that PKCtheta plays an important role in host defense against the Gram-negative, intracellular bacterium Salmonella typhimurium, as reflected both by markedly decreased survival and a significantly enhanced number of bacteria in spleen and liver of PKCtheta (-/-) mice, when compared to wild-type mice. Of note, albeit macrophages do not express detectable PKCtheta, PKCtheta mRNA expression was found to be profoundly upregulated during the first hours of lipopolysaccharide (LPS)/interferon-gamma (IFNgamma)-, but not IL-4-mediated cell polarization conditions in vitro. Mechanistically, despite expressing normal levels of classically activated macrophage (CAM) markers, PKCtheta-deficient CAMs expressed significantly higher levels of the anti-inflammatory cytokine IL-10 in vivo and in vitro when challenged with S. typhimurium or LPS/IFNgamma. Neutralization of IL-10 recovered immune control to S. typhimurium infection in PKCtheta-deficient macrophages.

CONCLUSIONS:

Taken together, our data provide genetic evidence that PKCtheta promotes a potent pro-inflammatory CAM phenotype that is instrumental to mounting protective anti-bacterial immunity. Mechanistically, PKCtheta exerts a host-protective role against S. typhimurium infection, and acts as an essential link between TLR4/IFNgammaR signaling and selective suppression of the anti-inflammatory cytokine IL-10 at the onset of CAM differentiation in the course of a bacterial infection.

KEYWORDS:

IL-10; Innate immunity; Macrophage polarization; Protein kinase C theta; Salmonella typhimurium

PMID:
27465248
PMCID:
PMC4964075
DOI:
10.1186/s12964-016-0137-y
[Indexed for MEDLINE]
Free PMC Article

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