title: Role of PKCtheta in macrophage-mediated immune response to Salmonella typhimurium infection in mice.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department for Pharmacology and Genetics, Division of Translational Cell Genetics, Peter Mayr Straße 1a, 6020, Innsbruck, Austria.|Department of Internal Medicine VI/Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University Innsbruck, Anichstraße 35, 6020, Innsbruck, Austria.
authors.forename: Christa
authors.initials: C
authors.lastname: Pfeifhofer-Obermair
authors.affiliation: Department for Pharmacology and Genetics, Division of Translational Cell Genetics, Peter Mayr Straße 1a, 6020, Innsbruck, Austria.
authors.forename: Karin
authors.initials: K
authors.lastname: Albrecht-Schgoer
authors.affiliation: Department for Pharmacology and Genetics, Division of Translational Cell Genetics, Peter Mayr Straße 1a, 6020, Innsbruck, Austria.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Peer
authors.affiliation: Department of Internal Medicine VI/Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University Innsbruck, Anichstraße 35, 6020, Innsbruck, Austria.
authors.forename: Manfred
authors.initials: M
authors.lastname: Nairz
authors.affiliation: Department for Pharmacology and Genetics, Division of Translational Cell Genetics, Peter Mayr Straße 1a, 6020, Innsbruck, Austria.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Siegmund
authors.affiliation: Department for Pharmacology and Genetics, Division of Translational Cell Genetics, Peter Mayr Straße 1a, 6020, Innsbruck, Austria.
authors.forename: Victoria
authors.initials: V
authors.lastname: Klepsch
authors.affiliation: Department of Internal Medicine VI/Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University Innsbruck, Anichstraße 35, 6020, Innsbruck, Austria.
authors.forename: David
authors.initials: D
authors.lastname: Haschka
authors.affiliation: Department for Pharmacology and Genetics, Division of Translational Cell Genetics, Peter Mayr Straße 1a, 6020, Innsbruck, Austria.
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Thuille
authors.affiliation: Department for Pharmacology and Genetics, Division of Translational Cell Genetics, Peter Mayr Straße 1a, 6020, Innsbruck, Austria.
authors.forename: Natascha
authors.initials: N
authors.lastname: Hermann-Kleiter
authors.affiliation: Department for Pharmacology and Genetics, Division of Translational Cell Genetics, Peter Mayr Straße 1a, 6020, Innsbruck, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gruber
authors.affiliation: Department of Internal Medicine VI/Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University Innsbruck, Anichstraße 35, 6020, Innsbruck, Austria.
authors.forename: Günter
authors.initials: G
authors.lastname: Weiss
authors.affiliation: Department for Pharmacology and Genetics, Division of Translational Cell Genetics, Peter Mayr Straße 1a, 6020, Innsbruck, Austria. gottfried.baier@i-med.ac.at.
authors.forename: Gottfried
authors.identifier: 0000-0002-2085-8325
authors.initials: G
authors.lastname: Baier
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D000074121:Protein Kinase C-theta; D012480:Salmonella Infections / Q000276:immunology*; D012486:Salmonella typhimurium / Q000276:immunology
chemical_list: D007527:Isoenzymes; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta
keywords: IL-10; Innate immunity; Macrophage polarization; Protein kinase C theta; Salmonella typhimurium