Protein Kinase Cε Is Required for Macrophage Activation and Defense Against Bacterial Infection

To assess directly the role of protein kinase C (PKC)ε in the immune system, we generated mice that carried a homozygous disruption of the PKCε locus. PKCε−/− animals appeared normal and were generally healthy, although female mice frequently developed a bacterial infection of the uterus. Macrophages from PKCε−/− animals demonstrated a severely attenuated response to lipopolysaccharide (LPS) and interferon (IFN)γ, characterized by a dramatic reduction in the generation of NO, tumor necrosis factor (TNF)-α, and interleukin (IL)-1β. Further analysis revealed that LPS-stimulated macrophages from PKCε−/− mice were deficient in the induction of nitric oxide synthase (NOS)-2, demonstrating a decrease in the activation of IκB kinase, a reduction in IκB degradation, and a decrease in nuclear factor (NF)κB nuclear translocation. After intravenous administration of Gram-negative or Gram-positive bacteria, PKCε−/− mice demonstrated a significantly decreased period of survival. This study provides direct evidence that PKCε is critically involved at an early stage of LPS-mediated signaling in activated macrophages. Furthermore, we demonstrate that in the absence of PKCε, host defense against bacterial infection is severely compromised, resulting in an increased incidence of mortality

Protein kinase Cϵ is required for macrophage activation and defense against bacterial infection

12 pages, 7 figures.-- et al.To assess directly the role of protein kinase C (PKC)epsilon in the immune system, we generated mice that carried a homozygous disruption of the PKCepsilon locus. PKCepsilon(-/-) animals appeared normal and were generally healthy, although female mice frequently developed a bacterial infection of the uterus. Macrophages from PKCepsilon(-/-) animals demonstrated a severely attenuated response to lipopolysaccharide (LPS) and interferon (IFN)gamma, characterized by a dramatic reduction in the generation of NO, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-1beta. Further analysis revealed that LPS-stimulated macrophages from PKCepsilon(-/-) mice were deficient in the induction of nitric oxide synthase (NOS)-2, demonstrating a decrease in the activation of IkappaB kinase, a reduction in IkappaB degradation, and a decrease in nuclear factor (NF)kappaB nuclear translocation. After intravenous administration of Gram-negative or Gram-positive bacteria, PKCepsilon(-/-) mice demonstrated a significantly decreased period of survival. This study provides direct evidence that PKCepsilon is critically involved at an early stage of LPS-mediated signaling in activated macrophages. Furthermore, we demonstrate that in the absence of PKCepsilon, host defense against bacterial infection is severely compromised, resulting in an increased incidence of mortality.This work was supported by the Imperial Cancer Research Fund, and grants FEDER 2FD-1997-1432 from Comisión Interministerial de Ciencia y Tecnología (CICYT) and PM98-0120 from Dirección General de Enseñanza Superior e Investigación Científica, Spain. F. Otto was supported by Deutsche Forschungsgemeinschaft grant Ot 134/1-1.Peer reviewe