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

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 PKC epsilon locus. PKC epsilon (-/-) animals appeared normal and were generally healthy, although female mice frequently developed a bacterial infection of the uterus. Macrophages from PKC epsilon (-/-) 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)-1 beta. Further analysis revealed that LPS-stimulated macrophages from PKC epsilon (-/-) mice were deficient in the induction of nitric oxide synthase (NOS)-2, demonstrating a decrease in the activation of I kappaB kinase, a reduction in I kappaB degradation, and a decrease in nuclear factor (NF)kappaB nuclear translocation. After intravenous administration of Gram-negative or Gram-positive bacteria, PKC epsilon (-/-) mice demonstrated a significantly decreased period of survival. This study provides direct evidence that PKC epsilon is critically involved at an early stage of LPS-mediated signaling in activated macrophages. Furthermore, we demonstrate that in the absence of PKC epsilon, host defense against bacterial infection is severely compromised, resulting in an increased incidence of mortality.