Protein kinase C epsilon is required for macrophage activation and defenseagainst 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 e psilon 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 seve rely attenuated response to lipopolysaccharide (LPS) and interferon (IFN)ga mma, characterized by a dramatic reduction in the generation of NO, tumor n ecrosis factor (TNF)-alpha, and interleukin (IL)-1 beta. Further analysis r evealed that LPS-stimulated macrophages from PKC epsilon (-/-) mice were de ficient in the induction of nitric oxide synthase (NOS)-2, demonstrating a decrease in the activation of I kappaB kinase, a reduction in I kappaB degr adation, and a decrease in nuclear factor (NF)kappaB nuclear translocation. After intravenous administration of Gram-negative or Gram-positive bacteri a, PKC epsilon (-/-) mice demonstrated a significantly decreased period of survival. This study provides direct evidence that PKC epsilon is criticall y involved at an early stage of LPS-mediated signaling in activated macroph ages. Furthermore, we demonstrate that in the absence of PKC epsilon, host defense against bacterial infection is severely compromised, resulting in a n increased incidence of mortality.