The Journal of Experimental Medicine
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Published 29 October 2001. doi:10.1084/jem.194.9.1231
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© Rockefeller University Press, 0022-1007/2001/11/1231/ $5.00
The Journal of Experimental Medicine, Volume 194, Number 9, November 5, 2001 1231-1242

Original Article

Protein Kinase C{epsilon} Is Required for Macrophage Activation and Defense Against Bacterial Infection

Antonio Castrillo1, Daniel J. Pennington2, Florian Otto3, Peter J. Parker2, Michael J. Owen2 and Lisardo Boscá1

1 Instituto de Bioquímica (Centro Mixto Consejo Superior de Investigaciones Cientificas-UCM), Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain
2 Imperial Cancer Research Fund, London WC2A 3PX, United Kingdom
3 Universitaetsklinik, Nothnagel-Laboratorien, D-79106 Freiburg, Germany

Address correspondence to Lisardo Boscá, Instituto de Bioquímica, Facultad de Farmacia, 28040 Madrid, Spain. Phone: 34-91394-1853; Fax: 34-91544-7254; E-mail: boscal{at}eucmax.sim.ucm.es

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)-1ß. 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{kappa}B kinase, a reduction in I{kappa}B degradation, and a decrease in nuclear factor (NF){kappa}B 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.

Key Words: nitric oxide • protein kinase C • nitric oxide synthase • macrophage activation • bacterial infection


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