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Departments of
* Biochemical Pharmacology and
Molecular Toxicology, University of Konstanz, Konstanz, Germany;
Medical School Hannover, Institute of Biochemistry, Hannover, Germany; and
Neurobiology, H. Lundbeck A/S, Valby, Denmark
Mitogen-activated protein kinase-activated protein kinase 2
(MK2) is one of several kinases activated through direct
phosphorylation by p38 mitogen-activated protein kinase. MK2 regulates
LPS-induced TNF mRNA translation, and targeted mutation of the MK2 gene
renders mice more resistant to D-galactosamine plus
LPS-induced liver damage. In the present study, we investigated the
role of MK2 in immune defense against Listeria
monocytogenes infection. MK2-deficient mice displayed
diminished resistance to L. monocytogenes due to
impaired control of bacterial growth. The increase in bacterial load in
MK2-/- mice was associated with normal levels of IL-1
,
IL-6, and IFN-
, whereas TNF production was strongly attenuated. In
line, MK2-deficient bone marrow-derived macrophages showed impaired
release of TNF, but not of IL-1, in response to various bacterial
stimuli in addition to decreased phagocytosis of fluorescence-labeled
bacteria. Furthermore, spleen cells from MK2-/- mice
displayed diminished IFN- synthesis after stimulation with L.
monocytogenes. In contrast, MK2 deficiency had no effect on
macrophage generation of NO or on oxidative burst activity in response
to L. moocytogenes. These results
indicate an essential role of MK2 in host defense against intracellular
bacteria probably via regulation of TNF and IFN- production required
for activation of antibacterial effector
mechanisms.
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