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*Center for Perinatal Research, The Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205;
Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43210;
Department of Veterinary Biosciences, The Ohio State University College of Veterinary Medicine, Columbus, OH 43210;
Department of Pediatrics, University of Kentucky Medical School, Lexington, KY 40536;
¶Forschungszentrum Karlsruhe, Institute of Toxicology and Genetics, Karlsruhe, Germany
MAPKs are crucial for TNF-
and IL-6 production by innate immune cells in response to TLR ligands. MAPK phosphatase 1 (Mkp-1) deactivates p38 and JNK, abrogating the inflammatory response. We have previously demonstrated that Mkp-1–/– mice exhibit exacerbated inflammatory cytokine production and increased mortality in response to challenge with LPS and heat-killed Staphylococcus aureus. However, the function of Mkp-1 in host defense during live Gram-negative bacterial infection remains unclear. We challenged Mkp-1+/+ and Mkp-1–/– mice with live Escherichia coli i.v. to examine the effects of Mkp-1 deficiency on animal survival, bacterial clearance, metabolic activity, and cytokine production. We found that Mkp-1 deficiency predisposed animals to accelerated mortality and was associated with more robust production of TNF-, IL-6 and IL-10, greater bacterial burden, altered cyclooxygenase-2 and iNOS expression, and substantial changes in the mobilization of energy stores. Likewise, knockout of Mkp-1 also sensitized mice to sepsis caused by cecal ligation and puncture. IL-10 inhibition by neutralizing Ab or genetic deletion alleviated increased bacterial burden. Treatment with the bactericidal antibiotic gentamicin, given 3 h after Escherichia coli infection, protected Mkp-1+/+ mice from septic shock but had no effect on Mkp-1–/– mice. Thus, during Gram-negative bacterial sepsis Mkp-1 not only plays a critical role in the regulation of cytokine production but also orchestrates the bactericidal activities of the innate immune system and controls the metabolic response to stress.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the National Institutes of Health Grants AI68956 and AI57798 (to Y.L.).
2 Address correspondence and reprint requests to Dr. Yusen Liu, Center for Perinatal Research, The Research Institute at Nationwide Children’s Hospital, 700 Children’s Drive, Columbus, OH 43205. E-mail address: yusen.liu{at}nationwidechildrens.org
3 Abbreviations used in this paper: MPO, myeloperoxidase; iNOS, inducible NO synthase; CLP, cecal ligation and puncture; COX-2, cyclooxygenase-2; Mkp-1, MAPK phosphatase 1.
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