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Increased Inflammation, Impaired Bacterial Clearance, and Metabolic Disruption after Gram-Negative Sepsis in Mkp-1-Deficient Mice¹

W. Joshua Frazier,^* Xianxi Wang,^* Lyn M. Wancket, Xiang-An Li, Xiaomei Meng,^* Leif D. Nelin,^* Andrew C. B. Cato,^¶ and Yusen Liu^2*

*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.

Correspondence: 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

¹ This work was supported by the National Institutes of Health Grants AI68956 and AI57798 (to Y.L.).