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* Center for Perinatal Research, Columbus Children’s Research Institute, Columbus Children’s Hospital, Columbus, OH 43205;
Department of Laboratory Medicine, Columbus Children’s Hospital, Columbus, OH 43205;
Department of Pediatrics and
Department of Pathology, The Ohio State University College of Medicine, Columbus, OH 43210; and
¶ Division of Infectious Diseases, Department of Pediatrics, University of Tennessee Health Science Center, and The Children’s Foundation Research Center, Le Bonheur Children’s Medical Center, Memphis, TN 38103
MAPK phosphatase (MKP)-1 is an archetypal member of the dual specificity protein phosphatase family that dephosphorylates MAPK. We have previously demonstrated that MKP-1 acts as a negative regulator of p38 and JNK in immortalized macrophages after stimulation with peptidoglycan isolated from Gram-positive bacteria. To define the physiological function of MKP-1 during Gram-positive bacterial infection, we studied the innate immune responses to Gram-positive bacteria using Mkp-1 knockout (KO) mice. We found that Mkp-1–/– macrophages exhibited prolonged activation of p38 and JNK, but not of ERK, following exposure to either peptidoglycan or lipoteichoic acid. Compared with wild-type (WT) macrophages, Mkp-1–/– macrophages produced more proinflammatory cytokines such as TNF-
and IL-6. Moreover, after challenge with peptidoglycan, lipoteichoic acid, live or heat-killed Staphylococcus aureus bacteria, Mkp-1 KO mice also mounted a more robust production of cytokines and chemokines, including TNF-, IL-6, IL-10, and MIP-1, than did WT mice. Accordingly, Mkp-1 KO mice also exhibited greater NO production, more robust neutrophil infiltration, and more severe organ damage than did WT mice. Surprisingly, WT and Mkp-1 KO mice exhibited no significant difference in either bacterial load or survival rates when infected with live S. aureus. However, in response to challenge with heat-killed S. aureus, Mkp-1 KO mice exhibited a substantially higher mortality rate compared with WT mice. Our studies indicate that MKP-1 plays a critical role in the inflammatory response to Gram-positive bacterial infection. MKP-1 serves to limit the inflammatory reaction by inactivating JNK and p38, thus preventing multiorgan failure caused by exaggerated inflammatory responses.
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 Columbus Children’s Research Institute and a grant from the National Institutes of Health (AI057798; to Y.L.).
2 Address correspondence and reprint requests to Dr. Yusen Liu, Center for Perinatal Research, Columbus Children’s Research Institute, 700 Children’s Drive, Columbus, OH 43205. E-mail address: liuy{at}pediatrics.ohio-state.edu
3 Abbreviations used in this paper: CA-MRSA, community acquired, methicillin-resistant strains of S. aureus; PepG, peptidoglycan; LTA, lipoteichoic acid; NOD, nucleotide oligomerization domain; iNOS, inducible NO synthase; eNOS, endothelial NO synthase; MKP, MAP kinase phosphatase; BUN, blood urea nitrogen; MPO, myeloperoxidase; WT, wild type; KO, knockout.
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