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

• Published in: The Journal of immunology (1950) 2009-12, Vol.183 (11), p.7411-7419
• Main Authors: Frazier, W. Joshua, Wang, Xianxi, Wancket, Lyn M, Li, Xiang-An, Meng, Xiaomei, Nelin, Leif D, Cato, Andrew C. B, Liu, Yusen
• Format: Article
• Language: English
• Subjects: Animals; Cyclooxygenase 2 - biosynthesis; Cyclooxygenase 2 - immunology; Dual Specificity Phosphatase 1 - deficiency; Dual Specificity Phosphatase 1 - immunology; Enzyme-Linked Immunosorbent Assay; Escherichia coli; Escherichia coli Infections - immunology; Escherichia coli Infections - metabolism; Glucose - metabolism; Glycogen - metabolism; Gram-Negative Bacterial Infections - immunology; Gram-Negative Bacterial Infections - metabolism; Hyperlipidemias - metabolism; Hyperlipidemias - microbiology; Inflammation - immunology; Inflammation - metabolism; Inflammation - microbiology; Interleukin-10 - biosynthesis; Interleukin-10 - immunology; Interleukin-6 - biosynthesis; Interleukin-6 - immunology; Lipid Metabolism - immunology; Mice; Mice, Knockout; Nitric Oxide Synthase Type II - biosynthesis; Nitric Oxide Synthase Type II - immunology; Sepsis - immunology; Sepsis - microbiology; Tumor Necrosis Factor-alpha - biosynthesis; Tumor Necrosis Factor-alpha - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.0804343

MAPKs are crucial for TNF-alpha 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-alpha, 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.