Increased inflammation, impaired bacterial clearance, and metabolic disruption after gram-negative sepsis in Mkp-1-deficient mice.
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.
Frazier
W Joshua
WJ
Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.
Wang
Xianxi
X
Wancket
Lyn M
LM
Li
Xiang-An
XA
Meng
Xiaomei
X
Nelin
Leif D
LD
Cato
Andrew C B
AC
Liu
Yusen
Y
D000818:Animals; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000276:immunology; D054638:Dual Specificity Phosphatase 1 / Q000172:deficiency / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D004926:Escherichia coli; D004927:Escherichia coli Infections / Q000276:immunology* / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D016905:Gram-Negative Bacterial Infections / Q000276:immunology / Q000378:metabolism; D006949:Hyperlipidemias / Q000378:metabolism / Q000382:microbiology; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D016753:Interleukin-10 / Q000096:biosynthesis / Q000276:immunology; D015850:Interleukin-6 / Q000096:biosynthesis / Q000276:immunology; D050356:Lipid Metabolism / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis / Q000276:immunology; D018805:Sepsis / Q000276:immunology* / Q000382:microbiology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology
D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D006003:Glycogen; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse; D005947:Glucose