MAP kinase phosphatase 1 controls innate immune responses and suppresses endotoxic shock.
Septic shock is a leading cause of morbidity and mortality. However, genetic factors predisposing to septic shock are not fully understood. Excessive production of proinflammatory cytokines, particularly tumor necrosis factor (TNF)-alpha, and the resultant severe hypotension play a central role in the pathophysiological process. Mitogen-activated protein (MAP) kinase cascades are crucial in the biosynthesis of proinflammatory cytokines. MAP kinase phosphatase (MKP)-1 is an archetypal member of the dual specificity protein phosphatase family that dephosphorylates MAP kinase. Thus, we hypothesize that knockout of the Mkp-1 gene results in prolonged MAP kinase activation, augmented cytokine production, and increased susceptibility to endotoxic shock. Here, we show that knockout of Mkp-1 substantially sensitizes mice to endotoxic shock induced by lipopolysaccharide (LPS) challenge. We demonstrate that upon LPS challenge, Mkp-1-/- cells exhibit prolonged p38 and c-Jun NH2-terminal kinase activation as well as enhanced TNF-alpha and interleukin (IL)-6 production compared with wild-type cells. After LPS challenge, Mkp-1 knockout mice produce dramatically more TNF-alpha, IL-6, and IL-10 than do wild-type mice. Consequently, Mkp-1 knockout mice develop severe hypotension and multiple organ failure, and exhibit a remarkable increase in mortality. Our studies demonstrate that MKP-1 is a pivotal feedback control regulator of the innate immune responses and plays a critical role in suppressing endotoxin shock.
Zhao
Qun
Q
Children's Research Institute, Columbus Children's Hospital, Department of Pediatrics, The Ohio State University, Columbus, OH 43205, USA.
Wang
Xianxi
X
Nelin
Leif D
LD
Yao
Yongxue
Y
Matta
Ranyia
R
Manson
Mary E
ME
Baliga
Reshma S
RS
Meng
Xiaomei
X
Smith
Charles V
CV
Bauer
John A
JA
Chang
Cheong-Hee
CH
Liu
Yusen
Y
D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D054638:Dual Specificity Phosphatase 1; D017874:Immediate-Early Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D007113:Immunity, Innate; D008070:Lipopolysaccharides; D017737:Macrophages, Peritoneal / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D012772:Shock, Septic / Q000401:mortality / Q000517:prevention & control*; D013154:Spleen / Q000166:cytology / Q000276:immunology
D018797:Cell Cycle Proteins; D016207:Cytokines; D017874:Immediate-Early Proteins; D008070:Lipopolysaccharides; D020928:Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse; D017027:Protein Tyrosine Phosphatases