title: MAP kinase phosphatase 1 controls innate immune responses and suppresses endotoxic shock.
abstract: 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.
authors.affiliation: Children's Research Institute, Columbus Children's Hospital, Department of Pediatrics, The Ohio State University, Columbus, OH 43205, USA.
authors.forename: Qun
authors.initials: Q
authors.lastname: Zhao
authors.forename: Xianxi
authors.initials: X
authors.lastname: Wang
authors.forename: Leif D
authors.initials: LD
authors.lastname: Nelin
authors.forename: Yongxue
authors.initials: Y
authors.lastname: Yao
authors.forename: Ranyia
authors.initials: R
authors.lastname: Matta
authors.forename: Mary E
authors.initials: ME
authors.lastname: Manson
authors.forename: Reshma S
authors.initials: RS
authors.lastname: Baliga
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Meng
authors.forename: Charles V
authors.initials: CV
authors.lastname: Smith
authors.forename: John A
authors.initials: JA
authors.lastname: Bauer
authors.forename: Cheong-Hee
authors.initials: CH
authors.lastname: Chang
authors.forename: Yusen
authors.initials: Y
authors.lastname: Liu
mesh_terms: 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
chemical_list: 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