The Journal of Experimental Medicine
StemCell Technologies
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Published online 27 December 2005 doi:10.1084/jem.20051794
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 1, 131-140
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ARTICLE

 MAP kinase phosphatase 1 controls innate immune responses and suppresses endotoxic shock

Qun Zhao1, Xianxi Wang1, Leif D. Nelin1, Yongxue Yao3, Ranyia Matta2, Mary E. Manson1, Reshma S. Baliga1, Xiaomei Meng1, Charles V. Smith1, John A. Bauer1, Cheong-Hee Chang3, and Yusen Liu1,2

1 Children's Research Institute, Columbus Children's Hospital, Department of Pediatrics, and 2 Integrated Biomedical Science Graduate Program, The Ohio State University, Columbus, OH 43205
3 Department of Microbiology and Immunology, Indiana University, Indianapolis, IN 47405

CORRESPONDENCE: Yusen Liu: liuy{at}pediatrics.ohio-state.edu

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.

Abbreviations used: ALT, alanine aminotransferase; ANOVA, analysis of variance; BUN, blood urea nitrogen; ERK, extracellular signal–regulated kinase; IRAK, IL-1 receptor–associated kinase; JNK, c-Jun NH2-terminal kinase; MAP, mitogen-activated protein; MK2, MAP kinase–activated protein kinase 2; MKP, MAP kinase phosphatase; qRT-PCR, quantitative real-time RT-PCR; SOCS, suppressor of cytokine signaling; TLR, Toll-like receptor.


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