Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 203, Issue 1, Pages 131-140Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20051794
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Funding
- NHLBI NIH HHS [R01 HL063067, HL063067] Funding Source: Medline
- NIAID NIH HHS [R21 AI057798, AI045811, AI057798, R01 AI057798, R01 AI045811] Funding Source: Medline
- NIGMS NIH HHS [R01 GM044263, GM044263] Funding Source: Medline
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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.
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