MAP kinase phosphatase 1 controls innate immune responses and suppresses endotoxic shock
| Autor: | Reshma S. Baliga, Qun Zhao, Yusen Liu, Ranyia Matta, Xianxi Wang, Mary E. Manson, Yongxue Yao, Xiaomei Meng, Leif D. Nelin, Cheong Hee Chang, John Anthony Bauer, Charles V. Smith |
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| Rok vydání: | 2005 |
| Předmět: |
Lipopolysaccharides
Lipopolysaccharide p38 mitogen-activated protein kinases Immunology Cell Cycle Proteins Mice Transgenic Article Proinflammatory cytokine Immediate-Early Proteins 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Protein Phosphatase 1 medicine Phosphoprotein Phosphatases Immunology and Allergy Animals Cells Cultured 030304 developmental biology 0303 health sciences biology Septic shock Dual Specificity Phosphatase 1 Dendritic Cells Articles medicine.disease Shock Septic Immunity Innate chemistry Mitogen-activated protein kinase Shock (circulatory) biology.protein MAP kinase phosphatase Macrophages Peritoneal Cytokines Tumor necrosis factor alpha medicine.symptom Mitogen-Activated Protein Kinases Protein Tyrosine Phosphatases Spleen 030215 immunology |
| Zdroj: | The Journal of Experimental Medicine |
| ISSN: | 0022-1007 |
| Popis: | 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)-α, 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-α and interleukin (IL)-6 production compared with wild-type cells. After LPS challenge, Mkp-1 knockout mice produce dramatically more TNF-α, 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. |
| Databáze: | OpenAIRE |
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