期刊
JOURNAL OF IMMUNOLOGY
卷 192, 期 3, 页码 1184-1195出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1300656
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资金
- National Basic Research Program of China [2010CB945301, 2011CB710900]
- National Natural Science Foundation for General and Key Programs [C81072396, C31171407, 30901908]
- Chinese Academy of Sciences for Distinguished Young Scientists Grant [KSCX2-EW-Q-7]
Neutrophils are critically involved in host defense and tissue damage. Intrinsic signal mechanisms controlling neutrophil activities are poorly defined. We found that the expression of wild-type p53-induced phosphatase 1 (Wip1) in mouse and human neutrophils was downregulated quickly after neutrophil activation through JNK-microRNA-16 pathway. Importantly, the Wip1 expression level was negatively correlated with inflammatory cytokine productions of neutrophils in sepsis patients. Wip1-deficient mice displayed increased bactericidal activities to Staphylococcus aureus and were hypersensitive to LPS-induced acute lung damage with increased neutrophil infiltration and inflammation. Mechanism studies showed that the enhanced inflammatory activity of neutrophils caused by Wip1 deficiency was mediated by p38 MAPK-STAT1 and NF-kappa B pathways. The increased migration ability of Wip1KO neutrophils was mediated by the decreased CXCR2 internalization and desensitization, which was directly regulated by p38 MAPK activity. Thus, our findings identify a previously unrecognized function of Wip1 as an intrinsic negative regulator for neutrophil proinflammatory cytokine production and migration through multiple signal pathways.
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