Dynamic regulation of pro- and anti-inflammatory cytokines by MAPK phosphatase 1 (MKP-1) in innate immune responses
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- Hongbo Chi
- *Section of Immunobiology,
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- Sean P. Barry
- *Section of Immunobiology,
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- Rachel J. Roth
- Department of Pharmacology, and
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- J. Julie Wu
- Department of Pharmacology, and
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- Elizabeth A. Jones
- *Section of Immunobiology,
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- Anton M. Bennett
- Department of Pharmacology, and
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- Richard A. Flavell
- *Section of Immunobiology,
抄録
<jats:p> Engagement of Toll-like receptors (TLRs) on macrophages leads to activation of the mitogen-activated protein kinases (MAPKs), which contribute to innate immune responses. MAPK activity is regulated negatively by MAPK phosphatases (MKPs). MKP-1, the founding member of this family of dual-specificity phosphatases, has been implicated in regulating lipopolysaccharide (LPS) responses, but its role in TLR-mediated immune responses <jats:italic>in vivo</jats:italic> has not been defined. Here, we show that mice deficient in MKP-1 were highly susceptible to endotoxic shock <jats:italic>in vivo</jats:italic> , associated with enhanced production of proinflammatory cytokines TNF-α and IL-6 and an anti-inflammatory cytokine, IL-10. We further examined the regulation and function of MKP-1 in macrophages, a major cell type involved in endotoxic shock. MKP-1 was transiently induced by TLR stimulation through pathways mediated by both myeloid differentiation factor 88 (MyD88) and TIR domain-containing adaptor inducing IFN-β (TRIF). MKP-1 deficiency led to sustained activation of p38 MAPK and c-Jun N-terminal kinase (JNK) in LPS-treated macrophages. In response to TLR signals, MKP-1-deficient macrophages produced 5- to 10-fold higher IL-10, which could be blocked by a p38 MAPK inhibitor. Thus, p38 MAPK plays a critical role in mediating IL-10 synthesis in TLR signaling. TNF-α was found to be more abundant in MKP-1-deficient macrophages within 2 hours of TLR stimulation, but its production was rapidly down-regulated by IL-10. Our studies demonstrate that MKP-1 attenuates the activities of p38 MAPK and JNK to regulate both pro- and anti-inflammatory cytokines in TLR signaling. These results highlight the complex mechanisms by which the MAPKs regulate innate immunity. </jats:p>
収録刊行物
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- Proceedings of the National Academy of Sciences
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Proceedings of the National Academy of Sciences 103 (7), 2274-2279, 2006-02-06
Proceedings of the National Academy of Sciences
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詳細情報 詳細情報について
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- CRID
- 1363107371190326016
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- NII論文ID
- 80019273083
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- ISSN
- 10916490
- 00278424
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