期刊
SHOCK
卷 23, 期 1, 页码 80-87出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/01.shk.0000145206.28812.60
关键词
LPS/endotoxin; MKP-1; TNF-alpha; p38; tolerance
资金
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM066839] Funding Source: NIH RePORTER
- NIGMS NIH HHS [1R01GM66839-01] Funding Source: Medline
Endotoxin tolerance has been characterized as diminished TNF-alpha expression after a second LIPS stimulus and is dependent on new protein synthesis. LPS-induced expression of TNF-alpha is partly regulated by the p38 mitogen-activated protein (MAP) kinase, which post-transcriptionally stabilizes TNF-a mRNA. The dual-specific phosphatase, MKP-1, has been shown to negatively regulate p38 via dephosphorylation. We hypothesized that MKP-1 expression induced during tolerance regulates TNF-alpha expression by inhibiting p38 activity. To test this hypothesis, tolerance was induced in THP-1 cells, and naive or tolerized cells were rechallenged 18 h later with LPS (1 mug/mL) and TNF-alpha production was measured. Under similar conditions, nuclear proteins were isolated after LIPS stimulation and were analyzed for phospho-p38 and MKP-1 by Western blot. Transient overexpression of MKP-1 was achieved using an adenoviral expression strategy and infected cells subsequently treated with LIPS for TNF-alpha production and p38 activation. Results showed that LIPS tolerance was induced as reflected by decreased TNF-alpha. Induction of LIPS hyporesponsiveness could be mimicked by overexpression of MKP-1 but not beta-gal. MKP-1 expression was noted only in LPS-tolerized or Ad-MKP-1 infected cells. In the canonical and Ad-MKP-1-mediated tolerance models, decreased phospho-p38 activity was observed. MKP-1s role in mediating endotoxin tolerance was further confirmed by demonstrating the inability to fully tolerize peritoneal macrophages isolated from MKP-1 null mutant (vs. wild type) mice (24% vs. 72% reductions, respectively). These data demonstrate that the dual specific phosphatase MKP-1 is an important mediator of endotoxin tolerance via p38 regulation.
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