Contribution of MKP-1 regulation of p38 to endotoxin tolerance

Marianne Nimah, Bin Zhao, Alvin G. Denenberg, Orlando Bueno, Jeffery Molkentin, Hector R. Wong, Thomas P. Shanley*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

56 Scopus citations

Abstract

Endotoxin tolerance has been characterized as diminished TNF-α expression after a second LPS stimulus and is dependent on new protein synthesis. LPS-induced expression of TNF-α is partly regulated by the p38 mitogen-activated protein (MAP) kinase, which post-transcriptionally stabilizes TNF-α 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-α 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 μg/mL) and TNF-α production was measured. Under similar conditions, nuclear proteins were isolated after LPS 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 LPS for TNF-α production and p38 activation. Results showed that LPS tolerance was induced as reflected by decreased TNF-α. Induction of LPS hyporesponsiveness could be mimicked by overexpression of MKP-1 but not β-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.

Original languageEnglish (US)
Pages (from-to)80-87
Number of pages8
JournalShock
Volume23
Issue number1
DOIs
StatePublished - Jan 2005

Keywords

  • LPS/endotoxin
  • MKP-1
  • TNF-α
  • Tolerance
  • p38

ASJC Scopus subject areas

  • Emergency Medicine
  • Critical Care and Intensive Care Medicine

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