Sufficient production of geranylgeraniol is required to maintain Endotoxin tolerance in macrophages

Jin Ye, Jinyong Kim, Joon No Lee, James Ye, Rosy Hao, Russell Debose-Boyd

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Endotoxin tolerance allows macrophages to produce large quantities of proinflammatory cytokines immediately after their contact with lipopolysaccharides (LPSs), but prevents their further production after repeated exposure to LPSs. While this response is known to prevent overproduction of proinflammatory cytokines, the mechanism through which endotoxin tolerance is established has not been identified. In the current study, we demonstrate that sufficient production of geranylgeraniol (GGOH) in macrophages is required to maintain endotoxin tolerance. We show that increased synthesis of 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR) protein following LPS treatment is required to produce enough GGOH to inhibit expression of Malt1, a protein known to stimulate expression of proinflammatory cytokines, in macrophages repeatedly exposed to LPSs. Depletion of GGOH caused by inhibition of HMGCR led to increased Malt1 expression in macrophages subjected to repeated exposure to LPSs. Consequently, endotoxin tolerance was impaired, and production of interleukin 1-β and other proinflammatory cytokines was markedly elevated in these cells.

Original languageEnglish (US)
Pages (from-to)3430-3437
Number of pages8
JournalJournal of lipid research
Volume54
Issue number12
DOIs
StatePublished - Dec 1 2013

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Keywords

  • HMG-CoA reductase
  • Interleukin 1-β
  • Malt1

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

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