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 Citations (Scopus)

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 2013

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Macrophages
Endotoxins
Lipopolysaccharides
Cytokines
Oxidoreductases
Interleukin-1
Proteins
geranylgeraniol
glutaryl-coenzyme A

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Endocrinology

Cite this

Sufficient production of geranylgeraniol is required to maintain Endotoxin tolerance in macrophages. / Ye, Jin; Kim, Jinyong; Lee, Joon No; Ye, James; Hao, Rosy; Debose-Boyd, Russell.

In: Journal of Lipid Research, Vol. 54, No. 12, 12.2013, p. 3430-3437.

Research output: Contribution to journalArticle

Ye, Jin ; Kim, Jinyong ; Lee, Joon No ; Ye, James ; Hao, Rosy ; Debose-Boyd, Russell. / Sufficient production of geranylgeraniol is required to maintain Endotoxin tolerance in macrophages. In: Journal of Lipid Research. 2013 ; Vol. 54, No. 12. pp. 3430-3437.
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