Effect of cross-tolerance between endotoxin and TNF-α or IL-1β on cellular signaling and mediator production

Marcella Ferlito, Olga G. Romanenko, Sarah Ashton, Francesco Squadrito, Perry V. Halushka, James A. Cook

Research output: Contribution to journalArticlepeer-review

59 Scopus citations


Endotoxin [lipopolysaccharide (LPS)] tolerance suppresses macrophage/monocyte proinflammatory-mediator production. This phenomenon also confers cross-tolerance to other stimuli including tumor necrosis factor (TNF) α and interleukin (IL)-1β. Post-receptor convergence of signal transduction pathways might occur after LPS, IL-1β, and TNF-α stimulation. Therefore, it was hypothesized that down-regulation of common signaling molecules induces cross-tolerance among these stimuli. LPS tolerance and cross-tolerance were examined in THP-1 cells. Phosphorylation of MAP kinases and degradation of inhibitor κBα (IκBα) DNA binding of nuclear factor-κB (NF-κB), and mediator production were examined. In naive cells, LPS, TNF-α, and IL-1β induced IκBα degradation, kinase phosphorylation, and NF-κB DNA binding. LPS stimulation induced production of TNF-α or TxB2 and degradation of IRAK. However, neither TNF-α nor IL-1β induced IRAK degradation or stimulated TNF-α or TxB2 production in naive cells. Pretreatment with each stimulus induced homologous tolerance to restimulation with the same agonist. LPS tolerance also suppressed LPS-induced TxB2 and TNF-α production. LPS pretreatment induced cross-tolerance to TNF-α or IL-1β stimulation. Pretreatment with TNF-α induced cross-tolerance to LPS-induced signaling events and TxB2 production. Although pretreatment with IL-1β did not induce cross-tolerance to LPS-induced signaling events, it strongly inhibited LPS TNF-α and TxB2 production. These data demonstrate that IL-1β induces cross-tolerance to LPS-induced mediator production without suppressing LPS-induced signaling to MAP kinases or NF-κB activation.

Original languageEnglish (US)
Pages (from-to)821-829
Number of pages9
JournalJournal of Leukocyte Biology
Issue number5
StatePublished - 2001
Externally publishedYes


  • MAP kinases
  • Macrophage/monocyte
  • Phosphorylation
  • Signal transduction

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Cell Biology


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