Superinduction of IL-6 by cycloheximide is associated with mRNA stabilization and sustained activation of p38 map kinase and NF-κB in cultured Caco-2 cells

Dan D. Hershko, Bruce W. Robb, Curtis J. Wray, Guan Ju Luo, Per Olof Hasselgren

Research output: Contribution to journalArticle

47 Scopus citations

Abstract

Protein synthesis inhibitors paradoxically increase the expression of early-gene products, including various cytokines, through a process known as superinduction. Superinduction is cell-specific and the mechanisms involved are not fully understood but are usually attributed to decreased mRNAdegradation. There is, however, increasing evidence that activation of signaling cascades and increased transcriptional activation may be involved as well. Recent studies suggest that IL-6 production in the intestinal mucosa is particularly important due to its anti-inflammatory and protective effects. The effect of protein synthesis inhibitors on IL-6 production in enterocytes, however, is unknown. Treatment of Caco-2 cells with cycloheximide (10 μg/ml) increased IL-6 mRNA and protein levels in IL-1 β-treated cells and this was associated with increased mRNA stabilization. In addition, cycloheximide suppressed IκBα resynthesis and prolonged p38MAP kinase activation and these changes were associated with sustained activation of the transcription factor NF-κB. NF-κB activation, in turn, was prevented by the specific p38MAP kinase inhibitor SB208350. Our results suggest that superinduction of IL-6 by cycloheximide in enterocytes results from both increased mRNA stabilization and upregulated transcriptional activity mediated by prolonged activation of the p38 MAP kinase and NF-κB.

Original languageEnglish (US)
Pages (from-to)951-961
Number of pages11
JournalJournal of Cellular Biochemistry
Volume91
Issue number5
DOIs
StatePublished - Dec 1 2004
Externally publishedYes

Keywords

  • Cell signaling
  • Cytokines
  • Enterocytes
  • Protein synthesis inhibitors
  • Transcription factors

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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