STAT signaling underlies difference between flagellin-induced and tumor necrosis factor-α-induced epithelial gene expression

Yimin Yu, Hui Zeng, Matam Vijay-Kumar, Andrew S. Neish, Didier Merlin, Shanthi V. Sitaraman, Andrew T. Gewirtz

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Both bacterial flagellin and the cytokine tumor necrosis factor-α (TNFα) are potent activators of intestinal epithelial cell pro-inflammatory gene expression in general; nonetheless, there seem to be distinct differences in the specific patterns of gene expression induced by these agonists. The goal of this study was to define one such difference and elucidate the signaling mechanism responsible for such differential gene induction by these agonists. We observed that expression of inducible nitric-oxide synthase is substantially induced by flagellin but only minimally expressed in response to TNFα. This difference seemed to be underlain by differential induction of signal transducers and activators of transcription (STAT) activation in that, whereas flagellin and TNFα seemed to be equipotent activators of p38 mitogen-activated protein kinase and nuclear factor-κB, flagellin induced substantially higher levels of STAT-1 and -3 tyrosine phosphorylation. Such flagellin-induced STAT activation exhibited delayed kinetics and was ablated by treatment with cycloheximide. Flagellin-induced activation of STAT-3 was abolished via neutralizing antibodies to interleukin (IL)-6, but not interferon (IFN)β nor IFNγ; none of these neutralizing antibodies had any effect on flagellin-induced STAT-1 tyrosine phosphorylation. Flagellin induced substantially more IL-6 expression than did TNFα, but neither agonist elicited detectable levels of IFN expression. Flagellin-induced expression of inducible nitric-oxide synthase but not IL-6, was abolished by blocking STAT activation with AG490, and was reduced by blocking STAT-3 activation with anti-IL-6. Together, these results indicate that epithelial cell induction of flagellin-specific gene expression is mediated, in part, by STAT activation that results from autocrine activation via IL-6.

Original languageEnglish (US)
Pages (from-to)35210-35218
Number of pages9
JournalJournal of Biological Chemistry
Volume279
Issue number34
DOIs
StatePublished - Aug 20 2004

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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