title: STAT signaling underlies difference between flagellin-induced and tumor necrosis factor-alpha-induced epithelial gene expression.
abstract: Both bacterial flagellin and the cytokine tumor necrosis factor-alpha (TNFalpha) 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 TNFalpha. This difference seemed to be underlain by differential induction of signal transducers and activators of transcription (STAT) activation in that, whereas flagellin and TNFalpha seemed to be equipotent activators of p38 mitogen-activated protein kinase and nuclear factor-kappaB, 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)beta nor IFNgamma; none of these neutralizing antibodies had any effect on flagellin-induced STAT-1 tyrosine phosphorylation. Flagellin induced substantially more IL-6 expression than did TNFalpha, 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.
authors.affiliation: Department of Pathology, Division of Digestive Diseases, Emory University, Atlanta, Georgia 30322, USA.
authors.forename: Yimin
authors.initials: Y
authors.lastname: Yu
authors.forename: Hui
authors.initials: H
authors.lastname: Zeng
authors.forename: Matam
authors.initials: M
authors.lastname: Vijay-Kumar
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Neish
authors.forename: Didier
authors.initials: D
authors.lastname: Merlin
authors.forename: Shanthi V
authors.initials: SV
authors.lastname: Sitaraman
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Gewirtz
mesh_terms: D019898:Autocrine Communication; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005408:Flagellin / Q000378:metabolism* / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D012486:Salmonella typhimurium; D015398:Signal Transduction / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D004268:DNA-Binding Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D005408:Flagellin