title: Interleukin-6 signal transduction in human intestinal epithelial cells.
abstract: The gut is an important source of inflammatory cytokines, but there is scant information on the mechanisms of cytokine action in gut epithelium. We hypothesized that in human Caco-2 cells, IL-6 acts directly through stimulation of Stat phosphorylation and that bacterial lipopolysaccharide (LPS) causes Stat activation indirectly because of its ability to cause the autocrine secretion and action of interleukin (IL)-6. Stat1, Stat5a, and Stat5b, but not Stat3, were detected in Caco-2 cells. DNA-binding activity corresponding to activated Stat5 was stimulated in a biphasic manner by IL-6, with a transient early phase, followed by sustained activation between 8 and 48 h. LPS also stimulated Stat5-like binding, but there was no early phase of activation. Functional tests of Stat5 activation showed that IL-6 stimulated Stat5-dependent reporter gene transcription but had no effect on Stat1-dependent transcription. LPS did not stimulate Stat-dependent transcription, nor did it alter the transcriptional response to IL-6. Tyrosine phosphorylation of both Stat5a and Stat5b was induced by IL-6. We infer from these data that IL-6 acts on intestinal epithelia through a Stat5-mediated transcriptional mechanism, whereas LPS does not induce gene expression through autocrine activation of enterocyte Stat signaling. These data provide a basis for testing the in vivo regulation of gut signaling and the interaction of gut reticuloendothelial cells with epithelial signal transduction.
authors.affiliation: Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Ohio 45267-0576, USA.
authors.forename: S L
authors.initials: SL
authors.lastname: Pratt
authors.forename: C K
authors.initials: CK
authors.lastname: Ogle
authors.forename: J X
authors.initials: JX
authors.lastname: Mao
authors.forename: W
authors.initials: W
authors.lastname: Zhao
authors.forename: G
authors.initials: G
authors.lastname: Lovell
authors.forename: N D
authors.initials: ND
authors.lastname: Horseman
mesh_terms: D015500:Chloramphenicol O-Acetyltransferase / Q000096:biosynthesis / Q000235:genetics; D003110:Colonic Neoplasms / Q000473:pathology; D004268:DNA-Binding Proteins / Q000502:physiology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D017930:Genes, Reporter; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008894:Milk Proteins; D009363:Neoplasm Proteins / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D050794:STAT1 Transcription Factor; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects*; D015534:Trans-Activators / Q000502:physiology; D014162:Transfection; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
chemical_list: D004268:DNA-Binding Proteins; D015850:Interleukin-6; D008070:Lipopolysaccharides; D008894:Milk Proteins; D009363:Neoplasm Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; C494095:STAT5B protein, human; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; D015500:Chloramphenicol O-Acetyltransferase