title: Prostaglandin E2 modulates IL-8 expression through formation of a multiprotein enhanceosome in human colonic epithelial cells.
abstract: Gastrointestinal inflammation is mediated by the pro-inflammatory mediators interleukin-8 (IL-8) and prostaglandin E(2) (PGE(2) ). PGE(2) binding and coupling through EP2/4 receptor subtypes on colonic epithelial cells stimulates cyclic adenosine monophosphate (cAMP) and IL-8 production. Here we determined the mechanisms whereby PGE(2) regu-lates IL-8 in Caco2 colonic epithelial cells and in cells over-expressing the EP2/4 receptors (EP2S/EP4S). PGE(2) coupling through EP2 activated the transcription factor inducible cAMP early repressor (ICER), whereas coupling through EP4 receptors activated the cyclic AMP-responsive element-binding protein (CREB). Activation of CREB in Caco2/EP2S was protein kinase A (PKA) dependent, whereas in EP4S cells, activation of CREB occurred through the PKA and phosphatidylinositol 3-kinase pathways. Since ICER lacks the transactivation domain, it functions as a transcription repressor as opposed to CREB. PGE(2) coupling through EP2/4 receptors can therefore acts in an opposing manner to either decrease (EP2) or promote IL-8 expression by recruiting CREB-binding protein (CBP) (EP4), which formed a multiprotein IL-8 enhanceosome. A novel half CRE (167CRE) and a composite NFAT1-AP1-like site in the IL-8 promoter participated in binding and complex formation as confirmed by mutagenesis and expression studies. These data unravel the mechanisms by which expression of IL-8 is controlled by different signalling pathways that are activated by PGE(2) but acting through different EP receptors.
authors.affiliation: Department of Microbiology, Immunology and Infectious Diseases, Health Sciences Centre, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Vikas
authors.initials: V
authors.lastname: Srivastava
authors.forename: Indranil
authors.initials: I
authors.lastname: Dey
authors.forename: Pearl
authors.initials: P
authors.lastname: Leung
authors.forename: Kris
authors.initials: K
authors.lastname: Chadee
mesh_terms: D018938:Caco-2 Cells; D003106:Colon / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D051786:Cyclic AMP Response Element Modulator / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015232:Dinoprostone / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology*; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020218:Response Elements / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology
chemical_list: C115163:CREB1 protein, human; C497410:CREM protein, human; C508606:CXCL8 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D016209:Interleukin-8; D046912:Multiprotein Complexes; C545644:PTGER2 protein, human; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D051786:Cyclic AMP Response Element Modulator; D019869:Phosphatidylinositol 3-Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D015232:Dinoprostone