title: Proteasome inhibitors exacerbate interleukin-8 production induced by protease-activated receptor 2 in intestinal epithelial cells.
abstract: Protease activated receptors (PARs) and the ubiquitin-proteasome system (UPS) regulate inflammatory response in intestinal cells. We aimed to elucidate putative connections between PARs and UPS pathways in intestinal epithelial cells. Caco-2 cells were treated by agonist peptides of PARs and/or IL-1β and/or proteasome inhibitors, bortezomib or MG132. Inflammatory response was evaluated by measuring IL-8 production. Proteasome activities were also evaluated. We showed that PAR-1 and -2 activation increased release of IL-8 compared with vehicle and independently of IL-1β. In contrast, PAR-4 agonist peptide had no effect. Caspase-like and chymotrypsin-like proteasomal activities were increased by PAR-2 activation only in the presence of IL-1β. Interestingly, in polarized Caco-2 cells, the release of IL-8 was predominantly upregulated in the side where PAR-2 agonist peptide was added, apical or basalolateral. In contrast, proteasome activities were only affected when PAR-2 agonist peptide was added in the apical side. Proteasome inhibitors, bortezomib and MG132, enhanced IL-8 production in both sides, apical and basolateral. In conclusion, PAR-2 activation alone did not affect proteasome but needed inflammatory stimulus IL-1β to synergistically increase chymotrypsin-like activity in intestinal epithelial cells. However, proteasome inhibition led to exacerbate inflammatory response induced by PAR-2 activation.
authors.affiliation: Normandie Univ, INSERM Unit 1073, Nutrition, Inflammation and Gut-Brain Axis, Rouen, France; University of Rouen, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France.
authors.forename: Ibtissem
authors.initials: I
authors.lastname: Ghouzali
authors.affiliation: Normandie Univ, INSERM Unit 1073, Nutrition, Inflammation and Gut-Brain Axis, Rouen, France; University of Rouen, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France.
authors.forename: Saïda
authors.initials: S
authors.lastname: Azhar
authors.affiliation: Normandie Univ, INSERM Unit 1073, Nutrition, Inflammation and Gut-Brain Axis, Rouen, France; University of Rouen, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Bôle-Feysot
authors.affiliation: Normandie Univ, INSERM Unit 1073, Nutrition, Inflammation and Gut-Brain Axis, Rouen, France; University of Rouen, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France; Department of Gastroenterology, Rouen University Hospital, Rouen, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Ducrotté
authors.affiliation: Normandie Univ, INSERM Unit 1073, Nutrition, Inflammation and Gut-Brain Axis, Rouen, France; University of Rouen, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France; Department of Nutrition, Rouen University Hospital, Rouen, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Déchelotte
authors.affiliation: Normandie Univ, INSERM Unit 1073, Nutrition, Inflammation and Gut-Brain Axis, Rouen, France; University of Rouen, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France; Department of Nutrition, Rouen University Hospital, Rouen, France. Electronic address: moise.coeffier@univ-rouen.fr.
authors.forename: Moïse
authors.initials: M
authors.lastname: Coëffier
mesh_terms: D000069286:Bortezomib / Q000494:pharmacology; D018938:Caco-2 Cells; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000276:immunology / Q000378:metabolism; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D007976:Leupeptins / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D044464:Receptor, PAR-2 / Q000819:agonists / Q000378:metabolism*
chemical_list: D053583:Interleukin-1beta; D016209:Interleukin-8; D007976:Leupeptins; D010455:Peptides; D061988:Proteasome Inhibitors; D044464:Receptor, PAR-2; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde
keywords: Interleukin; Intestinal epithelial cells; Protease-activated receptor-2; Proteasome