title: Human mucosa/submucosa interactions during intestinal inflammation: involvement of the enteric nervous system in interleukin-8 secretion.
abstract: Interleukin-8 (IL-8) is a key chemokine upregulated in various forms of intestinal inflammation, especially those induced by bacteria such as Clostridium difficile (C. difficile). Although interactions between different mucosal and submucosal cellular components have been reported, whether such interactions are involved in the regulation of IL-8 secretion during C. difficile infection is unknown. Moreover, whether the enteric nervous system, a major component of the submucosa, is involved in IL-8 secretion during an inflammatory challenge remains to be determined. In order to investigate mucosa/submucosa interactions that regulate IL-8 secretion, we co-cultured human intestinal mucosa and submucosa. In control condition, IL-8 secretion in co-culture was lower than the sum of the IL-8 secretion of both tissue layers cultured alone. Contrastingly, IL-8 secretion increased in co-culture after mucosal challenge with toxin B of C. difficile through an IL-1 beta-dependent pathway. Moreover, we observed that toxin B of C. difficile increased IL-8 immunoreactivity in submucosal enteric neurones in co-culture and in intact preparations of mucosa/submucosa, through an IL-1 beta-dependent pathway. IL-1 beta also increased IL-8 secretion and IL-8 mRNA expression in human neuronal cell lines (NT2-N and SH-SY5Y), through p38 and ERK1/2 MAP kinase-dependent pathways. Our results demonstrate that mucosa/submucosa interactions regulate IL-8 secretion during inflammatory processes in human through IL-1 beta-dependent pathways. Finally we observed that human submucosal neurones synthesize IL-8, whose production in neurones is induced by IL-1 beta via MAPK-dependent pathways.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U539, Hôpital Hôtel-Dieu, 44035 Nantes, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Tixier
authors.forename: Florent
authors.initials: F
authors.lastname: Lalanne
authors.forename: Ingo
authors.initials: I
authors.lastname: Just
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Galmiche
authors.forename: Michel
authors.initials: M
authors.lastname: Neunlist
mesh_terms: D000368:Aged; D001426:Bacterial Proteins / Q000494:pharmacology*; D001427:Bacterial Toxins / Q000494:pharmacology*; D002478:Cells, Cultured; D016360:Clostridioides difficile / Q000502:physiology; D018920:Coculture Techniques; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D007375:Interleukin-1 / Q000494:pharmacology; D016209:Interleukin-8 / Q000096:biosynthesis*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000382:microbiology / Q000473:pathology; D009092:Mucous Membrane / Q000187:drug effects / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D016601:RNA-Binding Proteins
chemical_list: D001426:Bacterial Proteins; D001427:Bacterial Toxins; D007375:Interleukin-1; D016209:Interleukin-8; D009363:Neoplasm Proteins; D016601:RNA-Binding Proteins; C403447:STRAP protein, human; C031815:toxB protein, Clostridium difficile; D048049:Extracellular Signal-Regulated MAP Kinases