title: Heterogeneity of subordination of the IL-18/IFN-γ axis to caspase-1 among patients with Crohn's disease.
abstract: In Crohn's disease (CD), hierarchical architecture of the inflammatory network, including subordination of IL-18, an IFN-γ-inducing cytokine, to the inflammasome, have remained undeciphered. Heterogeneity among patients of such a subordination cannot be evaluated by animal models, monofactorial in their etiology and homogenous in disease progression. To address these issues, we set up an ex vivo model of inflamed mucosa explant cultures from patients with active long-standing CD. Th1 cytokine production, especially IFN-γ and IL-18, was assessed in relation with inflammation intensity. Subordination of the Th1 response to caspase-1, effector of the inflammasome, was determined in explant cultures subjected to pharmacological inhibition of caspase-1 by YVAD. We showed a correlation between secreted IFN-γ/IL-18 levels, and caspase-1 activation, with inflammation intensity of intestinal CD mucosa explants. Inhibition of caspase-1 activation using the specific inhibitor YVAD identified a homogenous non responder group featuring a caspase-1-independent IL-18/IFN-γ response, and a heterogenous responder group, in which both IL-18 and IFN-γ responses were caspase-1-dependent, with a 40-70% range of inhibition by YVAD. These findings bring out the concept of heterogeneity of subordination of the Th1 response to inflammasome activation among CD patients. This ex vivo model should have therapeutic relevance in allowing to determine eligibility of CD patients for new targeted therapies.
authors.affiliation: Université de Nantes, EA 4273 Biometadys, Faculté de Médecine, Nantes, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Jarry
authors.affiliation: Université de Nantes, EA 4273 Biometadys, Faculté de Médecine, Nantes, France.|CHU Nantes, Service d'Anatomie et Cytologie Pathologiques, Nantes, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Bossard
authors.affiliation: Université de Nantes, EA 4273 Biometadys, Faculté de Médecine, Nantes, France.|CHU Nantes, Service d'Anatomie et Cytologie Pathologiques, Nantes, France.
authors.forename: Laure
authors.initials: L
authors.lastname: Droy-Dupré
authors.affiliation: CHU Nantes, Plateforme de Biométrie, Nantes, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Volteau
authors.affiliation: CHU Nantes, Institut des Maladies de l'Appareil Digestif (IMAD) et Service d'Hépatogastroentérologie, Nantes, France.|UMR INSERM 913, Faculté de Médecine, Nantes, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Bourreille
authors.affiliation: CHU Nantes, Clinique de Chirurgie Digestive et Endocrinienne, Nantes, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Meurette
authors.affiliation: Université de Nantes, EA 4273 Biometadys, Faculté de Médecine, Nantes, France.|CHU Nantes, Service d'Anatomie et Cytologie Pathologiques, Nantes, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Mosnier
authors.affiliation: Université de Nantes, EA 4273 Biometadys, Faculté de Médecine, Nantes, France.|CHU Nantes, Service d'Anatomie et Cytologie Pathologiques, Nantes, France.
authors.forename: Christian L
authors.initials: CL
authors.lastname: Laboisse
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D020170:Caspase 1 / Q000737:chemistry / Q000378:metabolism*; D061945:Caspase Inhibitors / Q000494:pharmacology; D003106:Colon / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D003424:Crohn Disease / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D004351:Drug Resistance; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D007082:Ileum / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D058847:Inflammasomes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism*; D020382:Interleukin-18 / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D012720:Severity of Illness Index; D046509:Tissue Culture Techniques; D014108:Tosylphenylalanyl Chloromethyl Ketone / Q000031:analogs & derivatives / Q000494:pharmacology; D055815:Young Adult
chemical_list: D015415:Biomarkers; D061945:Caspase Inhibitors; C573415:IFNG protein, human; C000589760:IL18 protein, human; D058847:Inflammasomes; D020382:Interleukin-18; C425776:tyrosyl-valyl-alanyl-aspartic acid fluoromethyl ketone; D014108:Tosylphenylalanyl Chloromethyl Ketone; D007371:Interferon-gamma; D020170:Caspase 1