title: Role of the IL-23/IL-17 axis in Crohn's disease.
abstract: Crohn's disease is an immune-mediated disease that is characterized by chronic intestinal inflammation. Effector CD4+ T-lymphocytes are expanded in Crohn's disease-associated inflammatory lesions and play a critical role in the pathogenesis of this condition. Recently, a novel population of effector T-lymphocytes has been identified, which is clearly separated from the traditional Th1 and Th2 lineages and is characterized by the secretion of IL-17, hence its designation as Th17. The development of this population has been closely linked to IL-23, a member of the IL-12 family of cytokines. Converging lines of evidence support the hypothesis that the IL-23/Th17 axis is of pathogenic relevance for Crohn's disease. Protein and mRNA levels of IL-23, IL-17, and other Th17 effector cytokines, such as IL-21 and IL-22, are elevated in areas with active Crohn's disease-related inflammation, whereas lamina propria mononuclear cells from patients with Crohn's disease secrete increased amounts of IL-17 upon T-cell receptor-specific stimulation. Genome-wide association studies have identified several Crohn's disease-associated polymorphisms in genes that encode for proteins of the IL-23/Th17 pathway. Functional studies have shown that Th17-related effector cytokines induce pro-inflammatory responses that are components of the pathogenetic mechanisms of Crohn's disease, including recruitment of neutrophils via IL-8 induction, upregulation of inflammatory mediators such as TNF-α, IL-1β, and IL-6, and secretion of metalloproteinases by intestinal fibroblasts. Finally, in several animal models of intestinal inflammation, disease severity is ameliorated when the IL-23/Th17 pathway is rendered deficient. These findings point to a critically important role for IL-23/Th17-mediated immune responses in Crohn's disease pathogenesis and may offer unique therapeutic opportunities for patients.
authors.affiliation: Gastroenterology Division, 1st Department of Propaedeutic and Internal Medicine, Ethnikon and Kapodistriakon Unversity School of Medical Sciences, Laikon Hospital, Athens, 11527, Greece.
authors.forename: Spyros I
authors.initials: SI
authors.lastname: Siakavellas
authors.forename: Giorgos
authors.initials: G
authors.lastname: Bamias
mesh_terms: D000818:Animals; D003424:Crohn Disease / Q000276:immunology / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism*; D053759:Interleukin-23 / Q000378:metabolism*
chemical_list: D016207:Cytokines; D020381:Interleukin-17; D053759:Interleukin-23