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Discov Med. 2012 Oct;14(77):253-62.

Role of the IL-23/IL-17 axis in Crohn's disease.

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  • 1Gastroenterology Division, 1st Department of Propaedeutic and Internal Medicine, Ethnikon and Kapodistriakon Unversity School of Medical Sciences, Laikon Hospital, Athens, 11527, Greece.

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.

PMID:
23114581
[PubMed - indexed for MEDLINE]
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