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Immunity. 2015 Oct 20;43(4):739-50. doi: 10.1016/j.immuni.2015.08.019. Epub 2015 Sep 29.

Differential Roles for Interleukin-23 and Interleukin-17 in Intestinal Immunoregulation.

Author information

1
Department of Inflammation, Amgen, Inc., 1201 Amgen Court West, Seattle, WA 98117, USA.
2
Department of Inflammation, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
3
Department of Clinical Immunology, Amgen, Inc., 1201 Amgen Court West, Seattle, WA 98117, USA.
4
Department of Molecular Sciences and Computational Biology, Amgen, Inc., 1201 Amgen Court West, Seattle, WA 98117, USA.
5
Department of Pharmacokinetics and Drug Metabolism, Amgen, Inc., 1201 Amgen Court West, Seattle, WA 98117, USA.
6
Department of Pathology, Amgen, Inc., 360 Binney Street, Cambridge, MA 02142, USA.
7
Department of Inflammation, Amgen, Inc., 1201 Amgen Court West, Seattle, WA 98117, USA. Electronic address: jtowne1@its.jnj.com.

Abstract

Interleukin-23 (IL-23) and IL-17 are cytokines currently being targeted in clinical trials. Although inhibition of both of these cytokines is effective for treating psoriasis, IL-12 and IL-23 p40 inhibition attenuates Crohn's disease, whereas IL-17A or IL-17 receptor A (IL-17RA) inhibition exacerbates Crohn's disease. This dichotomy between IL-23 and IL-17 was effectively modeled in the multidrug resistance-1a-ablated (Abcb1a(-/-)) mouse model of colitis. IL-23 inhibition attenuated disease by decreasing colonic inflammation while enhancing regulatory T (Treg) cell accumulation. Exacerbation of colitis by IL-17A or IL-17RA inhibition was associated with severe weakening of the intestinal epithelial barrier, culminating in increased colonic inflammation and accelerated mortality. These data show that IL-17A acts on intestinal epithelium to promote barrier function and provide insight into mechanisms underlying exacerbation of Crohn's disease when IL-17A or IL-17RA is inhibited.

PMID:
26431947
DOI:
10.1016/j.immuni.2015.08.019
[Indexed for MEDLINE]
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