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

Joseph R Maxwell; Yu Zhang; William A Brown; Carole L Smith; Fergus R Byrne; Mike Fiorino; Erin Stevens; Jeannette Bigler; John A Davis; James B Rottman; Alison L Budelsky; Antony Symons; Jennifer E Towne

doi:10.1016/j.immuni.2015.08.019

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

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

Authors

Affiliations

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.

PMID: 26431947
DOI: 10.1016/j.immuni.2015.08.019

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.

Publication types

Comparative Study

MeSH terms

ATP Binding Cassette Transporter, Subfamily B / deficiency
Animals
Colitis / drug therapy
Colitis / etiology
Colitis / immunology*
Colitis / microbiology
Disease Models, Animal
Disease Progression
Epithelium / physiopathology
Female
Forkhead Transcription Factors / analysis
Gene Expression Regulation / immunology
Helicobacter Infections / complications
Helicobacter Infections / immunology
Immunization, Passive
Immunoglobulin G / therapeutic use
Interleukin-12 Subunit p40 / antagonists & inhibitors
Interleukin-17 / immunology
Interleukin-17 / physiology*
Interleukin-23 / immunology
Interleukin-23 / physiology*
Interleukin-23 Subunit p19 / antagonists & inhibitors
Interleukin-23 Subunit p19 / immunology
Intestinal Mucosa / physiopathology
Mice
Mice, Knockout
Permeability
Receptors, Interleukin-17 / antagonists & inhibitors
Receptors, Interleukin-17 / immunology
Receptors, Interleukin-17 / physiology*
T-Lymphocyte Subsets / immunology
T-Lymphocytes, Regulatory / immunology
Transcriptome

Substances

ATP Binding Cassette Transporter, Subfamily B
Forkhead Transcription Factors
Foxp3 protein, mouse
Il17ra protein, mouse
Immunoglobulin G
Interleukin-12 Subunit p40
Interleukin-17
Interleukin-23
Interleukin-23 Subunit p19
Receptors, Interleukin-17
multidrug resistance protein 3

Associated data

GEO/GSE72212