title: Differential Roles for Interleukin-23 and Interleukin-17 in Intestinal Immunoregulation.
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.
authors.affiliation: Department of Inflammation, Amgen, Inc., 1201 Amgen Court West, Seattle, WA 98117, USA.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Maxwell
authors.affiliation: Department of Inflammation, Amgen, Inc., 1201 Amgen Court West, Seattle, WA 98117, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Inflammation, Amgen, Inc., 1201 Amgen Court West, Seattle, WA 98117, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Brown
authors.affiliation: Department of Inflammation, Amgen, Inc., 1201 Amgen Court West, Seattle, WA 98117, USA.
authors.forename: Carole L
authors.initials: CL
authors.lastname: Smith
authors.affiliation: Department of Inflammation, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
authors.forename: Fergus R
authors.initials: FR
authors.lastname: Byrne
authors.affiliation: Department of Inflammation, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
authors.forename: Mike
authors.initials: M
authors.lastname: Fiorino
authors.affiliation: Department of Clinical Immunology, Amgen, Inc., 1201 Amgen Court West, Seattle, WA 98117, USA.
authors.forename: Erin
authors.initials: E
authors.lastname: Stevens
authors.affiliation: Department of Molecular Sciences and Computational Biology, Amgen, Inc., 1201 Amgen Court West, Seattle, WA 98117, USA.
authors.forename: Jeannette
authors.initials: J
authors.lastname: Bigler
authors.affiliation: Department of Pharmacokinetics and Drug Metabolism, Amgen, Inc., 1201 Amgen Court West, Seattle, WA 98117, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Davis
authors.affiliation: Department of Pathology, Amgen, Inc., 360 Binney Street, Cambridge, MA 02142, USA.
authors.forename: James B
authors.initials: JB
authors.lastname: Rottman
authors.affiliation: Department of Inflammation, Amgen, Inc., 1201 Amgen Court West, Seattle, WA 98117, USA.
authors.forename: Alison L
authors.initials: AL
authors.lastname: Budelsky
authors.affiliation: Department of Inflammation, Amgen, Inc., 1201 Amgen Court West, Seattle, WA 98117, USA.
authors.forename: Antony
authors.initials: A
authors.lastname: Symons
authors.affiliation: Department of Inflammation, Amgen, Inc., 1201 Amgen Court West, Seattle, WA 98117, USA. Electronic address: jtowne1@its.jnj.com.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Towne
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency; D000818:Animals; D003092:Colitis / Q000188:drug therapy / Q000209:etiology / Q000276:immunology* / Q000382:microbiology; D004195:Disease Models, Animal; D018450:Disease Progression; D004848:Epithelium / Q000503:physiopathology; D005260:Female; D051858:Forkhead Transcription Factors / Q000032:analysis; D005786:Gene Expression Regulation / Q000276:immunology; D016481:Helicobacter Infections / Q000150:complications / Q000276:immunology; D007116:Immunization, Passive; D007074:Immunoglobulin G / Q000627:therapeutic use; D053762:Interleukin-12 Subunit p40 / Q000037:antagonists & inhibitors; D020381:Interleukin-17 / Q000276:immunology / Q000502:physiology*; D053759:Interleukin-23 / Q000276:immunology / Q000502:physiology*; D053760:Interleukin-23 Subunit p19 / Q000037:antagonists & inhibitors / Q000276:immunology; D007413:Intestinal Mucosa / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D010539:Permeability; D053722:Receptors, Interleukin-17 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D016176:T-Lymphocyte Subsets / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D059467:Transcriptome
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C491673:Il17ra protein, mouse; D007074:Immunoglobulin G; D053762:Interleukin-12 Subunit p40; D020381:Interleukin-17; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D053722:Receptors, Interleukin-17; C095122:multidrug resistance protein 3