title: Interleukin-23-Independent IL-17 Production Regulates Intestinal Epithelial Permeability.
abstract: Whether interleukin-17A (IL-17A) has pathogenic and/or protective roles in the gut mucosa is controversial and few studies have analyzed specific cell populations for protective functions within the inflamed colonic tissue. Here we have provided evidence for IL-17A-dependent regulation of the tight junction protein occludin during epithelial injury that limits excessive permeability and maintains barrier integrity. Analysis of epithelial cells showed that in the absence of signaling via the IL-17 receptor adaptor protein Act-1, the protective effect of IL-17A was abrogated and inflammation was enhanced. We have demonstrated that after acute intestinal injury, IL-23R(+) γδ T cells in the colonic lamina propria were the primary producers of early, gut-protective IL-17A, and this production of IL-17A was IL-23 independent, leaving protective IL-17 intact in the absence of IL-23. These results suggest that IL-17-producing γδ T cells are important for the maintenance and protection of epithelial barriers in the intestinal mucosa.
authors.affiliation: Merck Research Laboratories, Palo Alto, CA 94304, USA.
authors.forename: Jacob S
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Merck Research Laboratories, Palo Alto, CA 94304, USA.
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Tato
authors.affiliation: Merck Research Laboratories, Palo Alto, CA 94304, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Joyce-Shaikh
authors.forename: Muhammet F
authors.initials: MF
authors.lastname: Gulen
authors.affiliation: Department of Immunology, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA.
authors.forename: Fatih
authors.initials: F
authors.lastname: Gulan
authors.affiliation: Merck Research Laboratories, Palo Alto, CA 94304, USA.
authors.forename: Corinne
authors.initials: C
authors.lastname: Cayatte
authors.affiliation: Merck Research Laboratories, Palo Alto, CA 94304, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Merck Research Laboratories, Palo Alto, CA 94304, USA.
authors.forename: Wendy M
authors.initials: WM
authors.lastname: Blumenschein
authors.affiliation: Merck Research Laboratories, Palo Alto, CA 94304, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Judo
authors.affiliation: Merck Research Laboratories, Palo Alto, CA 94304, USA.
authors.forename: Gulesi
authors.initials: G
authors.lastname: Ayanoglu
authors.affiliation: Merck Research Laboratories, Palo Alto, CA 94304, USA.
authors.forename: Terrill K
authors.initials: TK
authors.lastname: McClanahan
authors.affiliation: Department of Immunology, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Li
authors.affiliation: Merck Research Laboratories, Palo Alto, CA 94304, USA. Electronic address: daniel.cua@merck.com.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Cua
mesh_terms: D000208:Acute Disease; D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000502:physiology; D000818:Animals; D045744:Cell Line, Tumor; D016764:Cell Polarity; D003092:Colitis / Q000139:chemically induced / Q000503:physiopathology*; D003110:Colonic Neoplasms / Q000473:pathology; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D004848:Epithelium / Q000503:physiopathology; D018398:Homeodomain Proteins / Q000502:physiology; D006801:Humans; D020381:Interleukin-17 / Q000172:deficiency / Q000494:pharmacology / Q000502:physiology*; D053759:Interleukin-23 / Q000502:physiology*; D007413:Intestinal Mucosa / Q000503:physiopathology*; D016131:Lymphocyte Subsets / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000172:deficiency; D062793:Occludin / Q000378:metabolism; D010539:Permeability; D021381:Protein Transport; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000032:analysis; D011994:Recombinant Proteins / Q000494:pharmacology; D019108:Tight Junctions / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018398:Homeodomain Proteins; C508717:IL17A protein, human; D020381:Interleukin-17; D053759:Interleukin-23; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D062793:Occludin; C568986:Ocln protein, mouse; D016692:Receptors, Antigen, T-Cell, gamma-delta; D011994:Recombinant Proteins; C539901:Rorc protein, mouse; C515963:Traf3ip2 protein, mouse; D014409:Tumor Necrosis Factor-alpha; C064658:RAG-1 protein; D016264:Dextran Sulfate