title: The Wnt5a-Ror2 axis promotes the signaling circuit between interleukin-12 and interferon-γ in colitis.
abstract: Wnt5a, which regulates various cellular functions in Wnt signaling, is involved in inflammatory responses, however the mechanism is not well understood. We examined the role of Wnt5a signaling in intestinal immunity using conditional knockout mice for Wnt5a and its receptor Ror2. Removing Wnt5a or Ror2 in adult mice suppressed dextran sodium sulfate (DSS)-induced colitis. It also attenuated the DSS-dependent increase in inflammatory cytokine production and decreased interferon-γ (IFN-γ)-producing CD4(+) Th1 cell numbers in the colon. Wnt5a was highly expressed in stromal fibroblasts in ulcerative lesions in the DSS-treated mice and inflammatory bowel disease patients. Dendritic cells (DCs) isolated from the colon of Wnt5a and Ror2 deficient mice reduced the ability to differentiate naïve CD4(+) T cells to IFN-γ-producing CD4(+) Th1 cells. In vitro experiments demonstrated that the Wnt5a-Ror2 signaling axis augmented the DCs priming effect of IFN-γ, leading to enhanced lipopolysaccharide (LPS)-induced interleukin (IL)-12 expression. Taken together, these results suggest that Wnt5a promotes IFN-γ signaling, leading to IL-12 expression in DCs, and thereby inducing Th1 differentiation in colitis.
authors.affiliation: Departments of Molecular Biology and Biochemistry.
authors.forename: Akira
authors.initials: A
authors.lastname: Sato
authors.affiliation: Microbiology and Immunology, and.
authors.forename: Hisako
authors.initials: H
authors.lastname: Kayama
authors.affiliation: Departments of Molecular Biology and Biochemistry.
authors.forename: Kensaku
authors.initials: K
authors.lastname: Shojima
authors.affiliation: Departments of Molecular Biology and Biochemistry.
authors.forename: Shinji
authors.initials: S
authors.lastname: Matsumoto
authors.affiliation: Departments of Molecular Biology and Biochemistry.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Koyama
authors.affiliation: Department of Physiology and Cell Biology, Graduate School of Medicine, Kobe University, 7-5-1 Kusunoki-cho, Chuoh-ku, Kobe 650-0017, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Minami
authors.affiliation: Pathology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita 565-0871, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nojima
authors.affiliation: Pathology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita 565-0871, Japan.
authors.forename: Eiichi
authors.initials: E
authors.lastname: Morii
authors.affiliation: Department of Disease Model, Research Institute of Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Honda
authors.affiliation: Microbiology and Immunology, and.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takeda
authors.affiliation: Departments of Molecular Biology and Biochemistry.
authors.forename: Akira
authors.initials: A
authors.lastname: Kikuchi
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D016264:Dextran Sulfate / Q000009:adverse effects; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D005347:Fibroblasts / Q000378:metabolism; D015870:Gene Expression; D018836:Inflammation Mediators / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism*; D018664:Interleukin-12 / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009928:Organ Specificity / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D057050:Receptor Tyrosine Kinase-like Orphan Receptors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D000071818:Wnt-5a Protein
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D012333:RNA, Messenger; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C438615:Wnt5a protein, mouse; D018664:Interleukin-12; D007371:Interferon-gamma; D016264:Dextran Sulfate; D057050:Receptor Tyrosine Kinase-like Orphan Receptors; C477010:Ror2 protein, mouse