title: Temporal expression of growth factors triggered by epiregulin regulates inflammation development.
abstract: In this study, we investigated the relationship between several growth factors and inflammation development. Serum concentrations of epiregulin, amphiregulin, betacellulin, TGF-α, fibroblast growth factor 2, placental growth factor (PLGF), and tenascin C were increased in rheumatoid arthritis patients. Furthermore, local blockades of these growth factors suppressed the development of cytokine-induced arthritis in mice by inhibiting chemokine and IL-6 expressions. We found that epiregulin expression was early and followed by the induction of other growth factors at different sites of the joints. The same growth factors then regulated the expression of epiregulin at later time points of the arthritis. These growth factors were increased in patients suffering from multiple sclerosis (MS) and also played a role in the development of an MS model, experimental autoimmune encephalomyelitis. The results suggest that the temporal expression of growth factors is involved in the inflammation development seen in several diseases, including rheumatoid arthritis and MS. Therefore, various growth factor pathways might be good therapeutic targets for various inflammatory diseases.
authors.affiliation: Division of Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-0815, Japan; Laboratory of Developmental Immunology, Japan Science and Technology Agency-Core Research for Engineering, Science, and Technology, Graduate School of Frontier Biosciences, Osaka University, Osaka 565-0871, Japan; Laboratory of Developmental Immunology, Japan Science and Technology Agency-Core Research for Engineering, Science, and Technology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan; Laboratory of Developmental Immunology, Japan Science and Technology Agency-Core Research for Engineering, Science, and Technology, World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan;
authors.forename: Masaya
authors.initials: M
authors.lastname: Harada
authors.affiliation: Division of Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-0815, Japan; Laboratory of Developmental Immunology, Japan Science and Technology Agency-Core Research for Engineering, Science, and Technology, Graduate School of Frontier Biosciences, Osaka University, Osaka 565-0871, Japan; Laboratory of Developmental Immunology, Japan Science and Technology Agency-Core Research for Engineering, Science, and Technology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan; Laboratory of Developmental Immunology, Japan Science and Technology Agency-Core Research for Engineering, Science, and Technology, World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan;
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kamimura
authors.affiliation: Division of Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-0815, Japan; Laboratory of Developmental Immunology, Japan Science and Technology Agency-Core Research for Engineering, Science, and Technology, Graduate School of Frontier Biosciences, Osaka University, Osaka 565-0871, Japan; Laboratory of Developmental Immunology, Japan Science and Technology Agency-Core Research for Engineering, Science, and Technology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan; Laboratory of Developmental Immunology, Japan Science and Technology Agency-Core Research for Engineering, Science, and Technology, World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan;
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Arima
authors.affiliation: Department of Medicine and Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8519, Japan;
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kohsaka
authors.affiliation: Department of Neurology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan;
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nakatsuji
authors.affiliation: Health Care Center, Osaka University, Osaka 560-0043, Japan;
authors.forename: Makoto
authors.initials: M
authors.lastname: Nishida
authors.affiliation: Division of Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-0815, Japan; Laboratory of Developmental Immunology, Japan Science and Technology Agency-Core Research for Engineering, Science, and Technology, Graduate School of Frontier Biosciences, Osaka University, Osaka 565-0871, Japan; Laboratory of Developmental Immunology, Japan Science and Technology Agency-Core Research for Engineering, Science, and Technology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan; Laboratory of Developmental Immunology, Japan Science and Technology Agency-Core Research for Engineering, Science, and Technology, World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan;
authors.forename: Toru
authors.initials: T
authors.lastname: Atsumi
authors.affiliation: Division of Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-0815, Japan; Laboratory of Developmental Immunology, Japan Science and Technology Agency-Core Research for Engineering, Science, and Technology, Graduate School of Frontier Biosciences, Osaka University, Osaka 565-0871, Japan; Laboratory of Developmental Immunology, Japan Science and Technology Agency-Core Research for Engineering, Science, and Technology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan; Laboratory of Developmental Immunology, Japan Science and Technology Agency-Core Research for Engineering, Science, and Technology, World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan;
authors.forename: Jie
authors.initials: J
authors.lastname: Meng
authors.affiliation: Division of Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-0815, Japan; Laboratory of Developmental Immunology, Japan Science and Technology Agency-Core Research for Engineering, Science, and Technology, Graduate School of Frontier Biosciences, Osaka University, Osaka 565-0871, Japan; Laboratory of Developmental Immunology, Japan Science and Technology Agency-Core Research for Engineering, Science, and Technology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan; Laboratory of Developmental Immunology, Japan Science and Technology Agency-Core Research for Engineering, Science, and Technology, World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan;
authors.forename: Hidenori
authors.initials: H
authors.lastname: Bando
authors.affiliation: Division of Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-0815, Japan;
authors.forename: Rajeev
authors.initials: R
authors.lastname: Singh
authors.affiliation: Division of Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-0815, Japan; Laboratory of Developmental Immunology, Japan Science and Technology Agency-Core Research for Engineering, Science, and Technology, Graduate School of Frontier Biosciences, Osaka University, Osaka 565-0871, Japan; Laboratory of Developmental Immunology, Japan Science and Technology Agency-Core Research for Engineering, Science, and Technology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan; Laboratory of Developmental Immunology, Japan Science and Technology Agency-Core Research for Engineering, Science, and Technology, World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan;
authors.forename: Lavannya
authors.initials: L
authors.lastname: Sabharwal
authors.affiliation: Division of Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-0815, Japan; Laboratory of Developmental Immunology, Japan Science and Technology Agency-Core Research for Engineering, Science, and Technology, Graduate School of Frontier Biosciences, Osaka University, Osaka 565-0871, Japan; Laboratory of Developmental Immunology, Japan Science and Technology Agency-Core Research for Engineering, Science, and Technology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan; Laboratory of Developmental Immunology, Japan Science and Technology Agency-Core Research for Engineering, Science, and Technology, World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan;
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Jiang
authors.affiliation: Division of Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-0815, Japan; Laboratory of Developmental Immunology, Japan Science and Technology Agency-Core Research for Engineering, Science, and Technology, Graduate School of Frontier Biosciences, Osaka University, Osaka 565-0871, Japan; Laboratory of Developmental Immunology, Japan Science and Technology Agency-Core Research for Engineering, Science, and Technology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan; Laboratory of Developmental Immunology, Japan Science and Technology Agency-Core Research for Engineering, Science, and Technology, World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan;
authors.forename: Noriko
authors.initials: N
authors.lastname: Kumai
authors.affiliation: Department of Medicine and Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8519, Japan;
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Miyasaka
authors.affiliation: Department of Neurology, National Hospital Organization Toneyama Hospital, Osaka 560-0045, Japan; and.
authors.forename: Saburo
authors.initials: S
authors.lastname: Sakoda
authors.affiliation: Health Care Center, Osaka University, Osaka 560-0043, Japan;
authors.forename: Keiko
authors.initials: K
authors.lastname: Yamauchi-Takihara
authors.affiliation: Division of Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-0815, Japan; Laboratory of Developmental Immunology, Japan Science and Technology Agency-Core Research for Engineering, Science, and Technology, Graduate School of Frontier Biosciences, Osaka University, Osaka 565-0871, Japan; Laboratory of Developmental Immunology, Japan Science and Technology Agency-Core Research for Engineering, Science, and Technology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan; Laboratory of Developmental Immunology, Japan Science and Technology Agency-Core Research for Engineering, Science, and Technology, World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan;
authors.forename: Hideki
authors.initials: H
authors.lastname: Ogura
authors.affiliation: Japan Science and Technology Agency-Core Research for Engineering, Science, and Technology, Osaka University, 565-0871, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Hirano
authors.affiliation: Division of Molecular Neuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-0815, Japan; Laboratory of Developmental Immunology, Japan Science and Technology Agency-Core Research for Engineering, Science, and Technology, Graduate School of Frontier Biosciences, Osaka University, Osaka 565-0871, Japan; Laboratory of Developmental Immunology, Japan Science and Technology Agency-Core Research for Engineering, Science, and Technology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan; Laboratory of Developmental Immunology, Japan Science and Technology Agency-Core Research for Engineering, Science, and Technology, World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan; murakami@igm.hokudai.ac.jp.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Murakami
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000097:blood / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D066260:Epiregulin / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D016207:Cytokines; D066260:Epiregulin; D036341:Intercellular Signaling Peptides and Proteins; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases