title: CTRP6 is an endogenous complement regulator that can effectively treat induced arthritis.
abstract: The complement system is important for the host defence against infection as well as for the development of inflammatory diseases. Here we show that C1q/TNF-related protein 6 (CTRP6; gene symbol C1qtnf6) expression is elevated in mouse rheumatoid arthritis (RA) models. C1qtnf6(-/-) mice are highly susceptible to induced arthritis due to enhanced complement activation, whereas C1qtnf6-transgenic mice are refractory. The Arthus reaction and the development of experimental autoimmune encephalomyelitis are also enhanced in C1qtnf6(-/-) mice and C1qtnf6(-/-) embryos are semi-lethal. We find that CTRP6 specifically suppresses the alternative pathway of the complement system by competing with factor B for C3(H2O) binding. Furthermore, treatment of arthritis-induced mice with intra-articular injection of recombinant human CTRP6 cures the arthritis. CTRP6 is expressed in human synoviocytes, and CTRP6 levels are increased in RA patients. These results indicate that CTRP6 is an endogenous complement regulator and could be used for the treatment of complement-mediated diseases.
authors.affiliation: Division of Experimental Animal Immunology, Center for Animal Disease Models, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba 278-0022, Japan.|Laboratory of Molecular Pathogenesis, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo (IMSUT), Tokyo 108-8639, Japan.|Department of Computational Biology, Graduate School of Frontier Sciences, The University of Tokyo, Chiba 277-0882, Japan.|Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Saitama 332-0012, Japan.
authors.forename: Masanori A
authors.initials: MA
authors.lastname: Murayama
authors.affiliation: Laboratory of Molecular Pathogenesis, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo (IMSUT), Tokyo 108-8639, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kakuta
authors.affiliation: Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan.
authors.forename: Asuka
authors.initials: A
authors.lastname: Inoue
authors.affiliation: Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Umeda
authors.affiliation: Division of Experimental Animal Immunology, Center for Animal Disease Models, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba 278-0022, Japan.|Department of Systems Biomedicine, National Research Institute of Child Health and Development, Tokyo 157-8535, Japan.
authors.forename: Tomo
authors.initials: T
authors.lastname: Yonezawa
authors.affiliation: Division of Experimental Animal Immunology, Center for Animal Disease Models, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba 278-0022, Japan.|Laboratory of Molecular Pathogenesis, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo (IMSUT), Tokyo 108-8639, Japan.
authors.forename: Takumi
authors.initials: T
authors.lastname: Maruhashi
authors.affiliation: Department of Applied Biochemistry, Tokai University, Hiratsuka, Kanagawa 259-1292, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Tateishi
authors.affiliation: Laboratory of Molecular Pathogenesis, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo (IMSUT), Tokyo 108-8639, Japan.
authors.forename: Harumichi
authors.initials: H
authors.lastname: Ishigame
authors.affiliation: Division of Experimental Animal Immunology, Center for Animal Disease Models, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba 278-0022, Japan.|Laboratory of Molecular Pathogenesis, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo (IMSUT), Tokyo 108-8639, Japan.|Department of Molecular Immunology, Medical Mycology Research Center, Chiba University, Chiba 260-8673, Japan.
authors.forename: Rikio
authors.initials: R
authors.lastname: Yabe
authors.affiliation: Laboratory of Molecular Pathogenesis, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo (IMSUT), Tokyo 108-8639, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ikeda
authors.affiliation: Division of Experimental Animal Immunology, Center for Animal Disease Models, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba 278-0022, Japan.|Laboratory of Molecular Pathogenesis, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo (IMSUT), Tokyo 108-8639, Japan.|Department of Computational Biology, Graduate School of Frontier Sciences, The University of Tokyo, Chiba 277-0882, Japan.
authors.forename: Akimasa
authors.initials: A
authors.lastname: Seno
authors.affiliation: Division of Experimental Animal Immunology, Center for Animal Disease Models, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba 278-0022, Japan.
authors.forename: Hsi-Hua
authors.initials: HH
authors.lastname: Chi
authors.affiliation: Division of Experimental Animal Immunology, Center for Animal Disease Models, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba 278-0022, Japan.
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Hashiguchi
authors.affiliation: Division of Experimental Animal Immunology, Center for Animal Disease Models, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba 278-0022, Japan.|Department of Systems Biomedicine, National Research Institute of Child Health and Development, Tokyo 157-8535, Japan.
authors.forename: Riho
authors.initials: R
authors.lastname: Kurata
authors.affiliation: Laboratory of Molecular Pathogenesis, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo (IMSUT), Tokyo 108-8639, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Tada
authors.affiliation: Division of Experimental Animal Immunology, Center for Animal Disease Models, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba 278-0022, Japan.|Laboratory of Molecular Pathogenesis, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo (IMSUT), Tokyo 108-8639, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Kubo
authors.affiliation: Laboratory of Molecular Pathogenesis, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo (IMSUT), Tokyo 108-8639, Japan.
authors.forename: Nozomi
authors.initials: N
authors.lastname: Sato
authors.affiliation: Laboratory of Molecular Pathogenesis, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo (IMSUT), Tokyo 108-8639, Japan.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Computational Biology, Graduate School of Frontier Sciences, The University of Tokyo, Chiba 277-0882, Japan.
authors.forename: Masahira
authors.initials: M
authors.lastname: Hattori
authors.affiliation: Laboratory of Molecular Pathogenesis, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo (IMSUT), Tokyo 108-8639, Japan.|Department of Molecular Immunology, Medical Mycology Research Center, Chiba University, Chiba 260-8673, Japan.
authors.forename: Shinobu
authors.initials: S
authors.lastname: Saijo
authors.affiliation: Department of Applied Biochemistry, Tokai University, Hiratsuka, Kanagawa 259-1292, Japan.
authors.forename: Misao
authors.initials: M
authors.lastname: Matsushita
authors.affiliation: Fukushima Prefectural General Hygiene Institute, Fukushima 960-8142, Japan.
authors.forename: Teizo
authors.initials: T
authors.lastname: Fujita
authors.affiliation: Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Sumida
authors.affiliation: Division of Experimental Animal Immunology, Center for Animal Disease Models, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba 278-0022, Japan.|Laboratory of Molecular Pathogenesis, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo (IMSUT), Tokyo 108-8639, Japan.|Department of Computational Biology, Graduate School of Frontier Sciences, The University of Tokyo, Chiba 277-0882, Japan.|Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Saitama 332-0012, Japan.|Department of Molecular Immunology, Medical Mycology Research Center, Chiba University, Chiba 260-8673, Japan.
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
mesh_terms: D054392:Adipokines / Q000235:genetics / Q000276:immunology*; D000328:Adult; D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D001183:Arthus Reaction / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015153:Blotting, Western; D003094:Collagen / Q000276:immunology / Q000378:metabolism; D050577:Complement C3-C5 Convertases / Q000276:immunology; D015926:Complement C3a / Q000276:immunology; D015936:Complement C5a / Q000276:immunology; D003170:Complement Pathway, Alternative / Q000235:genetics / Q000276:immunology*; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D047468:Immunoprecipitation; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008875:Middle Aged; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013583:Synovial Membrane / Q000166:cytology / Q000378:metabolism
chemical_list: D054392:Adipokines; C561455:C1qTNF6 protein, human; C000606745:CTRP6 protein, mouse; D015926:Complement C3a; D015936:Complement C5a; D003094:Collagen; D050577:Complement C3-C5 Convertases