title: The role of Cas-L/NEDD9 as a regulator of collagen-induced arthritis in a murine model.
abstract: Cas-L/NEDD9 is a cytoplasmic docking protein downstream of β1 integrin-mediated signaling pathway and is essential for cellular migration and β1 integrin-mediated costimulation of T cells. We previously found that increased number of Cas-L positive leukocytes migrated into the inflamed joints of HTLV-I tax transgenic mice which spontaneously develop polyarthritis, suggesting a role of Cas-L in rheumatoid arthritis (RA) pathophysiology. Our current study expanded these findings on the role of Cas-L/NEDD9 in the development of RA by analyzing the pathophysiological changes in a Nedd9(-/-) mouse collagen-induced arthritis (CIA) model. Nedd9(-/-) mice exhibited a decrease in arthritis severity as compared to Nedd9(+/+) mice. In addition, as being conducted bone marrow transplantation experiments with a CIA model, Nedd9(-/-)→Nedd9(+/+) transplant showed a decrease in the incidence and severity score of arthritis, compared to those of Nedd9(+/+)→Nedd9(-/-) transplant. For analysis of serum levels of various cytokines, IL-1β, IL-6, IL-17, TNF-α, IFN-γ and anti-collagen antibody were decreased, while IL-4 and IL-10 levels were increased, in Nedd9(-/-) mice as compared to those in Nedd9(+/+) mice. Furthermore, collagen-mediated cellular responses of lymphocytes isolated from spleen or affected lymph nodes of Nedd9(-/-) mice were reduced. Our results strongly suggest that Cas-L/NEDD9 plays a pivotal role in the pathophysiology of CIA, and that Cas-L/NEDD9 may be a potential molecular target for the treatment of RA.
authors.affiliation: Division of Clinical Immunology, Advanced Clinical Research Center, IMSUT Hospital, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Katayose
authors.affiliation: Division of Clinical Immunology, Advanced Clinical Research Center, IMSUT Hospital, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Iwata
authors.affiliation: Department of Laboratory Medicine, IMSUT Hospital, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Oyaizu
authors.affiliation: Department of Rheumatology and Allergy, IMSUT Hospital, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Hosono
authors.affiliation: Department of Pathology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
authors.forename: Taketo
authors.initials: T
authors.lastname: Yamada
authors.affiliation: Division of Hematology/Oncology, University of Florida, 1600 SW Archer Road, Box 100278, Room MSB M410A, Gainesville, FL 32610, USA.
authors.forename: Nam H
authors.initials: NH
authors.lastname: Dang
authors.affiliation: Division of Clinical Immunology, Advanced Clinical Research Center, IMSUT Hospital, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Hatano
authors.affiliation: Division of Clinical Immunology, Advanced Clinical Research Center, IMSUT Hospital, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan; Department of Rheumatology and Allergy, IMSUT Hospital, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: Department of Rheumatology and Allergy, IMSUT Hospital, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. Electronic address: kohnuma@juntendo.ac.jp.
authors.forename: Kei
authors.initials: K
authors.lastname: Ohnuma
authors.affiliation: Division of Clinical Immunology, Advanced Clinical Research Center, IMSUT Hospital, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan; Department of Rheumatology and Allergy, IMSUT Hospital, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Chikao
authors.initials: C
authors.lastname: Morimoto
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism / Q000503:physiopathology*; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D003094:Collagen / Q000009:adverse effects*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D018836:Inflammation Mediators / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013154:Spleen / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; D018836:Inflammation Mediators; C505592:NEDD9 protein, mouse; D003094:Collagen
keywords: Cas-L/NEDD9; Collagen-induced arthritis; IL-10; Rheumatoid arthritis; T cell