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: Tomoki Katayose, Satoshi Iwata, Naoki Oyaizu, Osamu Hosono, Taketo Yamada, Nam H Dang, Ryo Hatano, Hirotoshi Tanaka, Kei Ohnuma, Chikao Morimoto
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 460 Issue 4 Pg. 1069-75 (May 15 2015) ISSN: 1090-2104 [Electronic] United States
• PMID: 25847598 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Adaptor Proteins, Signal Transducing
• Cytokines
• Inflammation Mediators
• NEDD9 protein, mouse
• Collagen

Topics

• Adaptor Proteins, Signal Transducing (genetics, physiology)
• Animals
• Arthritis, Experimental (metabolism, physiopathology)
• B-Lymphocytes (immunology, pathology)
• Collagen (adverse effects)
• Cytokines (metabolism)
• Disease Models, Animal
• Inflammation Mediators (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Spleen (pathology)
• T-Lymphocytes (immunology, pathology)