Tissue-specific expression of human calcineurin-binding protein 1 in mouse synovial tissue can suppress inflammatory
Dong Hoon Yu1, Jun Ku Yi, Seo Jin Park
1School of Life Sciences and Biotechnology, Kyungpook National University, Daegu, Korea.
Abstract:
Calcineurin (CN) is a calcium- and calmodulin-dependent serine/threonine phosphatase. In immune cells, CN controls the activity of a wide range of transcription factors, including nuclear factor of activated T, nuclear factor-kappa B, c-fos, and Elk-1. CN plays an important role in synoviocyte activation and arthritis progression in vivo and this function is tightly linked to dysregulated intracellular Ca(2+) store and Ca(2+) response triggered by proinflammatory cytokines. In the present study, transgenic mice expressing human calcineurin-binding protein 1 (hCabin1) were generated, driven by type II collagen promoter, and the efficiency of these mice was investigated by experimental arthritis. These transgenic mice successfully expressed hCabin1 in joint tissue as well as other organs such as liver, heart, and brain. The overexpression of hCabin1 reduced the disease severity during collagen-induced arthritis. In fibroblast-like synoviocytes (FLSs) from hCabin1 transgenic mice, the productions of these cytokines, including interleukin (IL)-2, IL-4, and IFN-γ, were decreased and matrix metalloproteinases were also depressed in transgenic mice FLS. In addition, these effects were only found in the joint tissue, which is a major inflammation site. These findings will provide a better knowledge of the pathogenic mechanisms of rheumatoid arthritis and a potential animal model of the chronic inflammatory conditions, including atherosclerosis and transplantation.
Insights
Overexpressing human calcineurin-binding protein 1 (hCabin1) in mice reduced rheumatoid arthritis severity. This suggests hCabin1 may be a therapeutic target for chronic inflammatory diseases.
Area of Science:
- Immunology
- Molecular Biology
- Rheumatology
Background:
- Calcineurin (CN) is a crucial phosphatase regulating immune cell transcription factors.
- CN activity is linked to rheumatoid arthritis pathogenesis via dysregulated calcium signaling and proinflammatory cytokines.
- Understanding CN's role is vital for developing targeted arthritis therapies.
Purpose of the Study:
- To investigate the therapeutic potential of human calcineurin-binding protein 1 (hCabin1) in a mouse model of rheumatoid arthritis.
- To assess the impact of hCabin1 overexpression on disease severity and inflammatory markers in experimental arthritis.
- To establish a transgenic mouse model for studying chronic inflammatory conditions.
Main Methods:
- Generation of transgenic mice overexpressing hCabin1 under the type II collagen promoter.
- Induction of collagen-induced arthritis (CIA) to evaluate disease progression in transgenic and wild-type mice.
- Analysis of cytokine and matrix metalloproteinase production in fibroblast-like synoviocytes (FLSs) from transgenic mice.
Main Results:
- Transgenic mice successfully expressed hCabin1 in joint tissues and other organs.
- Overexpression of hCabin1 significantly reduced disease severity in collagen-induced arthritis.
- hCabin1 transgenic mice exhibited decreased production of key cytokines (IL-2, IL-4, IFN-γ) and matrix metalloproteinases in joint FLSs.
- These beneficial effects were localized primarily to the inflamed joint tissue.
Conclusions:
- hCabin1 overexpression demonstrates a protective effect against rheumatoid arthritis progression in a preclinical model.
- The findings highlight the role of CN signaling in arthritis and identify hCabin1 as a potential therapeutic target.
- These transgenic mice serve as a valuable model for studying rheumatoid arthritis and other chronic inflammatory diseases like atherosclerosis and in transplantation research.
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