Immune Netw.  2006 Mar;6(1):33-41. 10.4110/in.2006.6.1.33.

Expression and Function of Calcineurin in Inflammatory Arthritis

• Park BH
• Yoo SA
• Hong KH
• Hyoung BJ
• Hwang YN
• Cho CS
• Park W
• Kim WU

• KMID: 2167987
• DOI: http://doi.org/10.4110/in.2006.6.1.33

Abstract

BACKGROUND: Calcineurin plays a crucial role in T cell activation, cell growth, apoptosis, and angiogenesis, and its over-expression has been implicated in the pathogenesis of cardiomyopathy and stroke. However, the expression and function of calcineurin in the pathologic lesion of chronic inflammatory diseases, like rheumatoid synovium, remain to be defined. This study was aimed to determine the role of calcineurin in inflammatory arthritis and investigate the expression and function of calcineurin in the rheumatoid synovium and synoviocytes, the actual site of chronic inflammation.
METHODS
Immunohistochemical staining using specific antibody to calcineurin was perfomed in the synovium of rheumatoid arthritis (RA). Fibroblast-like synoviocytes (FLS) from RA and osteoarthritis (OA) patients were isolated from RA and OA patients, and cultured with IL-1beta and TNF-alpha in the presence or absence of cyclosporin A, a calcineurin inhibitor. The calcineurin expression was assessed by phosphatase assay and Western blotting analysis. IL-6, -10, -17, matrix metalloproteinase (MMP)-1, -2, -3, and -9 released into the culture supernatants were measured by ELISA. After transfection with GFP-Cabin 1 gene into synoviocytes, the levels of IL-6 and MMPs were measured by ELISA.
RESULTS
Calcineurin was highly expressed in the lining layer of synovium and cultured synoviocytes of RA patients. The elevated calcineurin activity in the rheumatoid synoviocytes was triggered by proinflammatory cytokines such as IL-1beta and TNF-alpha. In contrast, IL-10, an anti-inflammatory cytokine, failed to increase the calcineurin activity. The targeted inhibition of calcineurin by the over-expression of Cabin 1, a natural calcineurin antagonist, inhibited the production of IL-6 and MMP-2 by rheumatoid synoviocytes in a similar manner to the calcineurin inhibitor, cyclosporin A.
CONCLUSION
These data suggest that abnormal activation of calcineurin in the synoviocytes may contribute to the pathogenesis of chronic arthritis, and thus provide a potential target for controlling inflammatory arthritis.

Keyword

Calcineurin; cabin 1; cyclosporin A; rheumatoid synoviocyte

MeSH Terms

Apoptosis
Arthritis*
Arthritis, Rheumatoid
Blotting, Western
Calcineurin*
Cardiomyopathies
Cyclosporine
Cytokines
Enzyme-Linked Immunosorbent Assay
Humans
Inflammation
Interleukin-10
Interleukin-6
Matrix Metalloproteinases
Osteoarthritis
Stroke
Synovial Membrane
Transfection
Tumor Necrosis Factor-alpha
Calcineurin
Cyclosporine
Cytokines
Interleukin-10
Interleukin-6
Matrix Metalloproteinases
Tumor Necrosis Factor-alpha