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Abstract Number: 1448

Inhibition of Calcium/Calmodulin-Dependent Protein Kinase IV Suppresses the Autoimmunity in Lupus-Prone Mice

Kunihiro Ichinose1, Atsushi Kawakami2 and George C. Tsokos3, 1Department of Immunology and Rheumatology, Unit of Translational Medicine, Department of Immunology and Rheumatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan, 2Department of Immunology and Rheumatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan, 3Medicine/Rheumatology, BIDMC, Harvard Medical School, Boston, MA

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: cytokines, signal transduction, systemic lupus erythematosus (SLE) and treatment

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Session Information

Title: Systemic Lupus Erythematosus - Animal Models

Session Type: Abstract Submissions (ACR)

Inhibition of Calcium/Calmodulin-Dependent Protein Kinase IV Suppresses the Autoimmunity in Lupus-Prone Mice.

Background/Purpose: Systemic lupus erythematosus (SLE) is a chronic inflammatory disease associated with abnormal immune cell function.SLE T cells express high levels of calcium/calmodulin-dependent protein kinase IV (CaMKIV). We have shown previously that pharmacologic (Arthritis Rheum. 2011) or genetic silencing of Camkiv (J Immunol. 2011) suppresses lupus nephritis in lupus-prone mice. The purpose of this study was to determine whether pharmacologic inhibition of CaMKIV would improve immune function abnormalities. Methods: We treated MRL/lpr mice with KN-93, a CaMKIV inhibitor. The agent was administered by intraperitoneal injections at a dosage of 2.67 ug/gm of body weight per mouse 3 times a week, starting at week 8 of age through week 16. We evaluated the presence of CD4+, CD8+, CD3+CD4-CD8- (double negative, DN) and CD62L low T cells and proinflammatory cytokine production. We also determined the effect of inhibition or silencing of CaMKIV on proinflammatory cytokine production by human T cells and macrophages. Results: CaMKIV inhibition in MRL/lpr mice resulted in significant suppression of DN and CD62L low of T cells population and IFN-g production by T cells. In human activated T cells and macrophages, pharmacologic inhibition of CaMKIV resulted in suppression of IFN-g production and CD69 expression by T cells and IL-1b, IL-6 and TNF-a by macrophages. Silencing of CaMKIV in human activated T cells showed increased expression of FoxP3 mRNA level and decreased IL-17A mRNA level. Conclusion: We conclude that pharmacologic inhibition of CaMKIV suppresses cell activation and cytokine production in lupus-prone mice. Our data justify the development of small-molecule CaMKIV inhibitors or silencing CaMKIV for the treatment of patients with SLE.

 


Disclosure:

K. Ichinose,
None;

A. Kawakami,
None;

G. C. Tsokos,
None.

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