Inhibition of Calcium/calmodulin-dependent protein kinase IV suppresses the autoimmunity in lupus-prone mice. (56.4)

Abstract

Abstract OBJECTIVE: 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, starting at week 8 of age through week 16 and evaluated the presence of CD4+, CD8+, CD3+CD4-CD8- (double negative, DN) and CD62Llow T cells and proinflammatory cytokine production. We also determined the effect of inhibition 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 CD62Llow of T cells population and IFN-γ production by T cells. In human activated T cells and macrophages, pharmacologic inhibition of CaMKIV resulted in suppression of IFN-γ production and CD69 expression by T cells and IL-1β, IL-6 and TNF-α by macrophages. 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 for the treatment of patients with SLE.