Suppression of autoimmunity and organ pathology in lupus‐prone mice upon inhibition of calcium/calmodulin‐dependent protein kinase type IV
Open Access
- 15 October 2010
- journal article
- systemic lupus-erythematosus
- Published by Wiley in Arthritis & Rheumatism
- Vol. 63 (2), 523-529
- https://doi.org/10.1002/art.30085
Abstract
Objective Systemic lupus erythematosus (SLE) is a chronic inflammatory disease associated with aberrant immune cell function. Treatment involves the use of indiscriminate immunosuppression, which results in significant side effects. SLE T cells express high levels of calcium/calmodulin‐dependent protein kinase type IV (CaMKIV), which translocates to the nucleus upon engagement of the T cell receptor–CD3 complex and accounts for abnormal T cell function. The purpose of this study was to determine whether inhibition of CaMKIV would improve disease pathology. Methods We treated MRL/lpr mice with KN‐93, a CaMKIV inhibitor, starting at week 8 or week 12 of age and continuing through week 16 and evaluated skin lesions, proteinuria, kidney histopathology, proinflammatory cytokine production, and costimulatory molecule expression. We also determined the effect of silencing of CAMK4 on interferon‐γ (IFNγ) expression by human SLE T cells. Results CaMKIV inhibition in MRL/lpr mice resulted in significant suppression of nephritis and skin disease, decreased expression of the costimulatory molecules CD86 and CD80 on B cells, and suppression of IFNγ and tumor necrosis factor α production. In human SLE T cells, silencing of CAMK4 resulted in suppression of IFNγ production. Conclusion We conclude that suppression of CaMKIV mitigates disease development in lupus‐prone mice by suppressing cytokine production and costimulatory molecule expression. Specific silencing of CAMK4 in human T cells results in similar suppression of IFNγ production. Our data justify the development of small‐molecule CaMKIV inhibitors for the treatment of patients with SLE.This publication has 29 references indexed in Scilit:
- Suppression of skin and kidney disease by inhibition of spleen tyrosine kinase in lupus‐prone miceArthritis & Rheumatism, 2010
- Pathogenesis of human systemic lupus erythematosus: recent advancesTrends in Molecular Medicine, 2010
- Mechanisms of Immune Complex–Mediated Neutrophil Recruitment and Tissue InjuryCirculation, 2009
- Calmodulin-dependent kinase IV links Toll-like receptor 4 signaling with survival pathway of activated dendritic cellsBlood, 2008
- HMGB1 release induced by liver ischemia involves Toll-like receptor 4–dependent reactive oxygen species production and calcium-mediated signalingThe Journal of Experimental Medicine, 2007
- Peripheral Circulating Activated B‐cell Populations are Associated with Nephritis and Disease Activity in Patients with Systemic Lupus ErythematosusScandinavian Journal of Immunology, 2007
- Interferons as pathogenic effectors in autoimmunityImmunological Reviews, 2005
- The origin of CD4−CD8−TCRαβ+ thymocytes: a model based on T-cell receptor avidityImmunology Today, 1995
- Treatment of Murine Lupus with CTLA4IgScience, 1994
- Studies on the role of tumor necrosis factor inmurine and human autoimmunityJournal of Autoimmunity, 1992