Open AccessSuppression of autoimmunity and organ pathology in lupus‐prone mice upon inhibition of calcium/calmodulin‐dependent protein kinase type IV
Author(s) -
Ichinose Kunihiro,
Juang YuangTaung,
Crispín José C.,
KisToth Katalin,
Tsokos George C.
Publication year - 2011
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/art.30085
Subject(s) - cd80 , immunology , cytokine , systemic lupus erythematosus , proinflammatory cytokine , biology , immune system , lupus nephritis , cd86 , t cell , tumor necrosis factor alpha , foxp3 , endocrinology , cancer research , medicine , inflammation , cytotoxic t cell , cd40 , disease , biochemistry , in vitro
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.