Suppression of autoimmunity and organ pathology in lupus-prone mice upon inhibition of calcium/calmodulin-dependent protein kinase type IV.
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.


CONCLUSIONS
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.
Ichinose
Kunihiro
K
Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115, USA.
Juang
Yuang-Taung
YT
Crispín
José C
JC
Kis-Toth
Katalin
K
Tsokos
George C
GC
D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D001596:Benzylamines / Q000494:pharmacology; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D020868:Gene Silencing; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D009393:Nephritis / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D012867:Skin / Q000187:drug effects / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D014162:Transfection; D000096926:Benzenesulfonamides
D001596:Benzylamines; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D007371:Interferon-gamma; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D013449:Sulfonamides; C072105:KN 93; D000096926:Benzenesulfonamides; C517683:CAMK4 protein, human; C517685:Camk4 protein, mouse