Calcium/calmodulin-dependent protein kinase II (CaMKII) regulates tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-mediated apoptosis of fibroblast-like synovial cells (FLS) by phosphorylation of Akt

Clinical and Experimental Rheumatology

Keita Fujikawa¹  Mami Tamai¹  Katsumi Eguchi¹  Atsushi Kawakami¹  Naoki Iwamoto¹  Fumiko Tanaka¹ 

关键词: Rheumatoid arthritis;    CaMKII;    FLS;    Akt;    TRAIL;   

DOI  :  

学科分类：医学（综合）

来源: Pacini Editore SpA

【 摘 要 】

OBJECTIVES:We tried to determine whether calcium/calmodulin-dependent protein kinase II (CaMKII) regulates tumour necrosis factor-related apoptosis inducing ligand (TRAIL)-mediated apoptosis of fibroblast-like synovial cells (FLS).METHODS:CaMKII expression in FLS was studied by both western blotting and real time reverse transcription polymerase chain reaction (RT-PCR). TRAIL-mediated apoptosis of FLS was quantified by disruption of mitochondrial transmembrane potential (&Dgr;&PSgr;m), Leu-Glu-His-Asp (IETD) ase activity and DNA degradation. Involvement of CaMKII and other kinases, including extracellular signal-regulated kinase (ERK), p38, c-Jun N-terminal kinase (JNK) and Akt during TRAIL-mediated apoptosis of FLS was estimated by the use of specific each kinase chemical inhibitor.RESULTS:Predominant expression of &dgr; and &ggr; isoform of CaMKII, especially &dgr; isoform, was determined in cultured FLS. TRAIL rapidly induced apoptosis of FLS as well as the phosphorylation of extracellular signal-regulated kinase (ERK), p38, c-Jun N-terminal kinase (JNK) and Akt. Chemical kinase inhibitor toward CaMKII and Akt significantly augmented TRAIL-mediated apoptosis of FLS whereas those toward ERK, p38 and JNK did not. Notably, CaMKII chemical inhibitor abrogated TRAIL-induced phosphorylation of Akt. Elevation of Leu-Glu-His-Asp (IETD) ase activity was associated with the apoptotic phenomena, which was almost suppressed by IETD competitive peptides.CONCLUSIONS:Our results suggest a first observation that CaMKII regulates TRAIL-mediated apoptosis of FLS through Akt, standing an upstream of caspase-8-dependent cascades. Furthermore, CaMKII is suggested to be a new therapeutic target molecule of rheumatoid arthritis (RA).

【 授权许可】

Unknown