Sequential activation of protein kinase C delta and JNK is required for interferon-alpha-induced expression of IFIT4.
A multitude of interferon (IFN)-inducible genes (IFIGs) are coordinately expressed in peripheral blood mononuclear cells (PBMCs) of patients with systemic lupus erythematosus (SLE), emphasising the globle activating of signal pathway mediated by IFN-I in SLE. In this study, we investigated the mechanisms of expression regulation of IFIT4 (interferon induced protein with tetratricopeptide repeats 4) by IFN-alpha. We found that IFN-alpha failed in inducing IFIT4 in STAT1-negative U3A cells. Ectopic expression of STAT1, but not mutant STAT1-S727A, almost completely restored IFN-alpha2a-induced IFIT4 expression. IFN-alpha induced the expression of IFIT4 and STAT1 in THP-1 cells, and this process was significantly antagonized by the specific inhibitors of both PKCdelta and JNK or their dominant negative mutants respectively. The inhibition of JNK activity by its specific inhibitor or its dominant negative mutant suppressed both IFIT4 expression and serine phosphorylation of STAT1 but not the activation of PKCdelta, while inhibition of PKCdelta suppressed activation of IFIT4, STAT1, and JNK. Our results suggest that the induction of IFIT4 transcription by IFN-alpha depends upon sequential activation of PKCdelta, JNK and STAT1, and that the influence of PKCdelta or JNK on IFN-alpha-mediated induction of IFIT4 is dependent upon the phosphorylation of STAT1 at Ser-727. The results in our experiment provide an in vitro model of the signaling mechanisms of IFIGs regulated by IFN-alpha, that is putatively thought to occur in vivo as the one of pathogenesis of SLE.
Huang
Xiangyang
X
Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China. yangyang1029@yahoo.com.cn
Yang
Nanping
N
Ou
Xuemei
X
Li
Dong
D
Wang
Zhongming
Z
Xie
Qibing
Q
Chen
Yongtao
Y
Lin
Hui
H
Yin
Gen
G
Wen
Fuqiang
F
D002460:Cell Line; D045744:Cell Line, Tumor; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008180:Lupus Erythematosus, Systemic / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D008954:Models, Biological; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D010766:Phosphorylation; D051745:Protein Kinase C-delta / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
C116468:IFIT3 protein, human; D016898:Interferon-alpha; D047908:Intracellular Signaling Peptides and Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D012694:Serine; D051745:Protein Kinase C-delta; D048670:MAP Kinase Kinase 4