Search of factors that intermediate cytokine-induced group IIA phospholipase A2 expression through the cytosolic phospholipase A2- and 12/15-lipoxygenase-dependent pathway
Search of factors that intermediate cytokine-induced group IIA phospholipase A2 expression through the cytosolic phospholipase A2- and 12/15-lipoxygenase-dependent pathway
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DOI：
10.1074/jbc.m500168200
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发表时间：
2005-07-08
影响因子：
4.8
通讯作者：
Kudo, I
中科院分区：
文献类型：
--
作者：
Kuwata, H;Nonaka, T;Kudo, I
IIA组大鼠成纤维3Y1细胞分泌性磷脂酶A(2) （sPLA(2)- IIA）被白细胞介素- 1 β (IL- 1 β)和肿瘤坏死因子- α (TNF α)诱导表达在IVA组胞浆性PLA(2) α和12/ 15-脂氧合酶（12/ 15- LOX）的控制下。我们在这里表明，这种细胞因子诱导sPLA2- IIA mRNA需要从头合成蛋白质。通过cDNA阵列分析，我们发现与对照细胞相比，12/ 15- LOX转染的细胞中CXC趋化因子MIP- 2（巨噬细胞炎症蛋白- 2）水平显著升高。IL-1 β / TNF α刺激的内源性MIP- 2诱导先于sPLA2- IIA，并且外源性MIP- 2诱导sPLA2- IIA的剂量依赖性。此外，MIP- 2特异性的反义寡核苷酸和小干扰RNA减弱了IL- 1 β / TNF α诱导的sPLA(2)-IIA的表达，这表明MIP- 2是最佳诱导sPLA2- IIA的绝对中间条件。此外，在12/ 15- LOX转染的细胞中，转录因子AP- 1的组分c- jun和fra- 1的表达升高，其中AP- 1与sPLA2- IIA启动子的细胞因子依赖性结合显著增加。相反，参与sPLA2- IIA表达下调的转化生长因子- β和血小板衍生生长因子受体在12/ 15- LOX过表达后减少。综上所述，sPLA2- IIA表达的12/ 15- LOX依赖性上调可能是MIP- 2信号加速、AP- 1激活和转化生长因子- β和血小板衍生生长因子信号减弱之间的相互作用所致。
Inducible expression of group IIA secretory phospholipase A(2) ( sPLA(2)- IIA) by interleukin- 1 beta( IL- 1 beta) and tumor necrosis factor- alpha( TNF alpha) is under the control of group IVA cytosolic PLA(2)alpha and 12/ 15- lipoxygenase ( 12/ 15- LOX) in rat fibroblastic 3Y1 cells. We show here that this cytokine induction of sPLA2- IIA mRNA requires de novo protein synthesis. By means of cDNA array analysis, we found that the level of the CXC chemokine MIP- 2 ( macrophage inflammatory protein- 2) was significantly elevated in 12/ 15- LOX- transfected cells compared with control cells. IL-1 beta/ TNF alpha- stimulated induction of endogenous MIP- 2 preceded that of sPLA2- IIA, and exogenous MIP- 2 induced sPLA2- IIA dose- dependently. Moreover, a MIP- 2- specific antisense oligonucleotide and small interfering RNA attenuated the IL- 1 beta/ TNF alpha- induced expression of sPLA(2)-IIA, suggesting that MIP- 2 is an absolute intermediate requirement for optimal induction of sPLA2- IIA. In addition, the expression of c- jun and fra- 1, which are components of the transcription factor AP- 1, was elevated in 12/ 15- LOX- transfected cells, in which cytokine- dependent binding of AP- 1 to the sPLA2- IIA promoter was increased significantly. Conversely, the receptors for transforming growth factor-beta and platelet- derived growth factor, which contributed to down- regulation of sPLA2- IIA expression, were decreased following 12/ 15- LOX overexpression. Taken together, 12/ 15- LOX- dependent up- regulation of sPLA2- IIA expression may result from the interplay between accelerated MIP- 2 signaling, AP- 1 activation, and attenuated transforming growth factor-beta and platelet- derived growth factor signaling.