Cyclosporin a and FK506 inhibit IL-12p40 production through the calmodulin/calmodulin-dependent protein kinase-activated phosphoinositide 3-kinase in lipopolysaccharide-stimulated human monocytic cells (Retracted Article)
Cyclosporin a and FK506 inhibit IL-12p40 production through the calmodulin/calmodulin-dependent protein kinase-activated phosphoinositide 3-kinase in lipopolysaccharide-stimulated human monocytic cells (Retracted Article)
复制标题
DOI：
10.1074/jbc.m611522200
复制
发表时间：
2007-05-04
影响因子：
4.8
通讯作者：
Kumar, Ashok
中科院分区：
文献类型：
--
作者：
Ma, Wei;Mishra, Sasmita;Kumar, Ashok
环孢霉素A（CyA）和FK 506是有效的免疫抑制剂，因为它们能够抑制Th 1细胞因子（包括白细胞介素（IL）-12）的产生。然而，CyA和FK 506对IL-12的关键组分IL-12 p40的产生的抑制作用的潜在机制仍然未知。CyA和FK 506都是钙信号通路中钙调神经磷酸酶的强效抑制剂。有趣的是，钙和磷脂酰肌醇3-激酶（PI 3 K）信号通路已被证明负调节脂多糖（LPS）诱导的小鼠IL-12 p40的生产。与这些观察结果相反，我们发现，LPS诱导的IL-12 p40在人单核细胞中的生产是积极调节的钙通道，特别是钙调蛋白（CaM）和钙调蛋白依赖性蛋白激酶II（CaMK-II）激活的PI 3 K。此外，LPS诱导的IL-12 p40的产生受PI 3 K的p110 α催化亚基的调节。此外，LPS通过CaM/CaMK-II激活的NF κ B B和AP- 1转录因子诱导IL-12 p40的产生。已知LPS诱导的IL-12 p40产生受c-Jun N-末端激酶（JNK）途径调节。重要的是，CyA和FK 506通过抑制CaM/CaMK-II激活的PI 3 K及其下游转录因子NF kappa B和AP-1下调LPS诱导的IL-12 p40转录，而不依赖于JNK途径。
Cyclosporine-A (CyA) and FK506 are potent immunosuppressive agents because of their ability to suppress the production of Th1 cytokines including interleukin (IL)-12. However, the mechanisms underlying the inhibitory effects of CyA and FK506 on the production of IL-12p40, a critical component of IL-12, remain unknown. Both CyA and FK506 are potent inhibitors of calcineurin in the calcium signaling pathway. Interestingly, calcium and phosphoinositide 3-kinase (PI3K) signaling pathways have been shown to negatively regulate lipopolysaccharide (LPS)-induced murine IL-12p40 production. Contrary to these observations, we show that LPS-induced IL-12p40 production in human monocytic cells is positively regulated by the calcium pathway and in particular by calmodulin-(CaM) and CaM-dependent protein kinase-II (CaMK-II)-activated PI3K. Furthermore, LPS-induced IL-12p40 production was regulated by the p110 alpha catalytic subunit of PI3K. Moreover, LPS induced IL-12p40 production through the CaM/CaMK-II-activated NF kappa B and AP- 1 transcription factors. LPS-induced IL-12p40 production is known to be regulated by the c-Jun N-terminal kinase (JNK) pathway. Importantly, both CyA and FK506 down-regulated LPS-induced IL-12p40 transcription by inhibiting CaM/CaMK-II-activated PI3K and their downstream transcription factors NF kappa B and AP-1 independent of the JNK pathway.