Tumor necrosis factor-α-induced secretion of RANTES and interleukin-6 from human airway smooth muscle cells -: Modulation by glucocorticoids and β-agonists
Tumor necrosis factor-α-induced secretion of RANTES and interleukin-6 from human airway smooth muscle cells -: Modulation by glucocorticoids and β-agonists
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DOI：
10.1165/ajrcmb.26.4.4681
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发表时间：
2002-04-01
影响因子：
6.4
通讯作者：
Panettieri, RA
中科院分区：
文献类型：
--
作者：
Ammit, AJ;Lazaar, AL;Panettieri, RA
最近的研究表明，肿瘤坏死因子（TNF-α）刺激白细胞介素（IL）-6的分泌，并调节激活，正常T细胞表达和分泌（RANTES）从气道平滑肌（ASM）细胞，与诱导的每一个分子的差异调节（IL-6增加，RANTES抑制）环磷酸腺苷（cAMP）升高剂。在这项研究中，我们确定的机制介导的IL-6和RANTES基因转录在人类ASM细胞。我们发现TNF-α通过核因子（NF）-κ B依赖性途径诱导ASM细胞中IL-6基因表达，而RANTES基因表达通过活化蛋白（AP）-1和活化T细胞核因子（NF-AT）的活化介导。TNF-α诱导的IL-6分泌仅被地塞米松部分抑制，但TNF-α诱导的RANTES分泌被取消。β-激动剂通过激活IL-6启动子的CRE区域诱导ASM分泌IL-6。β-激动剂增强TNF-α诱导的IL-6分泌，反映了NF-κ B和CRE应答元件对IL-6基因表达的累加效应。相反，β-激动剂通过AP-1非依赖性途径抑制TNF-α诱导的RANTES分泌。总的来说，这些数据阐明了转录机制介导的TNF-α诱导的IL-6和RANTES分泌的ASM细胞，并确定特定的顺式或陷阱作用元件，确定糖皮质激素和cAMP升高剂对这些基因的表达的差异效应。
Recent studies have demonstrated that tumor necrosis factor (TNF-alpha)- stimulates the secretion of interleukin (IL)-6 and regulated on activation, normal T cells expressed and secreted (RANTES) from airway smooth muscle (ASM) cells, with the induction of each molecule being differentially regulated (IL-6 increased, RANTES inhibited) by cyclic adenosine monophosphate (cAMP)-elevating agents. In this study we identify the mechanisms mediating IL-6 and RANTES gene transcription in human ASM cells. We found that TNF-alpha induced IL-6 gene expression in ASM cells via a nuclear factor (NF)-KB-dependent pathway, whereas RANTES gene expression was mediated via activation of activator protein (AP)-1 and nuclear factor of activated T cells (NF-AT). TNF-alpha-induced IL-6 secretion was only partially inhibited by dexamethasone, yet TNF-alpha-induced RANTES secretion was abolished. (beta-Agonists induced IL-6 secretion from ASM via activation of the CRE region of the IL-6 promoter. (beta-Agonists augmented TNF-alpha-induced IL-6 secretion, reflecting an additive effect of NF-KB and CRE response elements on IL-6 gene expression. In contrast, (3-agonists inhibited TNF-a-induced RANTES secretion via an AP-1-independent pathway. Collectively, these data elucidate transcriptional mechanisms mediating TNF-alpha-induced IL-6 and RANTES secretion from ASM cells, and identify the specific cis- or traps-acting elements that determine the differential effects of glucocorticoids and CAMP-elevating agents on the expression of these genes.