IL-17A induces eotaxin-1/CC chemokine ligand 11 expression in human airway smooth muscle cells: Role of MAPK (Erk1/2, JNK, and p38) pathways
IL-17A induces eotaxin-1/CC chemokine ligand 11 expression in human airway smooth muscle cells: Role of MAPK (Erk1/2, JNK, and p38) pathways
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DOI：
10.4049/jimmunol.177.6.4064
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发表时间：
2006-09-15
影响因子：
4.4
通讯作者：
Gounni, Abdelilah Soussi
中科院分区：
文献类型：
--
作者：
Rahman, Muhammad Shahidur;Yamasaki, Akira;Gounni, Abdelilah Soussi
最近，IL-17A在哮喘患者的呼吸道分泌物中表达水平升高，并与气道高反应性相关。尽管这些研究提出了IL-17A可能影响过敏性疾病的可能性，但其机制尚不清楚。在这项研究中，我们研究了il - 17a介导的CC趋化因子（eotaxin-1/CCL11）从人气道平滑肌（ASM）细胞产生的分子机制。我们发现，与il - 17a孵育的人ASM细胞导致eotaxin-1/CCL11的释放显著增加，而通过中和抗il - 17a单抗可以减少这种释放。此外，IL-17A可显著诱导eotaxin-1/CCL11的释放和mRNA的表达，而环己亚胺和放线菌素D可消除这一作用。此外，使用含有eotaxin-1/CCL11近端启动子的荧光素酶驱动的报告结构进行转染研究表明，IL-17A在转录水平上诱导eotaxin-1/CCL11。IL-17A还显著增强了IL-1 β介导的eotaxin-1/CCL11 mRNA、蛋白释放和ASM细胞启动子活性。用MAPK p38、p42/p44、ERK、JNK或JAK抑制剂预处理的原代人ASM细胞在IL-17A处理后，eotaxin-1/CCL11的释放显著减少。此外，IL-17A介导了ASM细胞中MAPK （p38、JNK和p42/44 ERK）和STAT-3的快速磷酸化，而不是STAT-6或STAT-5的快速磷酸化。综上所述，我们的数据首次提供了il - 17a通过MAPK （p38, p42/p44 ERK， JNK）信号通路诱导ASM细胞中eotaxin-1/CCL11表达的证据。我们的研究结果提出了IL-17A可能通过诱导eotaxin-1/CCL11的产生在过敏性哮喘中发挥作用的可能性。
Recently, IL-17A has been shown to be expressed in higher levels in respiratory secretions from asthmatics and correlated with airway hyperresponsiveness. Although these studies raise the possibility that IL-17A may influence allergic disease, the mechanisms remain unknown. In this study, we investigated the molecular mechanisms involved in IL-17A-mediated CC chemokine (eotaxin-1/CCL11) production from human airway smooth muscle (ASM) cells. We found that incubation of human ASM cells with rIL-17A resulted in a significant increase of eotaxin-1/CCL11 release from ASM cells that was reduced by neutralizing anti-IL-17A mAb. Moreover, IL-17A significantly induced eotaxin-1/CCL11 release and mRNA expression, an effect that was abrogated with cycloheximide and actinomycin D treatment. Furthermore, transfection studies using a luciferase-driven reporter construct containing eotaxin-1/CCL11 proximal promoter showed that IL-17A induced eotaxin-1/CCL11 at the transcriptional level. IL-17A also enhanced significantly IL-1 beta-mediated eotaxin-1/CCL11 mRNA, protein release, and promoter activity in ASM cells. Primary human ASM cells pretreated with inhibitors of MAPK p38, p42/p44 ERK, JNK, or JAK but not PI3K, showed a significant decrease in eotaxin-1/CCL11 release upon IL-17A treatment. In addition, IL-17A mediated rapid phosphorylation of MAPK (p38, JNK, and p42/44 ERK) and STAT-3 but not STAT-6 or STAT-5 in ASM cells. Taken together, our data provide the first evidence of IL-17A-induced eotaxin-1/CCL11 expression in ASM cells via MAPK (p38, p42/p44 ERK, JNK) signaling pathways. Our results raise the possibility that IL-17A may play a role in allergic asthma by inducing eotaxin-1/CCL11 production.