IL-17A acts via p38 MAPK to increase stability of TNF-β-induced IL-8 mRNA in human ASM

被引:86
作者
Henness, S
van Thoor, E
Ge, Q
Armour, CL
Hughes, JM
Ammit, AJ [1 ]
机构
[1] Univ Sydney, Fac Pharm, Resp Res Grp, Sydney, NSW 2006, Australia
[2] Univ Sydney, Dept Pharmacol, Sydney, NSW 2006, Australia
关键词
inflammation; cytokines; messenger ribonucleic acid stability; neutrophils; structural cells; airway smooth muscle; interleukin; mitogen-activated protein kinase; tumor necrosis factor; 17A;
D O I
10.1152/ajplung.00367.2005
中图分类号
Q4 [生理学];
学科分类号
071003 ;
摘要
Human airway smooth muscle (ASM) plays an immunomodulatory role in asthma. Recently, IL-17A has become of increasing interest in asthma, being found at elevated levels in asthmatic airways and emerging as playing an important role in airway neutrophilia. IL-17A predominantly exerts its neutrophil orchestrating role indirectly via the induction of cytokines by resident airway structural cells. Here, we perform an in vitro study to show that although IL-17A did not induce secretion of the CXC chemokine IL-8 from ASM cells, IL-17A significantly potentiates TNF-alpha-induced IL-8 protein secretion and gene expression in a concentration-and time-dependent manner (P < 0.05). Levels of IL-8 protein produced after 24 h of incubation with TNF-alpha were enhanced 2.7-fold in the presence of IL-17A, and conditioned media significantly enhanced neutrophil chemotaxis in vitro. As IL-17A had no effect on the activity of NF-kappa B, a key transcriptional regulator of IL-8 gene expression, we then examined whether IL-17A acts at the posttranscriptional level. We found that IL-17A significantly augmented TNF-alpha-induced IL-8 mRNA stability. Interestingly, this enhanced stability occurred via a p38 MAPK-dependent pathway. The decay of IL-8 mRNA transcripts proceeded at a significantly faster rate when cells were pretreated with the p38 MAPK inhibitor SB203580 ( - 0.05763 +/- 0.01964, t(1/2) = 12.0 h), compared with vehicle ( - 0.01030 +/- 0.007963, t(1/2) = 67.3 h) [ results are expressed as decay constant ( means +/- SE) and half- life (t(1/2) in h): P < 0.05]. Collectively, these results demonstrate that IL-17A amplifies the synthetic function of ASM cells, acting via a p38 MAPK-dependent posttranscriptional pathway to augment TNF-alpha-induced secretion of the potent neutrophil chemoattractant IL-8 from ASM cells.
引用
收藏
页码:L1283 / L1290
页数:8
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