1. IL-17A acts via p38 MAPK to increase stability of TNF-[alpha]-induced IL-8 mRNA in human ASM
- Author
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Henness, Sheridan, van Thoor, Eveline, Ge, Qi, Armour, Carol L., Hughes, J. Margaret, and Ammit, Alaina J.
- Subjects
Airway (Medicine) -- Physiological aspects ,Cytokines -- Research ,Cytokines -- Properties ,Inflammation -- Research ,Interleukins -- Research ,Messenger RNA -- Analysis ,Neutrophils -- Research ,Biological sciences - Abstract
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 SB-203580 (-0.05763 [+ or -] 0.01964, [t.sub.1/2] = 12.0 h), compared with vehicle (-0.01030 [+ or -] 0.007963, [t.sub.1/2] = 67.3 h) [results are expressed as decay constant (means [+ or -] SE) and half-life ([t.sub.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. inflammation; cytokines; messenger ribonucleic acid stability; neutrophils; structural cells; airway smooth muscle: interleukin; mitogenactivated protein kinase; tumor necrosis factor; interleukin 17A
- Published
- 2006