Abstract
Interleukin-8 (IL-8/CXCL8) is an important neutrophil chemoattractant known to be elevated in the airways of cigarette smokers and in patients with chronic obstructive pulmonary disease (COPD), a syndrome associated with chronic cigarette smoking. We examined the acute effect of aqueous cigarette smoke extract (CSE) on IL-8 expression in normal human bronchial smooth muscle cells (HBSMC) and alveolar macrophages. CSE upregulates IL-8 mRNA levels in a concentration and time-dependent manner and such an effect was accompanied by IL-8 secretion into the extracellular medium. CSE-evoked elevation of IL-8 mRNA was mimicked by its component acrolein at concentrations (3-30µM) found in CSE. Both CSE and acrolein induced p38 mitogen-activated protein kinase (MAPK) phosphorylation which was accompanied by the phosphorylation of MAPK-activated kinase 2 (MK2), a known downstream substrate of the p38 MAPK. In both HBSMC and human alveolar macrophages, pharmacological inhibition of p38 MAPK or MK2 strongly accelerated the decay of IL-8 mRNA levels upon stimulation with CSE or acrolein and subsequent blockade of mRNA neosynthesis with actinomycin D. Conversely, pharmacological inhibition of extracellular-signal-regulated kinases 1/2 (ERK1/2) signalling did not affect mRNA stability but inhibited both CSE- and acrolein-induced steady-state levels of IL-8 mRNA, suggesting a transcriptional effect. In sum, p38 MAPK/MK2 signalling appear to be an important post-transcriptional mechanism underlying CSE-induced IL-8 mRNA upregulation.
- © 2012 ERS