Cigarette smoke and its component acrolein augment IL-8/CXCL8 mRNA stability via p38 MAPK/MK2 signaling in human pulmonary cells.

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). We examined the acute effect of aqueous cigarette smoke extract (CSE) on IL-8 expression in primary human pulmonary cells, in particular in normal human bronchial smooth muscle cells (HBSMCs). IL-8 mRNA levels increased upon CSE exposure in a concentration- and time-dependent manner, and such an effect was accompanied by IL-8 secretion. CSE-evoked elevation of IL-8 mRNA was mimicked by its component acrolein. Both CSE and acrolein induced p38 mitogen-activated protein kinase (MAPK) phosphorylation, accompanied by the phosphorylation of MAPK-activated kinase 2 (MK2), a known downstream substrate of the p38 MAPK, both in HBSMCs and in human airway epithelial cells. Furthermore, 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 in pulmonary structural cells (HBSMCs and airways epithelial cells) as well as in human alveolar macrophages. Conversely, pharmacological inhibition of ERK1/2 signaling inhibited CSE-induced steady-state levels of IL-8 mRNA without affecting mRNA stability, thus suggesting inhibition at the transcriptional level. In sum, p38 MAPK/MK2 signaling is an important posttranscriptional mechanism underlying upregulation of IL-8 mRNA levels elicited by CSE and acrolein. Given the pivotal role of IL-8 in neutrophil chemotaxis and activation, our results shed light on the mechanisms through which cigarette smoke can initiate inflammation in the lung.

• Authors: Nadia Moretto, Serena Bertolini, Claudia Iadicicco, Gessica Marchini, Manminder Kaur, Giorgia Volpi, Riccardo Patacchini, Dave Singh, Fabrizio Facchinetti
• Journal: American journal of physiology. Lung cellular and molecular physiology (Am J Physiol Lung Cell Mol Physiol) Vol. 303 Issue 10 Pg. L929-38 (Nov 15 2012) ISSN: 1522-1504 [Electronic] United States
• PMID: 22983351 (Publication Type: Clinical Trial, Journal Article)

Chemical References

• CXCL8 protein, human
• Interleukin-8
• Intracellular Signaling Peptides and Proteins
• Nucleic Acid Synthesis Inhibitors
• RNA, Messenger
• Tobacco Smoke Pollution
• Dactinomycin
• Acrolein
• MAP-kinase-activated kinase 2
• Protein Serine-Threonine Kinases
• p38 Mitogen-Activated Protein Kinases

Topics

• Acrolein (toxicity)
• Bronchi (metabolism, pathology)
• Cells, Cultured
• Chemotaxis (drug effects)
• Dactinomycin (pharmacology)
• Epithelial Cells (metabolism, pathology)
• Female
• Humans
• Interleukin-8 (biosynthesis)
• Intracellular Signaling Peptides and Proteins (metabolism)
• MAP Kinase Signaling System (drug effects)
• Male
• Middle Aged
• Myocytes, Smooth Muscle (metabolism, pathology)
• Neutrophil Activation (drug effects)
• Neutrophils (metabolism, pathology)
• Nucleic Acid Synthesis Inhibitors (pharmacology)
• Pneumonia (metabolism, pathology)
• Protein Serine-Threonine Kinases (metabolism)
• Pulmonary Disease, Chronic Obstructive (metabolism, pathology)
• RNA Stability (drug effects)
• RNA, Messenger (biosynthesis)
• Respiratory Mucosa (metabolism, pathology)
• Tobacco Smoke Pollution (adverse effects)
• p38 Mitogen-Activated Protein Kinases (metabolism)