title: 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.affiliation: Dept. of Pharmacology, Chiesi Farmaceutici, Parma, Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: Moretto
authors.forename: Serena
authors.initials: S
authors.lastname: Bertolini
authors.forename: Claudia
authors.initials: C
authors.lastname: Iadicicco
authors.forename: Gessica
authors.initials: G
authors.lastname: Marchini
authors.forename: Manminder
authors.initials: M
authors.lastname: Kaur
authors.forename: Giorgia
authors.initials: G
authors.lastname: Volpi
authors.forename: Riccardo
authors.initials: R
authors.lastname: Patacchini
authors.forename: Dave
authors.initials: D
authors.lastname: Singh
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Facchinetti
mesh_terms: D000171:Acrolein / Q000633:toxicity*; D001980:Bronchi / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects; D003609:Dactinomycin / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D018375:Neutrophil Activation / Q000187:drug effects; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D011014:Pneumonia / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism / Q000473:pathology; D020871:RNA Stability / Q000187:drug effects*; D012333:RNA, Messenger / Q000096:biosynthesis*; D020545:Respiratory Mucosa / Q000378:metabolism* / Q000473:pathology; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D000171:Acrolein; D003609:Dactinomycin; D016209:Interleukin-8; D047908:Intracellular Signaling Peptides and Proteins; D019384:Nucleic Acid Synthesis Inhibitors; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D014028:Tobacco Smoke Pollution; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C508606:CXCL8 protein, human