title: Inhibition of NFkappaB activation and IL-8 expression in human bronchial epithelial cells by acrolein.
abstract: Lipid oxidation and environmental pollutants are major sources of alpha,beta-unsaturated aldehydes such as acrolein and 4-hydroxynonenal. Acrolein (2-propenal), a major product of organic combustion such as tobacco smoke, represents the most reactive alpha,beta-unsaturated aldehyde, with high reactivity toward nucleophilic targets such as sulfhydryl groups. To investigate how acrolein affects respiratory tract cell activation, we exposed either primary (NHBE) or immortalized human bronchial epithelial cells (HBE1) to 0-25 microM acrolein, and determined effects on basal and tumor necrosis factor-alpha (TNFalpha)-induced production of the chemokine interleukin (IL)-8. Cell exposure to acrolein dose-dependently suppressed IL-8 mRNA levels in HBE1 cells (26, 40, and 79% at 5, 10, and 25 microM acrolein concentrations, respectively) and resulted in corresponding decreases in IL-8 production. Studies of nuclear factor-kappaB (NFkappaB) activation, an essential event in IL-8 production, showed decreased TNFalpha-induced NFkappaB activation by acrolein, illustrated by inhibition of nuclear translocation of NFkappaB and reduced IkappaBalpha degradation. Immunochemical analysis of IkappaB kinase (IKK), a redox-sensitive regulator of NFkappaB activation, indicated direct modification of the IKK beta-subunit by acrolein, suggesting that acrolein may act directly on IKK. In summary, our results demonstrate that acrolein can suppress inflammatory processes in the airways by inhibiting epithelial IL-8 production through direct or indirect inhibitory effects on NFkappaB activation.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, UC Davis, Davis, CA 95616, USA.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Valacchi
authors.forename: Elisa
authors.initials: E
authors.lastname: Pagnin
authors.forename: Anh
authors.initials: A
authors.lastname: Phung
authors.forename: Mirella
authors.initials: M
authors.lastname: Nardini
authors.forename: Bettina C
authors.initials: BC
authors.lastname: Schock
authors.forename: Carroll E
authors.initials: CE
authors.lastname: Cross
authors.forename: Albert
authors.initials: A
authors.lastname: van der Vliet
mesh_terms: D000171:Acrolein / Q000494:pharmacology*; D021581:Active Transport, Cell Nucleus; D015153:Blotting, Western; D001980:Bronchi / Q000166:cytology* / Q000187:drug effects; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000166:cytology* / Q000187:drug effects; D006801:Humans; D051550:I-kappa B Kinase; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D007249:Inflammation; D016209:Interleukin-8 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012137:Respiratory System / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016209:Interleukin-8; D016328:NF-kappa B; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000171:Acrolein; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human