title: Glycogen synthase kinase-3 regulates cigarette smoke extract- and IL-1β-induced cytokine secretion by airway smooth muscle.
abstract: Glycogen synthase kinase-3 (GSK-3) is a constitutively active kinase that regulates multiple signaling proteins and transcription factors involved in inflammation. Its role in inflammatory lung diseases, including chronic obstructive pulmonary disease (COPD), is largely unknown. We investigated the role of GSK-3 in the secretion of chemokines and growth factors by human airway smooth muscle cells after exposure to cigarette smoke extract (CSE) or interleukin-1β (IL-1β), important factors involved in the development of COPD. Cultured human airway smooth muscle cells were exposed to increasing concentrations of CSE (1-15%) and IL-1β (0.01-1.0 ng/ml), which induced the secretion of VEGF-A and IL-8, whereas eotaxin secretion was induced by IL-1β only. Inhibition of GSK-3 by the selective inhibitor SB216763 or CHIR/CT99021 attenuated the cytokine and growth factor release induced by CSE and/or IL-1β, without affecting the basal release. Secretion of the cytokines by airway smooth muscle partially depends on NF-κB signaling, and GSK-3 has been implicated in regulating multiple steps in activating the NF-κB signaling pathway. IL-1β treatment induced degradation of the NF-κB inhibitory protein Iκ-Bα followed by nuclear translocation and DNA binding of p65 NF-κB, which were unaffected by inhibition of GSK-3. However, induction of NF-κB-dependent transcriptional activity by IL-1β and CSE was largely reduced upon GSK-3 inhibition by SB216763. Collectively, we demonstrate that CSE and IL-1β activate airway smooth muscle cells to secrete the proinflammatory cytokines IL-8, eotaxin, and VEGF-A. Furthermore, we show that GSK-3 regulates the release of these cytokines induced by CSE and IL-1β by promoting NF-κB-dependent gene transcription.
authors.affiliation: Department of Molecular Pharmacology, University of Groningen, The Netherlands. H.A.Baarsma@rug.nl
authors.forename: Hoeke A
authors.initials: HA
authors.lastname: Baarsma
authors.forename: Herman
authors.initials: H
authors.lastname: Meurs
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Halayko
authors.forename: Mark H
authors.initials: MH
authors.lastname: Menzen
authors.forename: Martina
authors.initials: M
authors.lastname: Schmidt
authors.forename: Huib A M
authors.initials: HA
authors.lastname: Kerstjens
authors.forename: Reinoud
authors.initials: R
authors.lastname: Gosens
mesh_terms: D015153:Blotting, Western; D001980:Bronchi / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000187:drug effects*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology*; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D012907:Smoking; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D016207:Cytokines; D053583:Interleukin-1beta; D016328:NF-kappa B; D038362:Glycogen Synthase Kinase 3