title: Simvastatin requires activation in accessory cells to modulate T-cell responses in asthma and COPD.
abstract: T-cell-dependent airway and systemic inflammation triggers the progression of chronic obstructive pulmonary disease (COPD) and asthma. Retrospective studies suggest that simvastatin has anti-inflammatory effects in both diseases but it is unclear, which cell types are targeted. We hypothesized that simvastatin modulates T-cell activity. Circulating CD4+ and CD8+ T-cells, either pure, co-cultured with monocytes or alveolar macrophages (AM) or in peripheral blood mononuclear cells (PBMCs), were ex vivo activated towards Th1/Tc1 or Th2/Tc2 and incubated with simvastatin. Markers for Th1/Tc1 (IFNγ) and Th2/Tc2 (IL-5, IL-13) were measured by ELISA; with PBMCs this was done comparative between 11 healthy never-smokers, 11 current smokers without airflow limitation, 14 smokers with COPD and 11 never-smokers with atopic asthma. T-cell activation induced IFNγ, IL-5 and IL-13 in the presence and absence of accessory cells. Simvastatin did not modulate cytokine expression in pure T-cell fractions. β-hydroxy-simvastatin acid (activated simvastatin) suppressed IL-5 and IL-13 in pure Th2- and Tc2-cells. Simvastatin suppressed IL-5 and IL-13 in Th2-cells co-cultivated with monocytes or AM, which was partially reversed by the carboxylesterase inhibitor benzil. Simvastatin suppressed IL-5 production of Th2/Tc2-cells in PBMCs without differences between cohorts and IL-13 stronger in never-smokers and asthma compared to COPD. Simvastatin induced IFNγ in Th1/Tc1-cells in PBMCs of all cohorts except asthmatics. Simvastatin requires activation in accessory cells likely by carboxylesterase to suppress IL-5 and IL-13 in Th2/Tc2-cells. The effects on Il-13 are partially reduced in COPD. Asthma pathogenesis prevents simvastatin-induced IFNγ up-regulation. Simvastatin has anti-inflammatory effects that could be of interest for asthma therapy.
authors.affiliation: Department of Internal Medicine III, Bergmannsheil University Hospital, Bochum, Germany; Department of Pneumology, Clinic III for Internal Medicine, University of Cologne, Cologne, Germany. Electronic address: juergen.knobloch@ruhr-uni-bochum.de.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Knobloch
authors.affiliation: Department of Internal Medicine III, Bergmannsheil University Hospital, Bochum, Germany; Department of Pneumology, Clinic III for Internal Medicine, University of Cologne, Cologne, Germany.
authors.forename: Yakup
authors.initials: Y
authors.lastname: Yakin
authors.affiliation: Department of Internal Medicine III, Bergmannsheil University Hospital, Bochum, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Körber
authors.affiliation: Department of Pneumology, Clinic III for Internal Medicine, University of Cologne, Cologne, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Grensemann
authors.affiliation: Department of Pneumology, Clinic III for Internal Medicine, University of Cologne, Cologne, Germany.
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Bendella
authors.affiliation: Department of Pneumology, Clinic III for Internal Medicine, University of Cologne, Cologne, Germany.
authors.forename: Niyazi
authors.initials: N
authors.lastname: Boyaci
authors.affiliation: Department of Internal Medicine III, Bergmannsheil University Hospital, Bochum, Germany.
authors.forename: Willem-Jakob
authors.initials: WJ
authors.lastname: Gallert
authors.affiliation: Department of Internal Medicine III, Bergmannsheil University Hospital, Bochum, Germany.
authors.forename: Sarah Derya
authors.initials: SD
authors.lastname: Yanik
authors.affiliation: Department of Internal Medicine III, Bergmannsheil University Hospital, Bochum, Germany; Department of Pneumology, Clinic III for Internal Medicine, University of Cologne, Cologne, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Jungck
authors.affiliation: Department of Internal Medicine III, Bergmannsheil University Hospital, Bochum, Germany; Department of Pneumology, Clinic III for Internal Medicine, University of Cologne, Cologne, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Koch
mesh_terms: D001249:Asthma / Q000188:drug therapy / Q000276:immunology*; D043182:Carboxylesterase / Q000378:metabolism; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D018793:Interleukin-13 / Q000378:metabolism; D015848:Interleukin-5 / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy / Q000276:immunology*; D019821:Simvastatin / Q000494:pharmacology* / Q000627:therapeutic use; D012907:Smoking / Q000009:adverse effects; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
chemical_list: D018793:Interleukin-13; D015848:Interleukin-5; D007371:Interferon-gamma; D019821:Simvastatin; D043182:Carboxylesterase
keywords: Anti-inflammatory activity; Asthma; COPD; Simvastatin; T-cells