Universität zu Köln

Knobloch, Juergen, Yakin, Yakup, Koerber, Sandra, Grensemann, Barbara, Bendella, Zeynep, Boyaci, Niyazi, Gallert, Willem-Jakob, Yanik, Sarah Derya, Jungck, David and Koch, Andrea (2016). Simvastatin requires activation in accessory cells to modulate T-cell responses in asthma and COPD. Eur. J. Pharmacol., 788. S. 294 - 306. AMSTERDAM: ELSEVIER SCIENCE BV. ISSN 1879-0712

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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 (IFN gamma) 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 IFN gamma, IL-5 and IL-13 in the presence and absence of accessory cells. Simvastatin did not modulate cytokine expression in pure T-cell fractions. beta-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 IFN gamma 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 IFN gamma up-regulation. Simvastatin has anti-inflammatory effects that could be of interest for asthma therapy. (C) 2016 Elsevier B.V. All rights reserved.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Knobloch, Juergen UNSPECIFIED UNSPECIFIED UNSPECIFIED Yakin, Yakup UNSPECIFIED UNSPECIFIED UNSPECIFIED Koerber, Sandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Grensemann, Barbara UNSPECIFIED UNSPECIFIED UNSPECIFIED Bendella, Zeynep UNSPECIFIED UNSPECIFIED UNSPECIFIED Boyaci, Niyazi UNSPECIFIED UNSPECIFIED UNSPECIFIED Gallert, Willem-Jakob UNSPECIFIED UNSPECIFIED UNSPECIFIED Yanik, Sarah Derya UNSPECIFIED UNSPECIFIED UNSPECIFIED Jungck, David UNSPECIFIED UNSPECIFIED UNSPECIFIED Koch, Andrea UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-258570
DOI:	10.1016/j.ejphar.2016.06.037
Journal or Publication Title:	Eur. J. Pharmacol.
Volume:	788
Page Range:	S. 294 - 306
Date:	2016
Publisher:	ELSEVIER SCIENCE BV
Place of Publication:	AMSTERDAM
ISSN:	1879-0712
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language OBSTRUCTIVE PULMONARY-DISEASE; ALVEOLAR MACROPHAGES; GLOBAL STRATEGY; MURINE MODEL; STATIN USE; PREVENTION; IL-5; EXACERBATIONS; LYMPHOCYTES; MANAGEMENT Multiple languages Pharmacology & Pharmacy Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/25857