title: L-thyroxine promotes a proliferative airway smooth muscle phenotype in the presence of TGF-β1.
abstract: Hypothyroidism may reduce, whereas hyperthyroidism may aggravate, asthma symptoms. The mechanisms underlying this relationship are largely unknown. Since thyroid hormones have central roles in cell growth and differentiation, we hypothesized that airway remodeling, in particular increased airway smooth muscle (ASM) mass, may be involved. To address this hypothesis, we investigated the effects of triiodothyronine (T3) and l-thyroxine (T4) in the absence and presence of the profibrotic transforming growth factor (TGF)-β1 on human ASM cell phenotype switching. T3 (1-100 nM) and T4 (1-100 nM) did not affect basal ASM proliferation. However, when combined with TGF-β1 (2 ng/ml), T4 synergistically increased the proliferative response, whereas only a minor effect was observed for T3. In line with a switch from a contractile to a proliferative ASM phenotype, T4 reduced the TGF-β1-induced contractile protein expression by ∼50%. Cotreatment with T3 reduced TGF-β1-induced contractile protein expression by ∼25%. The synergistic increase in proliferation was almost fully inhibited by the integrin αvβ3 antagonist tetrac (100 nM), whereas no significant effects of the thyroid receptor antagonist 1-850 (3 μM) were observed. Inhibition of MEK1/2, downstream of the integrin αvβ3, also inhibited the T4- and TGF-β1-induced proliferative responses. Collectively, the results indicate that T4, and to a lesser extent T3, promotes a proliferative ASM phenotype in the presence of TGF-β1, which is predominantly mediated by the membrane-bound T4 receptor αvβ3. These results indicate that thyroid hormones may enhance ASM remodeling in asthma, which could be of relevance for hyperthyroid patients with this disease.
authors.affiliation: Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands; Groningen Research Institute for Asthma and COPD, University of Groningen, Groningen, The Netherlands; b.g.j.dekkers@umcg.nl.
authors.forename: Bart G J
authors.initials: BG
authors.lastname: Dekkers
authors.affiliation: Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands; Department of Pharmacology, Faculty of Veterinary Medicine, Semnan University, Semnan, Iran;
authors.forename: Saeideh
authors.initials: S
authors.lastname: Naeimi
authors.affiliation: Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands; Groningen Research Institute for Asthma and COPD, University of Groningen, Groningen, The Netherlands;
authors.forename: I Sophie T
authors.initials: IS
authors.lastname: Bos
authors.affiliation: Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands; Groningen Research Institute for Asthma and COPD, University of Groningen, Groningen, The Netherlands;
authors.forename: Mark H
authors.initials: MH
authors.lastname: Menzen
authors.affiliation: Department of Physiology, University of Manitoba, Winnipeg, Canada; and.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Halayko
authors.affiliation: Department of Pharmacology, Faculty of Veterinary Medicine, University of Tehran, Teheran, Iran.
authors.forename: Goudarz Sadeghi
authors.initials: GS
authors.lastname: Hashjin
authors.affiliation: Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands; Groningen Research Institute for Asthma and COPD, University of Groningen, Groningen, The Netherlands;
authors.forename: Herman
authors.initials: H
authors.lastname: Meurs
mesh_terms: D056151:Airway Remodeling; D001980:Bronchi / Q000473:pathology; D002460:Cell Line; D049109:Cell Proliferation; D015536:Down-Regulation; D015870:Gene Expression; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000502:physiology*; D010641:Phenotype; D013974:Thyroxine / Q000502:physiology*; D053773:Transforming Growth Factor beta1 / Q000502:physiology*; D014284:Triiodothyronine / Q000502:physiology
chemical_list: D039302:Integrin alphaVbeta3; D009124:Muscle Proteins; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; D014284:Triiodothyronine; D013974:Thyroxine
keywords: airway smooth muscle contractile protein expression; airway smooth muscle proliferation; l-thyroxine; transforming growth factor-β1; triiodothyronine