title: TNFα-induced airway smooth muscle cell proliferation depends on endothelin receptor signaling, GM-CSF and IL-6.
abstract: Pathological proliferation of human airway smooth muscle cells (HASMCs) causes hyperplasia in chronic lung diseases. Signaling pathways that link airway inflammation to HASMC proliferation might provide therapeutic targets for the prevention of airway remodeling and chronic lung diseases. Endothelin-1 (ET-1) signals via endothelin-A- and B-receptors (ETAR, ETBR) to perpetuate HASMC-associated and TNFα-dependent inflammatory processes.
  
  
  OBJECTIVE
  endothelin receptor antagonists (ERAs) suppress HASMC proliferation induced by inflammatory cytokines. HASMCs were stimulated ex vivo with cytokines in the presence or absence of ERAs (ETAR-specific/selective: BQ123, ambrisentan; ETBR-specific: BQ788; non-selective: bosentan, macitentan, ACT-132577) or cytokine-blocking antibodies. Cell counts, DNA-synthesis (BrdU-incorporation assay), cytokine production (ELISA) and ETBR expression (whole-genome microarray data, western blot) were analyzed. ET-1-induced HASMC proliferation and DNA-synthesis were reduced by protein kinase inhibitors and ETAR-specific/selective ERAs but not by BQ788. TNFα-induced HASMC proliferation and DNA-synthesis were reduced by all ERAs. TNFα induced ET-1 and ETBR expression. TNFα- and ET-1-induced GM-CSF releases were both reduced by BQ123 and BQ788. TNFα- and ET-1-induced IL-6 releases were both reduced by BQ123 but not by BQ788. Combined but not single blockade of GM-CSF-receptor-α-chain and IL-6 reduced TNFα- and ET-1-induced HASMC proliferation and DNA-synthesis. Combined but not single treatment with GM-CSF and IL-6 induced HASMC proliferation and DNA-synthesis in the presence of ET-1. In conclusion, TNFα induces HASMC proliferation via ET-1/GM-CSF/IL-6. ETBR requires up-regulation by TNFα to mediate ET-1 effects on HASMC proliferation. This signaling cascade links airway inflammation to HASMC-associated remodeling processes and is sensitive to ERAs. Therefore, ERAs could prevent inflammation-induced airway smooth muscle hyperplasia.
authors.affiliation: Medical Clinic III for Pneumology, Allergology, Sleep- and Respiratory Medicine, Bergmannsheil University Hospital, Bochum, Germany. Electronic address: Juergen.Knobloch@ruhr-uni-bochum.de.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Knobloch
authors.affiliation: Medical Clinic III for Pneumology, Allergology, Sleep- and Respiratory Medicine, Bergmannsheil University Hospital, Bochum, Germany.
authors.forename: Sarah Derya
authors.initials: SD
authors.lastname: Yanik
authors.affiliation: Medical Clinic III for Pneumology, Allergology, Sleep- and Respiratory Medicine, Bergmannsheil University Hospital, Bochum, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Körber
authors.affiliation: Thoracic Surgery, Lungenklinik, Hospital of Cologne, University Witten/Herdecke, Germany.
authors.forename: Erich
authors.initials: E
authors.lastname: Stoelben
authors.affiliation: Medical Clinic III for Pneumology, Allergology, Sleep- and Respiratory Medicine, Bergmannsheil University Hospital, Bochum, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Jungck
authors.affiliation: Medical Clinic III for Pneumology, Allergology, Sleep- and Respiratory Medicine, Bergmannsheil University Hospital, Bochum, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Koch
mesh_terms: D019138:Antibodies, Blocking / Q000494:pharmacology; D015415:Biomarkers / Q000378:metabolism; D001980:Bronchi / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D001984:Bronchial Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D002277:Carcinoma / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004261:DNA Replication / Q000187:drug effects; D065128:Endothelin Receptor Antagonists / Q000494:pharmacology; D019332:Endothelin-1 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006965:Hyperplasia / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D015850:Interleukin-6 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D009130:Muscle, Smooth / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D044022:Receptor, Endothelin A / Q000819:agonists / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D044023:Receptor, Endothelin B / Q000819:agonists / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000093242:Interleukin-6 Inhibitors
chemical_list: D019138:Antibodies, Blocking; D015415:Biomarkers; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D015850:Interleukin-6; D047428:Protein Kinase Inhibitors; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors; C000588596:EDNRB protein, human; C508600:IL6 protein, human; C439524:TNF protein, human
keywords: Cell proliferation; Cytokine; Hyperplasia; Inflammation; Lung; Smooth muscle