Interleukin-6 overexpression induces pulmonary hypertension.
Inflammatory cytokine interleukin (IL)-6 is elevated in the serum and lungs of patients with pulmonary artery hypertension (PAH). Several animal models of PAH cite the potential role of inflammatory mediators. We investigated role of IL-6 in the pathogenesis of pulmonary vascular disease. Indices of pulmonary vascular remodeling were measured in lung-specific IL-6-overexpressing transgenic mice (Tg(+)) and compared to wild-type (Tg(-)) controls in both normoxic and chronic hypoxic conditions. The Tg(+) mice exhibited elevated right ventricular systolic pressures and right ventricular hypertrophy with corresponding pulmonary vasculopathic changes, all of which were exacerbated by chronic hypoxia. IL-6 overexpression increased muscularization of the proximal arterial tree, and hypoxia enhanced this effect. It also reproduced the muscularization and proliferative arteriopathy seen in the distal arteriolar vessels of PAH patients. The latter was characterized by the formation of occlusive neointimal angioproliferative lesions that worsened with hypoxia and were composed of endothelial cells and T-lymphocytes. IL-6-induced arteriopathic changes were accompanied by activation of proangiogenic factor, vascular endothelial growth factor, the proproliferative kinase extracellular signal-regulated kinase, proproliferative transcription factors c-MYC and MAX, and the antiapoptotic proteins survivin and Bcl-2 and downregulation of the growth inhibitor transforming growth factor-beta and proapoptotic kinases JNK and p38. These findings suggest that IL-6 promotes the development and progression of pulmonary vascular remodeling and PAH through proproliferative antiapoptotic mechanisms.
Steiner
M Kathryn
MK
Division of Pulmonary Critical Care Medicine, University of Massachusetts Memorial Medical Center, Worcester, MA 01655, USA. marciakathryn.steiner@umassmemorial.org
Syrkina
Olga L
OL
Kolliputi
Narasaish
N
Mark
Eugene J
EJ
Hales
Charles A
CA
Waxman
Aaron B
AB
D000818:Animals; D017209:Apoptosis; D001160:Arterioles / Q000276:immunology / Q000473:pathology; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D001794:Blood Pressure; D049109:Cell Proliferation; D002908:Chronic Disease; D042783:Endothelial Cells / Q000276:immunology / Q000473:pathology; D006965:Hyperplasia; D006976:Hypertension, Pulmonary / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D000860:Hypoxia / Q000150:complications; D051034:Inhibitor of Apoptosis Proteins; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D011651:Pulmonary Artery / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D012097:Repressor Proteins; D000077022:Survivin; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014655:Vascular Resistance; D016278:Ventricular Function, Right; D017725:Ventricular Pressure
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C117749:Birc5 protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D015850:Interleukin-6; D008869:Microtubule-Associated Proteins; C489428:Myc protein, mouse; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D012097:Repressor Proteins; D000077022:Survivin; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C052617:Bcl2 protein, mouse; C068422:Max protein, mouse; D020928:Mitogen-Activated Protein Kinases