Document Detail


BMP type II receptor deficiency confers resistance to growth inhibition by TGF-β in pulmonary artery smooth muscle cells: role of proinflammatory cytokines.
MedLine Citation:
PMID:  22227206     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Mutations in the bone morphogenetic protein (BMP) type II receptor (BMPR-II) underlie most cases of heritable pulmonary arterial hypertension (HPAH) and a significant proportion of sporadic cases. Pulmonary artery smooth muscle cells (PASMCs) from patients with pulmonary arterial hypertension (PAH) not only exhibit attenuated growth suppression by BMPs, but an abnormal mitogenic response to transforming growth factor (TGF)-β1. We sought to define the mechanism underlying this loss of the antiproliferative effects of TGF-β1 in BMPR-II-deficient PASMCs. The effect of TGF-β1 on PASMC proliferation was characterized in three different models of BMPR-II dysfunction: 1) HPAH PASMCs, 2) Bmpr2(+/-) mouse PASMCs, and 3) control human PASMCs transfected with BMPR-II small interfering RNA. BMPR-II reduction consistently conferred insensitivity to growth inhibition by TGF-β1. This was not associated with altered canonical TGF-β1/Smad signaling but was associated with a secreted factor. Microarray analysis revealed that the transcriptional responses to TGF-β1 differed between control and HPAH PASMCs, particularly regarding genes associated with interleukins and inflammation. HPAH PASMCs exhibited enhanced IL-6 and IL-8 induction by TGF-β1, an effect reversed by NF-κB inhibition. Moreover, neutralizing antibodies to IL-6 or IL-8 restored the antiproliferative effect of TGF-β1 in HPAH PASMCs. This study establishes that BMPR-II deficiency leads to failed growth suppression by TGF-β1 in PASMCs. This effect is Smad-independent but is associated with inappropriately altered NF-κB signaling and enhanced induction of IL-6 and IL-8 expression. Our study provides a rationale to test anti-interleukin therapies as an intervention to neutralize this inappropriate response and restore the antiproliferative response to TGF-β1.
Authors:
Rachel J Davies; Alan M Holmes; John Deighton; Lu Long; Xudong Yang; Lucy Barker; Christoph Walker; David C Budd; Paul D Upton; Nicholas W Morrell
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-01-06
Journal Detail:
Title:  American journal of physiology. Lung cellular and molecular physiology     Volume:  302     ISSN:  1522-1504     ISO Abbreviation:  Am. J. Physiol. Lung Cell Mol. Physiol.     Publication Date:  2012 Mar 
Date Detail:
Created Date:  2012-03-16     Completed Date:  2012-07-16     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  100901229     Medline TA:  Am J Physiol Lung Cell Mol Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  L604-15     Citation Subset:  IM    
Affiliation:
Division of Respiratory Medicine, Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, UK.
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MeSH Terms
Descriptor/Qualifier:
Animals
Bone Morphogenetic Protein Receptors, Type II / deficiency*,  metabolism
Cell Growth Processes / physiology
Cells, Cultured
Gene Expression
Humans
Hypertension, Pulmonary / genetics,  metabolism
Interleukin-6 / antagonists & inhibitors,  genetics,  metabolism*
Interleukin-8 / antagonists & inhibitors,  genetics,  metabolism*
Mice
Myocytes, Smooth Muscle / metabolism*
NF-kappa B / metabolism
Pulmonary Artery / metabolism*
RNA, Small Interfering / genetics
Smad Proteins / metabolism
Transfection / methods
Transforming Growth Factor beta1 / metabolism*
Grant Support
ID/Acronym/Agency:
GR077167MA//Wellcome Trust; RG/08/002/24718//British Heart Foundation
Chemical
Reg. No./Substance:
0/Interleukin-6; 0/Interleukin-8; 0/NF-kappa B; 0/RNA, Small Interfering; 0/Smad Proteins; 0/Transforming Growth Factor beta1; EC 2.7.11.30/Bone Morphogenetic Protein Receptors, Type II
Comments/Corrections

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