Role of endogenous TGF-β in glucocorticoid-induced lung type II cell differentiation

Theresa M. McDevitt, Linda W. Gonzales, Rashmin C. Savani, Philip L. Ballard

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

In the fetal lung, endogenous transforming growth factor (TGF)-β inhibits early morphogenesis and blocks hormone-induced type II cell differentiation. We hypothesized that endogenous TGF-β inhibits type II cell differentiation and that the stimulatory effects of glucocorticoids result in part from suppression of TGF-β. Epithelial cells were isolated from human fetal lung and cultured under defined conditions with and without dexamethasone plus cAMP to promote type II cell differentiation. Control cells produced TGF-β, which was activated in part by αVβ 6-integrin. Treatment with dexamethasone, but not cAMP, reduced TGF-β1 and -β2 transcripts and TGF-β bioactivity in culture medium. To examine the effects of decreased TGF-β in the absence of glucocorticoid, cells were treated with antibodies to TGF-β and its receptors. By real-time RT-PCR, antibody blockade of TGF-β reduced serpine1, a TGF-β-inducible gene, and increased gene expression for sftpa, sftpb, sftpc, and titf1, mimicking the response to hormone treatment. By microarray analysis, 29 additional genes were induced by both TGF-β antibody and hormone treatment, and 20 other genes were repressed by both treatments. For some genes, the fold response was comparable for antibody and hormone treatment. We conclude that endogenous TGF-β suppresses expression of surfactant proteins and selected other type II cell genes in fetal lung, in part secondary to increased expression of titf1, and we propose that the mechanism of glucocorticoid-induced type II cell differentiation includes antagonism of TGF-β gene suppression. Surfactant production during fetal development is likely influenced by relative levels of TGF-β and glucocorticoids.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume292
Issue number1
DOIs
StatePublished - Jan 2007

Fingerprint

Transforming Growth Factors
Glucocorticoids
Cell Differentiation
Lung
Genes
Antibodies
Hormones
Surface-Active Agents
Dexamethasone
Growth Factor Receptors
Microarray Analysis
Fetal Development
Morphogenesis
Integrins
Growth Hormone
Culture Media
Real-Time Polymerase Chain Reaction

Keywords

  • Dexamethasone
  • Gene expression
  • Integrin
  • Surfactant protein
  • Thyroid transcription factor-1

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Cell Biology
  • Physiology

Cite this

Role of endogenous TGF-β in glucocorticoid-induced lung type II cell differentiation. / McDevitt, Theresa M.; Gonzales, Linda W.; Savani, Rashmin C.; Ballard, Philip L.

In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 292, No. 1, 01.2007.

Research output: Contribution to journalArticle

@article{bcd53141749544ca8e1e9e3a013164c1,
title = "Role of endogenous TGF-β in glucocorticoid-induced lung type II cell differentiation",
abstract = "In the fetal lung, endogenous transforming growth factor (TGF)-β inhibits early morphogenesis and blocks hormone-induced type II cell differentiation. We hypothesized that endogenous TGF-β inhibits type II cell differentiation and that the stimulatory effects of glucocorticoids result in part from suppression of TGF-β. Epithelial cells were isolated from human fetal lung and cultured under defined conditions with and without dexamethasone plus cAMP to promote type II cell differentiation. Control cells produced TGF-β, which was activated in part by αVβ 6-integrin. Treatment with dexamethasone, but not cAMP, reduced TGF-β1 and -β2 transcripts and TGF-β bioactivity in culture medium. To examine the effects of decreased TGF-β in the absence of glucocorticoid, cells were treated with antibodies to TGF-β and its receptors. By real-time RT-PCR, antibody blockade of TGF-β reduced serpine1, a TGF-β-inducible gene, and increased gene expression for sftpa, sftpb, sftpc, and titf1, mimicking the response to hormone treatment. By microarray analysis, 29 additional genes were induced by both TGF-β antibody and hormone treatment, and 20 other genes were repressed by both treatments. For some genes, the fold response was comparable for antibody and hormone treatment. We conclude that endogenous TGF-β suppresses expression of surfactant proteins and selected other type II cell genes in fetal lung, in part secondary to increased expression of titf1, and we propose that the mechanism of glucocorticoid-induced type II cell differentiation includes antagonism of TGF-β gene suppression. Surfactant production during fetal development is likely influenced by relative levels of TGF-β and glucocorticoids.",
keywords = "Dexamethasone, Gene expression, Integrin, Surfactant protein, Thyroid transcription factor-1",
author = "McDevitt, {Theresa M.} and Gonzales, {Linda W.} and Savani, {Rashmin C.} and Ballard, {Philip L.}",
year = "2007",
month = "1",
doi = "10.1152/ajplung.00088.2006",
language = "English (US)",
volume = "292",
journal = "American Journal of Physiology - Heart and Circulatory Physiology",
issn = "0363-6135",
publisher = "American Physiological Society",
number = "1",

}

TY - JOUR

T1 - Role of endogenous TGF-β in glucocorticoid-induced lung type II cell differentiation

AU - McDevitt, Theresa M.

AU - Gonzales, Linda W.

AU - Savani, Rashmin C.

AU - Ballard, Philip L.

PY - 2007/1

Y1 - 2007/1

N2 - In the fetal lung, endogenous transforming growth factor (TGF)-β inhibits early morphogenesis and blocks hormone-induced type II cell differentiation. We hypothesized that endogenous TGF-β inhibits type II cell differentiation and that the stimulatory effects of glucocorticoids result in part from suppression of TGF-β. Epithelial cells were isolated from human fetal lung and cultured under defined conditions with and without dexamethasone plus cAMP to promote type II cell differentiation. Control cells produced TGF-β, which was activated in part by αVβ 6-integrin. Treatment with dexamethasone, but not cAMP, reduced TGF-β1 and -β2 transcripts and TGF-β bioactivity in culture medium. To examine the effects of decreased TGF-β in the absence of glucocorticoid, cells were treated with antibodies to TGF-β and its receptors. By real-time RT-PCR, antibody blockade of TGF-β reduced serpine1, a TGF-β-inducible gene, and increased gene expression for sftpa, sftpb, sftpc, and titf1, mimicking the response to hormone treatment. By microarray analysis, 29 additional genes were induced by both TGF-β antibody and hormone treatment, and 20 other genes were repressed by both treatments. For some genes, the fold response was comparable for antibody and hormone treatment. We conclude that endogenous TGF-β suppresses expression of surfactant proteins and selected other type II cell genes in fetal lung, in part secondary to increased expression of titf1, and we propose that the mechanism of glucocorticoid-induced type II cell differentiation includes antagonism of TGF-β gene suppression. Surfactant production during fetal development is likely influenced by relative levels of TGF-β and glucocorticoids.

AB - In the fetal lung, endogenous transforming growth factor (TGF)-β inhibits early morphogenesis and blocks hormone-induced type II cell differentiation. We hypothesized that endogenous TGF-β inhibits type II cell differentiation and that the stimulatory effects of glucocorticoids result in part from suppression of TGF-β. Epithelial cells were isolated from human fetal lung and cultured under defined conditions with and without dexamethasone plus cAMP to promote type II cell differentiation. Control cells produced TGF-β, which was activated in part by αVβ 6-integrin. Treatment with dexamethasone, but not cAMP, reduced TGF-β1 and -β2 transcripts and TGF-β bioactivity in culture medium. To examine the effects of decreased TGF-β in the absence of glucocorticoid, cells were treated with antibodies to TGF-β and its receptors. By real-time RT-PCR, antibody blockade of TGF-β reduced serpine1, a TGF-β-inducible gene, and increased gene expression for sftpa, sftpb, sftpc, and titf1, mimicking the response to hormone treatment. By microarray analysis, 29 additional genes were induced by both TGF-β antibody and hormone treatment, and 20 other genes were repressed by both treatments. For some genes, the fold response was comparable for antibody and hormone treatment. We conclude that endogenous TGF-β suppresses expression of surfactant proteins and selected other type II cell genes in fetal lung, in part secondary to increased expression of titf1, and we propose that the mechanism of glucocorticoid-induced type II cell differentiation includes antagonism of TGF-β gene suppression. Surfactant production during fetal development is likely influenced by relative levels of TGF-β and glucocorticoids.

KW - Dexamethasone

KW - Gene expression

KW - Integrin

KW - Surfactant protein

KW - Thyroid transcription factor-1

UR - http://www.scopus.com/inward/record.url?scp=33846248810&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33846248810&partnerID=8YFLogxK

U2 - 10.1152/ajplung.00088.2006

DO - 10.1152/ajplung.00088.2006

M3 - Article

VL - 292

JO - American Journal of Physiology - Heart and Circulatory Physiology

JF - American Journal of Physiology - Heart and Circulatory Physiology

SN - 0363-6135

IS - 1

ER -