TNF-alpha induces TGF-beta1 expression in lung fibroblasts at the transcriptional level via AP-1 activation.
Tumour necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta(1) (TGF-beta(1)) are peptides with multiple biological activities that influence neoplastic, immunologic and fibroproliferative diseases. There are clear interrelationships and overlap between the actions of TNF-alpha and TGF-beta(1) in lung fibrosis; therefore, we postulated that TNF-alpha may play a significant role in regulating TGF-beta(1) expression in lungs. We recently reported that TNF-alpha activates the extracellular regulated kinase (ERK)-specific pathway in fibroblasts resulting in stabilization of TGF-beta(1) mRNA and increased expression of TGF-beta(1). In the current study, we further investigated the molecular mechanisms involved in TNF-alpha regulation of TGF-beta(1) expression. Nuclear run-on assays showed that treatment of Swiss 3T3 fibroblasts with TNF-alpha increased transcription of the TGF-beta(1) gene in an ERK independent manner. Pre-treatment with the activator protein-1 (AP-1) inhibitor curcumin attenuated TNF-alpha induced transcription of the TGF-beta(1) gene. TNF-alpha induced increased levels of c-Jun and C-Fos in the nucleus accompanied by phosphorylation of c-Jun. In electrophoretic mobility shift assays, AP-1 binding to an AP-1 binding site found within the TGF-beta(1) promoter was increased in nuclear extracts from Swiss 3T3 fibroblasts treated with TNF-alpha. Together, these results suggest that TNF-alpha induces expression and DNA binding of AP-1 resulting in increased transcription of the TGF-beta(1) gene. It is essential to know which transcription pathways are activated because of the wide distribution of TNF-alpha and TGF-beta(1), the general lack of effective treatments for fibroproliferative disease and the possibility that targeting the correct transcription factors could be palliative.
Sullivan
Deborah E
DE
Department of Microbiology and Immunology, Biomedical Sciences Graduate Program, Tulane University School of Medicine, New Orleans, LA, USA.
Ferris
MaryBeth
M
Nguyen
Hong
H
Abboud
Elizabeth
E
Brody
Arnold R
AR
D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D051379:Mice; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D017931:DNA Primers; D018808:Transcription Factor AP-1; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha