Transforming growth factor-beta stimulates interleukin-11 transcription via complex activating protein-1-dependent pathways.
Studies were undertaken to characterize the mechanism by which transforming growth factor-beta1 (TGF-beta1) stimulates epithelial cell interleukin (IL)-11 production. Nuclear run-on studies demonstrated that TGF-beta1 is a potent stimulator of IL-11 gene transcription. TGF-beta1 also stimulated the luciferase activity in cells transfected with reporter gene constructs containing nucleotides -728 to +58 of the IL-11 promoter. Studies with progressive 5' deletion constructs and site-specific mutations demonstrated that this stimulation was dependent on 2 AP-1 sites between nucleotides -100 and -82 in the IL-11 promoter. Mobility shift assays demonstrated that TGF-beta1 stimulated AP-1 protein-DNA binding to both AP-1 sites. Supershift analysis demonstrated that JunD was the major moiety contributing to AP-1-DNA binding in unstimulated cells and that c-Jun-, Fra-1-, and Fra-2-DNA binding were increased whereas JunD-DNA binding was decreased in TGF-beta1-stimulated cells. The sequence in the IL-11 promoter that contains the AP-1 sites also conferred TGF-beta1 responsiveness, in a position-independent fashion, on a heterologous minimal promoter. Thus, TGF-beta1 stimulates IL-11 gene transcription via a complex AP-1-dependent pathway that is dependent on 2 AP-1 motifs between nucleotides -100 and -82 that function as an enhancer in the IL-11 promoter.
Tang
W
W
Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, Department of Internal Medicine, New Haven, Connecticut 06520-8057, USA.
Yang
L
L
Yang
Y C
YC
Leng
S X
SX
Elias
J A
JA
D001483:Base Sequence; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000032:analysis; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D017370:Interleukin-11 / Q000235:genetics*; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed / Q000235:genetics; D009687:Nuclear Proteins / Q000032:analysis; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000502:physiology; D011650:Pulmonary Alveoli / Q000502:physiology; D012136:Respiratory Syncytial Viruses / Q000235:genetics; D017384:Sequence Deletion / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000502:physiology*; D015533:Transcriptional Activation / Q000502:physiology; D014162:Transfection / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D004268:DNA-Binding Proteins; D017370:Interleukin-11; D009687:Nuclear Proteins; D018808:Transcription Factor AP-1; D016212:Transforming Growth Factor beta