Transforming Growth Factor-β Stimulates Interleukin-11 Transcription via Complex Activating Protein-1-dependent Pathways

• Published in: The Journal of biological chemistry 1998-03, Vol.273 (10), p.5506
• Main Authors: Weiliang Tang, Liu Yang, Yu-Chung Yang, Shawn X. Leng, Jack A. Elias
• Format: Article
• Language: English
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.273.10.5506

Studies were undertaken to characterize the mechanism by which transforming growth factor-β 1 (TGF-β 1 ) stimulates epithelial cell interleukin (IL)-11 production. Nuclear run-on studies demonstrated that TGF-β 1 is a potent stimulator of IL-11 gene transcription. TGF-β 1 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-β 1 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-β 1 -stimulated cells. The sequence in the IL-11 promoter that contains the AP-1 sites also conferred TGF-β 1 responsiveness, in a position-independent fashion, on a heterologous minimal promoter. Thus, TGF-β 1 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.