Evidence for TGF-beta1 and bleomycin intracellular signaling through autocrine regulation of Smad 3 binding to the proximal promoter of the Smad 7 gene.

Both Bleomycin and TGF-beta1 increase the transcription of the COL1A1 gene. Bleomycin acts through TGF-beta1. Bleomycin stimulates the COL1A1 promoter through the distal TGF-beta response element by intracellular and extracellular signaling. As demonstrated in this manuscript, Bleomycin's intracellular signaling can be explained by a decrease of Smad 3 transcription factor binding to the SBE located in the proximal promoter of the inhibitory Smad 7 gene. This would result in TGF-beta1-induced activated SMADS, which would result in more collagen. Bleomycin's extracellular signaling results from the secretion of more latent TGF-beta produced by lung fibroblasts and cleaved to active TGF-beta extracellularly. Since the TGF-beta genes are auto-induced in human embryonic IMR-90 lung fibroblasts, this study indicates an autocrine mechanism to maintain homeostasis in vivo for fibroblasts and other cell types, which produce TGF-beta1 to limit the fibrogenic response to TGF-beta1 and Bleomycin.