Simplified schematic drawing of the TGF-β-Smad pathway. Binding of TGF-β to its type II receptor in concert with the type I receptor (A) leads to formation of a receptor complex and phosphorylation of the type I receptor. The type I receptor subsequently phosphorylates Smad2 or 3 (B), allowing this complex to associate with Smad4 and move into the nucleus (C). In the nucleus, the Smad complex associates with a transcription factor and this complex binds to specific enhancers in target genes (down-) regulating transcription (D). TNF is able to interfere with TGF-β signaling through the upregulation of the inhibitory Smad7 protein (E). Smad7 is capable of inhibiting the Smad2 and 3 phosphorylating process by competing with the receptor interaction but Smad7 also can dephosphorylate the complex. In addition, Smad7 itself is capable to upregulate TGFβ gene expression. As described in the discussion, CSE is most likely capable to interfere with the Smad pathway although this is not yet fully elucidated. (F). Phosphorylated Smad3 is able to stimulate the transcription of the decorin gene (G). Adapted from [18, 19, 35, 36].