Figure 4.

TLR4 activation enhances TGF-β signaling and expression of TGF-β target genes. In unstimulated quiescent cells (top), basal production of active TGF-β engages cell surface TGF-β receptors resulting in SMAD phosphorylation and low-level transcription of SMAD-responsive genes. A fraction of TGF-βRII complexes with the TGF-β pseudoreceptor Bambi instead of TGF-βRI rendering the type II receptor signaling incompetent.^{(e.g., 156,157)} Upon engagement of TLR4 with EDA (bottom), increased generation of active TGF-β1 coupled with Bambi downregulation sensitizes cells to TGF-β1 in the immediate microenvironment increasing TGF-βR signaling and the expression of SMAD target genes. A significant faction of profibrotic factors is induced specifically by SMAD2/3.