TGFβ1 is the most prominent inductor of fibrosis. It induces differentiation of fibroblasts (or stellate cells in the liver) into fibrogenic myofibroblasts, which produce excessive extracellular matrix (ECM), the hallmark of fibrosis in the liver, kidney, and lung. Chronic or pathogenic levels of active TGFβ1 can lead to increased synthesis and decreased degradation of ECM resulting in fibrosis in these organs. Transgenic mice overexpressing TGFβ1 develop fibrosis in these organs, while blockage of TGFβ1 activity by neutralizing antibodies against TGFβ1 or soluble TGFβ1 type II receptor can prevent the accumulation of ECM in models of kidney, lung, and liver fibrosis, which in turn, causes a reversal of or protection from the pathological state.
TGFβ1 signals through two highly conserved transmembrane receptors (type I and type II receptors) with intracellular serine-threonine kinase domains. TGFβ1 binds to the type II receptor and recruits the type I receptor to from a heterotetrameric complex with the type II receptor. The type II receptor in turn phosphorylates threonine residues in the glycine-serine (GS)-rich domain of the type I receptor (ALK5) and activates it. The ALK5 receptor activates the Smad and the p38 mitogen-activated protein kinase (MAPK) signaling pathways, which have both been implicated in the upregulation of ECM proteins. When phosphorylated, Smad2 and/or Smad3 are released from a cytoplasmic anchorage protein and form a stable complex with Smad4 which translocates into the nucleus, recruits transcription factors, and initiates the transcription of specific TGFβ1-related genes, some of which are essential for the integrity of the ECM architecture. Inhibitors of TGFβ1 receptor will inhibit TGFβ1 signaling and may prevent progression of fibrosis and even cause reversal of fibrosis.
