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- BMP, bone morphogenetic protein
- ECM, extracellular matrix
- ERK, extracellular signal-regulated kinase
- HGF, hepatocyte growth factor
- HSC, hepatic stellate cells
- IFN, interferon
- IgRE, IFN γ responsive element
- JNK, c-Jun N-terminal kinase
- LAP, latency-associated peptide
- MAPK, mitogen-activated protein kinase
- MMP, matrix metalloproteinase
- PDGF, platelet-derived growth factor
- TbRE, TGF-β-responsive element
- TGF, transforming growth factor
- TNF, tumour necrosis factor
Irrespective of initial stimuli, increased production of type I collagen is a common hallmark of fibrotic diseases in various organs including the liver. A dynamic balance between the production and degradation of collagen is seen, which is rigorously controlled by several growth factors and cytokines. Of these, transforming growth factor β (TGFβ) is the most potent factor in stimulating type I collagen gene transcription. It also regulates expression of matrix metalloproteinases and their inhibitors, and modulates inflammatory reactions by influencing T cell functions. Therefore, TGFβ is considered to be the major factor accelerating liver fibrosis. Identification and characterisation of Smad proteins, intracellular mediators of the signal transduction of TGFβ, have led to a better understanding of the precise mechanisms of TGFβ functions from the viewpoint of its intracellular signalling pathway and crosstalk with other factors. Several studies have focused on the suppression of TGFβ activation and intervention of the TGFβ/Smad signalling pathways to treat liver fibrosis. However, as generalised blockade of TGFβ activity may result in the promotion of carcinogenesis and excessive immune reactions, much attention has to be paid to selective intervention of the TGFβ/Smad signal specifically in collagen-producing cells in the fibrotic tissue. TGFβ also affects the growth and differentiation of stem and progenitor cells. From this point of view, a new concept of the treatment for liver fibrosis may arise from the discipline of stem cell biology by modulating TGFβ and Smad signalling in stem/progenitor cells.
TGFβ is a member of a large family of pleiotropic cytokines that includes bone morphogenetic proteins (BMPs), activins and other related factors. Mammals have three different forms of TGFβ (β1, β2 and β3). Although the three isoforms of TGFβ are encoded by distinct genes located on different chromosomes, they have approximately 80% homology at the level of amino acid sequence. Of …
Competing interests: None declared.