Upstream eventIncreased pro-inflammatory mediators
Activation, Stellate cells
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Protein Alkylation leading to Liver Fibrosis||adjacent||High|
Life Stage Applicability
|All life stages||High|
Key Event Relationship Description
HSC Initiation is associated with rapid gene induction resulting from paracrine stimulation by inflammatory cells and injured hepatocytes . Also Kupffer cell infiltration and activation play a prominent role in HSC activation.[Li et al., 2008]
Lymphocytes, especially CD4 T-helper (Th) lymphocytes, help orchestrate the host response via cytokine production and can differentiate into Th1 and Th2 subsets. In general, Th1 cells produce cytokines promoting cell-mediated immunity, including interferon (IFN)-γ, TNF, and interleukin (IL)-2. Th2 cells produce IL-4, IL-5, IL-6, and IL-13 and promote humoral immunity. Results from previous experimental models imply that Th2 lymphocytes favor fibrogenesis in liver injury over Th1 lymphocytes. [Shi et al., 1997] However, recent studies of Wynn [Wynn,2004] suggest that more than two T-cell subsets underlying a highly complex, orchestrated response are involved, and they also provide us a more important paradigm for how these intersecting pathways may regulate fibrosis. In animal models, IL-13 has emerged as a key mediator because it increases TGF-β1 and MMP expression by macrophages, whereas IL-4 has a limited role. One study examined the activity of IL-13 in cultured HSCs and suggested that IL-4 and IL-13 directly affect HSCs by increasing collagen production and suppressing HSC proliferation. [Sugimoto et al., 2005]
Leukocytes recruited to the liver during injury join with Kupffer cells in producing compounds that modulate HSC behavior
Transforming growth factor beta 1 (TGF-β1) is the most potent fibrogenic factor for hepatic stellate cells (HSCs). In response to TGF-β1, HSCs activate into myofibroblast-like cells, producing type I, III and IV collagen, proteoglycans like biglycan and decorin, glycoproteins like laminin, fibronectin, tenascin and glycosaminoglycan. [Kisseleva and Brenner, 2007] In the further course of events activated HSCs themselves express TGF-β1. TGF-β1 induces its own mRNA to sustain high levels in local sites of liver injury. The effects of TGF-β1 are mediated by intracellular signalling via Smad proteins. Smads 2 and 3 are stimulatory whereas Smad 7 is inhibitory. Smad1/5/8, MAP kinase and PI3 kinase are further signalling pathways in different cell types for TGF-β1 effects. [Parsons et al., 2007] Concomitant with increased TGF-β production, HSC increase production of collagen. Connective tissue growth factor (CTGF) is a profibrogenic peptide induced by TGF-β, that stimulates the synthesis of collagen type I and fibronectin and may mediate some of the downstream effects of TGF-β. It is upregulated during activation of HSC, suggesting that its expression is another determinant of a fibrogenic response to TGF-β. [Williams et al.,2000] During fibrogenesis, tissue and blood levels of active TGF-β are elevated and overexpression of TGF-β1 in transgenic mice can induce fibrosis. Additionally, experimental fibrosis can be inhibited by anti-TGF-β treatments with neutralizing antibodies or soluble TbRs (TGF-β receptors). [Qi et al., 1999]
Evidence Supporting this KER
There is good understanding and broad acceptance of this KER. [Kisseleva and Brenner, 2007; Williams et al., 2000; Qi et al., 1999; Gressner et al., 2002; Kolios et al., 2006; Bataller and Brenner, 2005; Guo and Friedman, 2007; Brenner, 2009; Kaimori et al., 2007; Kershenobich Stalnikowitz and Weissbrod, 2003; Li et al., 2008; Matsuoka and Tsukamoto, 1990; Kisseleva and Brenner, 2008; Poli, 2000; Parsons et al., 2007; Friedman, 2008; Liu et al., 2006]
It is difficult to get experimental evidence in vitro for TGF-β1-induced HSC activation because HSCs undergo spontaneous activation when cultured on plastic; nevertheless qualitative empirical evidence for temporal and incidence concordance for this KER exists. Czaja et al could prove that treatment of cultured hepatic cells with TGF-β1 increased type I pro-collagen mRNA levels 13-fold due to post-transcriptional gene regulation. Tan et al. discovered that short TGF-β1 pulses can exert long-lasting effects on fibroblasts. HSCs activated in culture do not fully reproduce the changes in gene expression observed in vivo. De Minicis et al investigated gene expression changes in 3 different models of HSC activation and compared gene expression profiles in culture (mice HSCs in co-culture with KCs) and in vivo and did not find a proper correlation. [Czaja et al., 1989; Tan et al., 2013; Yin et al., 2013; De Minicis et al., 2007]
Uncertainties and Inconsistencies
Quantitative Understanding of the Linkage
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Human [Kolios et al., 2006; Guo and Friedman, 2007]
Rat [Dooley et al., 2000]
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- Brenner, D.A. (2009), Molecular Pathogenesis of Liver Fibrosis, Trans Am Clin Climatol Assoc, vol. 120, pp. 361–368.
- Czaja, M.J. et al. (1989), In vitro and in vivo association of transforming growth factor-beta 1 with hepatic fibrosis, J Cell Biol, vol. 108, no. 6, pp. 2477-2482.
- De Minicis, S. et al. (2007), Gene expression profiles during hepatic stellate cell activation in culture and in vivo, Gastroenterology, vol. 132, no. 5, pp. 1937-1946.
- Dooley, S. et al. (2000), Modulation of transforming growth factor b response and signaling during transdifferentiation of rat hepatic stellate cells to myofibroblasts,Hepatology, vol. 31, no. 5, pp. 1094-1106.
- Friedman, S.L. (2008), Mechanisms of Hepatic Fibrogenesis, Gastroenterology, vol. 134, no. 6, pp. 1655–1669.
- Gressner , A.M. et al. (2002), Roles of TGF-β in hepatic fibrosis. Front Biosci, vol. 7, pp. 793-807.
- Guo, J. and S. L. Friedman (2007), Hepatic fibrogenesis, Semin Liver Dis, vol. 27, no. 4, pp. 413-426.
- Jing-Ting Li, Zhang-Xiu Liao, Jie Ping, Dan Xu, and Hui Wang, Molecular mechanism of hepatic stellate cell activation and antifi brotic therapeutic strategies, J Gastroenterol 2008; 43:419–428
- Kaimori, A. et al. (2007), Transforming growth factor-beta1 induces an epithelial-to-mesenchymal transition state in mouse hepatocytes in vitro, J Biol Chem, vol. 282, no. 30, pp. 22089-22101.
- Kershenobich Stalnikowitz, D. and A.B. Weissbrod (2003), Liver Fibrosis and Inflammation. A Review, Annals of Hepatology, vol. 2, no. 4, pp.159-163.
- Kisseleva T and Brenner DA, (2008), Mechanisms of Fibrogenesis, Exp Biol Med, vol. 233, no. 2, pp. 109-122.
- Kisseleva, T. and Brenner, D.A. (2007), Role of hepatic stellate cells in fibrogenesis and the reversal of fibrosis, Journal of Gastroenterology and Hepatology, vol. 22, Suppl. 1; pp. S73–S78.
- Kolios, G., V. Valatas and E. Kouroumalis (2006), Role of Kupffer cells in the pathogenesis of liver disease, World J.Gastroenterol, vol. 12, no. 46, pp. 7413-7420.
- Li, Jing-Ting et al. (2008), Molecular mechanism of hepatic stellate cell activation and antifibrotic therapeutic strategies, J Gastroenterol, vol. 43, no. 6, pp. 419–428.
- Liu, Xingjun et al. (2006), Therapeutic strategies against TGF-beta signaling pathway in hepatic fibrosis. Liver Int, vol.26, no.1, pp. 8-22.
- Matsuoka, M. and H. Tsukamoto, (1990), Stimulation of hepatic lipocyte collagen production by Kupffer cell-derived transforming growth factor beta: implication for a pathogenetic role in alcoholic liver fibrogenesis, Hepatology, vol. 11, no. 4, pp. 599-605.
- Parsons, C.J., M.Takashima and R.A. Rippe (2007), Molecular mechanisms of hepatic fibrogenesis. J Gastroenterol Hepatol, vol. 22, Suppl.1, pp. S79-S84.
- Poli, G. (2000), Pathogenesis of liver fibrosis: role of oxidative stress, Mol Aspects Med, vol. 21, no. 3, pp. 49 – 98.
- Qi Z et al. (1999), Blockade of type beta transforming growth factor signaling prevents liver fibrosis and dysfunction in the rat, Proc Natl Acad Sci USA, vol. 96, no. 5, pp. 2345-2349.
- Shi Z, Wakil AE, Rockey DC. Strain-specifi c differences in mouse hepatic wound healing are mediated by divergent T helper cytokine responses. Proc Natl Acad Sci USA 1997;94:10663–8.
- Sugimoto R, Enjoji M, Nakamuta M, Ohta S, Kohjima M, Fukushima M, et al. Effect of IL-4 and IL-13 on collagen production in cultured LI90 human hepatic stellate cells. Liver Int 2005;25:420–8.
- Tan, A.B. et al. (2013), Cellular re- and de-programming by microenvironmental memory: why short TGF-β1 pulses can have long effects, Fibrogenesis Tissue Repair, vol. 6, no. 1, p. 12.
- Williams, E.J. et al. (2000), Increased expression of connective tissue growth factor in fibrotic human liver and in activated hepatic stellate cells, J Hepatol, vol. 32, no. 5, pp. 754-761.
- Wynn TA. Fibrotic disease and the T(H)1/T(H)2 paradigm. Nat Rev Immunol 2004;4:583–94.
- Yin, C. et al. (2013), Hepatic stellate cells in liver development, regeneration, and cancer, J Clin Invest, vol. 123, no. 5, pp. 1902–1910.