Upstream eventTissue resident cell activation
Increased pro-inflammatory mediators
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Protein Alkylation leading to Liver Fibrosis||adjacent||High|
|Increased DNA damage leading to increased risk of breast cancer||adjacent||Moderate||Not Specified|
|Increased reactive oxygen and nitrogen species (RONS) leading to increased risk of breast cancer||adjacent||Moderate||Not Specified|
Life Stage Applicability
|All life stages||High|
Key Event Relationship Description
Following activation the liver resident macrophages, Kupffer cells (KCs), become a major source for inflammatory mediators including cytokines, chemokines, lysosomal, and proteolytic enzymes and for reactive oxygen species (ROS) and also the main source for TGF-β1, the most potent profibrogenic cytokine. [Luckey and Petersen 2001; Winwood and Arthur 1993]
Expressed TNF-α (Tumor Necrosis Factor -alpha), TRAIL (TNF-related apoptosis-inducing ligand), and FasL (Fas Ligand) are pro-inflammatory active and also capable of inducing death receptor-mediated apoptosis in hepatocytes.
Activated KCs are an important source of ROS like superoxide (generated by NADPH oxidase (NOX). KCs express TNF-α, IL-1 (Interleukin-1) and MCP-1 (monocyte-chemoattractant protein-1), all being mitogens and chemoattractants for HSCs and induce the expression of platelet-derived growth factor (PDGF) receptors on hepatic stellate cells (HSCs) which further enhances HSCs proliferation. [Kamimura and Tsukamoto, 1995; Li et al.,2008; Kolios et al., 2006; Bataller and Brenner, 2005; Lee and Friedman,2011; Brenner,2009, Fujiwara and Kobayashi, 2005; Kirkham, 2007; Reuter et al., 2010
Evidence Supporting this KER
The functional relationship between these KEs is consistent with biological knowledge. [Kamimura and Tsukamoto, 1995; Li et al.,2008; Kolios et al., 2006; Bataller and Brenner, 2005; Lee and Friedman,2011; Guo and Friedman, 2007; Brenner,2009, Fujiwara and Kobayashi, 2005; Kirkham, 2007; Reuter et al., 2010]
Cytokine release is one of the features that define KC activation and there is sound empirical evidence for this KER. Experimental studies have shown enhanced cytokine gene expression by KCs in evolution of experimental liver injury. Northern blot analysis of freshly isolated KCs showed enhanced mRNA expression of three acute phase cytokines by the hepatic resident macrophages, TNF-α, IL-6 and TGF-β. [Kamimura and Tsukamoto, 1995; De Bleser et al., 1997; Chu et al., 2013]
Experiments by Matsuoka and Tsukamoto already 1990 showed that KCs isolated from rat liver with alcoholic fibrosis express and release TGF-β1 and that this cytokine is largely responsible for the KC-conditioned medium-induced stimulation of collagen formation by HSCs. [Matsuoka and Tsukamoto, 1990]
Uncertainties and Inconsistencies
Quantitative Understanding of the Linkage
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
- Bataller, R. and D.A. Brenner (2005), Liver Fibrosis, J.Clin. Invest, vol. 115, no. 2, pp. 209-218.
- Brenner, D.A. (2009), Molecular Pathogenesis of Liver Fibrosis, Trans Am Clin Climatol Assoc, vol. 120, pp. 361–368.
- Chu, P.S. et al. (2013), C-C motif chemokine receptor 9 positive macrophages activate hepatic stellate cells and promote liver fibrosis in mice, Hepatology, vol. 58, no. 1, pp. 337-350.
- De Bleser, P.J. et al. (1997), Transforming growth factor-beta gene expression in normal and fibrotic rat liver, J Hepatol, vol. 26, no. 4, pp. 886-893.
- Fujiwara, N. and K. Kobayashi (2005), Macrophages in inflammation, Curr Drug Targets Inflamm Allergy, vol. 4, no. 3, pp. 281-286.
- Guo, J. and S. L. Friedman (2007), Hepatic fibrogenesis, Semin Liver Dis, vol. 27, no. 4, pp. 413-426.
- Kamimura, S. and H. Tsukamoto (1995), Cytokine gene expression by Kupffer cells in experimental alcoholic liver disease, Hepatology, vol. 22, no. 4, pp. 1304-1309.
- Kirkham, P. (2007), Oxidative stress and macrophage function: a failure to resolve the inflammatory response, Biochem Soc Trans, vol. 35, no. 2, pp. 284-287.
- 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.
- Lee, U.E. and S.L. Friedman (2011), Mechanisms of Hepatic Fibrogenesis, Best Pract Res Clin Gastroenterol, vol. 25, no. 2, pp. 195-206.
- 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.
- Luckey, S.W., and D.R. Petersen (2001), Activation of Kupffer cells during the course of carbon tetrachloride-induced liver injury and fibrosis in rats, Exp Mol Pathol, vol. 71, no. 3, pp. 226-240
- 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.
- Reuter, S. et al. (2010), Oxidative stress, inflammation, and cancer: how are they linked? Free Radic Biol Med, vol. 49, no. 11, pp. 1603-1616.
- Winwood, P.J., and M.J. Arthur (1993), Kupffer cells: their activation and role in animal models of liver injury and human liver disease, Semin Liver Dis, vol. 13, no. 1, pp. 50-59.