API

Relationship: 147

Title

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Increased, Activation and Recruitment of Hepatic macrophages (Kupffer Cells) leads to Up Regulation, TGFbeta1 expression

Upstream event

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Increased, Activation and Recruitment of Hepatic macrophages (Kupffer Cells)

Downstream event

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Up Regulation, TGFbeta1 expression

Key Event Relationship Overview

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AOPs Referencing Relationship

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AOP Name Adjacency Weight of Evidence Quantitative Understanding
Protein Alkylation leading to Liver Fibrosis adjacent High

Taxonomic Applicability

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Term Scientific Term Evidence Link
human Homo sapiens High NCBI
Rattus norvegicus Rattus norvegicus High NCBI

Sex Applicability

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Life Stage Applicability

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Key Event Relationship Description

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Following activation Kupffer cells (KCs) become the main source for TGF-β1, the most potent profibrogenic cytokine, as well as a major source for inflammatory mediators and for reactive oxygen species (ROS).

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

[1] [2] [3] [4] [5] [6] [7] [8] [9] [10]

Evidence Supporting this KER

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Biological Plausibility

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The functional relationship between these KEs is consistent with biological knowledge. [1] [2] [3] [4] [5] [6] [7] [8] [9] [10]

Empirical Evidence

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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.[1]

[11][12]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. [13]

Uncertainties and Inconsistencies

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there are no inconsistencies

Quantitative Understanding of the Linkage

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no quantitative data

Response-response Relationship

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Time-scale

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Known modulating factors

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Known Feedforward/Feedback loops influencing this KER

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Domain of Applicability

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Human: [4][3] Rat: [11]

References

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  1. 1.0 1.1 1.2 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.
  2. 2.0 2.1 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.
  3. 3.0 3.1 3.2 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.
  4. 4.0 4.1 4.2 Bataller, R. and D.A. Brenner (2005), Liver Fibrosis, J.Clin. Invest, vol. 115, no. 2, pp. 209-218.
  5. 5.0 5.1 Lee, U.E. and S.L. Friedman (2011), Mechanisms of Hepatic Fibrogenesis, Best Pract Res Clin Gastroenterol, vol. 25, no. 2, pp. 195-206.
  6. 6.0 6.1 Guo, J. and S. L. Friedman (2007), Hepatic fibrogenesis, Semin Liver Dis, vol. 27, no. 4, pp. 413-426.
  7. 7.0 7.1 Brenner, D.A. (2009), Molecular Pathogenesis of Liver Fibrosis, Trans Am Clin Climatol Assoc, vol. 120, pp. 361–368.
  8. 8.0 8.1 Fujiwara, N. and K. Kobayashi (2005), Macrophages in inflammation, Curr Drug Targets Inflamm Allergy, vol. 4, no. 3, pp. 281-286.
  9. 9.0 9.1 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.
  10. 10.0 10.1 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.
  11. 11.0 11.1 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.
  12. 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.
  13. 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.