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Expression of the Metalloproteinase ADAM8 Is Upregulated in Liver Inflammation Models and Enhances Cytokine Release
Tanzeela Awan1, Aaron Babendreyer1, Justyna Wozniak1
1Institute of Molecular Pharmacology, RWTH Aachen University, Aachen, Germany.
Abstract:
Acute and chronic liver inflammation is driven by cytokine and chemokine release from various cell types in the liver. Here, we report that the induction of inflammatory mediators is associated with a yet undescribed upregulation of the metalloproteinase ADAM8 in different murine hepatitis models. We further show the importance of ADAM8 expression for the production of inflammatory mediators in cultured liver cells. As a model of acute inflammation, we investigated liver tissue from lipopolysaccharide- (LPS-) treated mice in which ADAM8 expression was markedly upregulated compared to control mice. In vitro, stimulation with LPS enhanced ADAM8 expression in murine and human endothelial and hepatoma cell lines as well as in primary murine hepatocytes. The enhanced ADAM8 expression was associated with an upregulation of TNF-α and IL-6 expression and release. Inhibition studies indicate that the cytokine response of hepatoma cells to LPS depends on the activity of ADAM8 and that signalling by TNF-α can contribute to these ADAM8-dependent effects. The role of ADAM8 was further confirmed with primary hepatocytes from ADAM8 knockout mice in which TNF-α and IL-6 induction and release were considerably attenuated. As a model of chronic liver injury, we studied liver tissue from mice undergoing high-fat diet-induced steatohepatitis and again observed upregulation of ADAM8 mRNA expression compared to healthy controls. In vitro, ADAM8 expression was upregulated in hepatoma, endothelial, and stellate cell lines by various mediators of steatohepatitis including fatty acid (linoleic-oleic acid), IL-1β, TNF-α, IFN-γ, and TGF-β. Upregulation of ADAM8 was associated with the induction and release of proinflammatory cytokines (TNF-α and IL-6) and chemokines (CX3CL1). Finally, knockdown of ADAM8 expression in all tested cell types attenuated the release of these mediators. Thus, ADAM8 is upregulated in acute and chronic liver inflammation and is able to promote inflammation by enhancing expression and release of inflammatory mediators.
Insights
The metalloproteinase ADAM8 is upregulated in both acute and chronic liver inflammation. ADAM8 promotes liver inflammation by increasing the release of inflammatory mediators like TNF-α and IL-6.
Area of Science:
- Hepatology
- Immunology
- Molecular Biology
Background:
- Liver inflammation, both acute and chronic, involves the release of cytokines and chemokines.
- The role of specific metalloproteinases in regulating inflammatory mediator production in the liver is not fully understood.
Purpose of the Study:
- To investigate the role of ADAM8 (a disintegrin and metalloproteinase domain-containing protein 8) in acute and chronic liver inflammation.
- To determine if ADAM8 expression influences the production of inflammatory mediators in liver cells.
Main Methods:
- Examined ADAM8 expression in murine models of lipopolysaccharide (LPS)-induced acute hepatitis and high-fat diet-induced steatohepatitis.
- Investigated ADAM8 expression and its effect on inflammatory mediator release in cultured murine and human liver cell lines (endothelial, hepatoma, stellate) and primary hepatocytes.
- Utilized ADAM8 knockout mice and knockdown experiments to assess the functional significance of ADAM8.
Main Results:
- ADAM8 expression was significantly upregulated in liver tissues from mice with both acute and chronic liver inflammation models.
- LPS stimulation in vitro increased ADAM8 expression, correlating with elevated TNF-α and IL-6 release.
- Inhibition of ADAM8 activity and its absence in knockout mice attenuated the inflammatory response, while ADAM8 knockdown reduced mediator release.
Conclusions:
- ADAM8 is a key mediator upregulated in acute and chronic liver inflammation.
- ADAM8 promotes liver inflammation by enhancing the expression and release of pro-inflammatory cytokines and chemokines.
- Targeting ADAM8 may represent a therapeutic strategy for liver inflammatory diseases.
