Presentation Title

The Role of IL-22 in a therapeutic effect of a new TLR7 ligand 1Z1 on mouse alcoholic steatohepatitis.

Faculty Mentor

Ekihiro Seki

Start Date

18-11-2017 2:15 PM

End Date

18-11-2017 3:15 PM

Location

BSC-Ursa Minor 98

Session

Poster 3

Type of Presentation

Poster

Subject Area

biological_agricultural_sciences

Abstract

Alcoholic liver disease (ALD) is a result of chronic intake of excessive alcohol. In the United States, 40% of liver-related death is associated with alcohol consumption. The spectrum of ALD ranges from alcoholic fatty liver, alcoholic hepatitis (AH), alcoholic cirrhosis and hepatocellular carcinoma (HCC). Although alcoholic fatty liver is considered a benign liver disease, the mortality of AH is high, as 40 % of severe AH patients die within 6 months. AH survivors may still progress to alcoholic liver cirrhosis and some of them eventually develop HCC. Treatment of AH is still largely dependent on corticosteroid and pentoxifylline, with no significant progress in the past 40 years.

Since the translocation of intestine-derived lipopolysaccharide (LPS) is observed in ALD, it is conceivable that Toll-like receptor (TLR) signaling contributes to the development of ALD. For a decade, Seki laboratory has investigated the molecular mechanisms of TLR-mediated ALD and examined the therapeutic agents targeting TLRs. TLR2, TLR4, and TLR9 signaling promotes the development of ALD. Our previous study found the protective role of TLR7 signaling in liver fibrosis, which is in contrast to other TLRs that promote liver disease. Our unpublished data demonstrated that TLR7 knockout mice had increased alcohol-induced liver injury and that treatment with 1Z1, a new TLR7 ligand, suppressed alcohol-induced liver injury. Therefore, targeting TLR7 using 1Z1 might be a therapeutic option for ALD. However, the underlying mechanism of how 1Z1 inhibits liver damage is still unknown. This project will investigate two hypotheses as the underlying mechanisms of TLR7-mediated liver protection in ALD.

Our data demonstrated that treatment with 1Z1 significantly suppressed alcohol-induced liver injury, fat tissue accumulation, and steatohepatitis. Initial results indicated higher numbers of plasmocytoid dendritic cells in the liver of mice given 1Z1. Our resuts indicated 1Z1 treatment stimulated an increase in IL-22 level in the liver and intestines.The exact cellular source of IL-22 has yet to be determined. Further studies are attempting to clarify the cellular mechanism of action propagated by TLR7 activation.

Summary of research results to be presented

In the current study, we used mice to model high alcohol intake conditions and compared the extent of liver damage. Our data demonstrated that treatment with 1Z1 suppressed alcohol-induced liver injury. Our work demonstrates the extent of liver damage inducible by alcohol consumption and the level of mediation achievable by oral ingestion of 1Z1. Therefore, we show targeting TLR7 using 1Z1 can be a therapeutic option for alcoholic liver disease. Further studies are attempting to clarify the cellular mechanism of action propagated by TLR7 activation. We have explored the relationship between TLR7 activation by 1Z1 and pDCs, which express large amounts of TLR7. Initial results indicated higher numbers of pDC in the liver of mice given 1Z1. IL-22 has also been examined using FACS and transgenic mice to determine their role in suppressing liver disease and their relationship with TLR7. Our resuts indicated 1Z1 treatment stimulated an increase in IL-22 level in the liver and intestines. The exact cellular source of IL-22 has yet to be determined.

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Nov 18th, 2:15 PM Nov 18th, 3:15 PM

The Role of IL-22 in a therapeutic effect of a new TLR7 ligand 1Z1 on mouse alcoholic steatohepatitis.

BSC-Ursa Minor 98

Alcoholic liver disease (ALD) is a result of chronic intake of excessive alcohol. In the United States, 40% of liver-related death is associated with alcohol consumption. The spectrum of ALD ranges from alcoholic fatty liver, alcoholic hepatitis (AH), alcoholic cirrhosis and hepatocellular carcinoma (HCC). Although alcoholic fatty liver is considered a benign liver disease, the mortality of AH is high, as 40 % of severe AH patients die within 6 months. AH survivors may still progress to alcoholic liver cirrhosis and some of them eventually develop HCC. Treatment of AH is still largely dependent on corticosteroid and pentoxifylline, with no significant progress in the past 40 years.

Since the translocation of intestine-derived lipopolysaccharide (LPS) is observed in ALD, it is conceivable that Toll-like receptor (TLR) signaling contributes to the development of ALD. For a decade, Seki laboratory has investigated the molecular mechanisms of TLR-mediated ALD and examined the therapeutic agents targeting TLRs. TLR2, TLR4, and TLR9 signaling promotes the development of ALD. Our previous study found the protective role of TLR7 signaling in liver fibrosis, which is in contrast to other TLRs that promote liver disease. Our unpublished data demonstrated that TLR7 knockout mice had increased alcohol-induced liver injury and that treatment with 1Z1, a new TLR7 ligand, suppressed alcohol-induced liver injury. Therefore, targeting TLR7 using 1Z1 might be a therapeutic option for ALD. However, the underlying mechanism of how 1Z1 inhibits liver damage is still unknown. This project will investigate two hypotheses as the underlying mechanisms of TLR7-mediated liver protection in ALD.

Our data demonstrated that treatment with 1Z1 significantly suppressed alcohol-induced liver injury, fat tissue accumulation, and steatohepatitis. Initial results indicated higher numbers of plasmocytoid dendritic cells in the liver of mice given 1Z1. Our resuts indicated 1Z1 treatment stimulated an increase in IL-22 level in the liver and intestines.The exact cellular source of IL-22 has yet to be determined. Further studies are attempting to clarify the cellular mechanism of action propagated by TLR7 activation.