Dataset Information

Kahweol Ameliorates the Liver Inflammation through the Inhibition of NF-?B and STAT3 Activation in Primary Kupffer Cells and Primary Hepatocytes.

ABSTRACT: Gut derived bacterial endotoxins, such as lipopolysaccharide (LPS), are involved in one of the important mechanisms that lead to inflammation associated with various liver diseases, including nonalcoholic fatty liver disease and alcoholic liver disease. Kahweol is a coffee-specific diterpene present in coffee bean and exhibits anti-angiogenic and anti-inflammatory activities. However, to date, the effect of kahweol on liver inflammation remains unknown. In this study, we examined whether kahweol exhibits a protective effect by inhibiting liver inflammation in primary Kupffer cells and primary hepatocytes cultures as well as their co-cultures. Kahweol decreased the LPS-induced production of interleukin 1 alpha, interleukin 1 beta, interleukin 6, and tumor necrosis factor alpha. The inhibitory effect of kahweol on the liver inflammation was associated with the down regulation of LPS-stimulated phospho-nuclear factor kappa B and -signal transducer and activator of transcription 3 expression. These results suggest that kahweol might be a novel potent agent to treat liver inflammation induced by LPS.

SUBMITTER: Seo HY

PROVIDER: S-EPMC6073512 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Kahweol Ameliorates the Liver Inflammation through the Inhibition of NF-κB and STAT3 Activation in Primary Kupffer Cells and Primary Hepatocytes.

Seo Hye-Young HY Kim Mi-Kyung MK Lee So-Hee SH Hwang Jae Seok JS Park Keun-Gyu KG Jang Byoung Kuk BK

Nutrients 20180704 7

Gut derived bacterial endotoxins, such as lipopolysaccharide (LPS), are involved in one of the important mechanisms that lead to inflammation associated with various liver diseases, including nonalcoholic fatty liver disease and alcoholic liver disease. Kahweol is a coffee-specific diterpene present in coffee bean and exhibits anti-angiogenic and anti-inflammatory activities. However, to date, the effect of kahweol on liver inflammation remains unknown. In this study, we examined whether kahweol ...[more]

PMID: 29973533

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Project description:Background & aimsComplex communications between hepatocytes and Kupffer cells (KCs) are known to drive or suppress hepatocarcinogenesis, with controversial data in the literature. In previous experiments that aimed to decipher hepatocyte/KC interactions, we unexpectedly unveiled a tumor-suppressing effect of polyinosinic-polycytidylic acid, a widely used inducer of MX dynamin like GTPase 1 (Mx1)-cre expression, which questioned a theory of interleukin 1a/6 cytokine circuit in hepatocyte/KC communication. The goal of this study was to clarify the controversy and decipher unique functions of KCs and non-KC macrophages in liver tumorigenesis.MethodsWe used the C-type lectin domain family 4 member F (Clec4f)-cre system to delete Src-homology 2 domain-containing tyrosine phosphatase 2 (Shp2)/protein tyrosine phosphatase nonreceptor 11 (Ptpn11) in KCs, and a combination of Clec4f-cre and adeno-associated virus-cre to delete Shp2 in KCs and hepatocytes to investigate the effects on hepatocellular carcinoma development and immune cell compositions/activities.ResultsAblating Shp2 in KCs generated a tumor-promoting niche, which was exacerbated further by concurrent removal of Shp2 in both KCs and hepatocytes. Shp2 deficiency induced KC apoptosis and decreased its numbers, which induced compensatory recruitment of bone marrow-derived monocytes into liver. These newly recruited monocytes differentiated into non-KC macrophages with tumor-associated macrophage function, leading to aggravated tumor progression through down-regulation of CD8 T cells. Tumor-associated macrophage blockade by anti-chemokine (C-C motif) ligand 2 (CCL2) antibody inhibited hepatocellular carcinoma progression, while depletion of all macrophages had a tumor-promoting effect by increasing myeloid-derived suppressor cells (M-MDSCs) and decreasing CD8 T cells.ConclusionsShp2 loss in KCs or hepatocytes generated a protumorigenic microenvironment, which was exacerbated by its removal in both cell types. These results show the complexity of intercellular signaling events in liver tumorigenesis and raises caution on the use of specific Shp2 inhibitor in liver cancer therapy. Transcript profiling: RNA sequencing data are available at Gene Expression Omnibus (GSE222594).

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Dataset Information

Kahweol Ameliorates the Liver Inflammation through the Inhibition of NF-?B and STAT3 Activation in Primary Kupffer Cells and Primary Hepatocytes.

Publications

Kahweol Ameliorates the Liver Inflammation through the Inhibition of NF-κB and STAT3 Activation in Primary Kupffer Cells and Primary Hepatocytes.

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