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Novel indirect co-culture of immortalized hepatocytes with monocyte derived macrophages is supported by pro-inflammatory cytokine networks

ABSTRACT: The liver is composed of different cell populations. Interactions of different cell populations can be investigated bya newly established indirect co-culture system consisting of immortalised primary human hepatocytes and human monocyte derived macrophages(MDMs). Using the time-dependent cytokine secretion of the co-cultures and singlecultures, correlation networks(includingthe cytokinesG-CSF, CCL3, MCP-1, CCL20, FGF, TGF-β1, GM-CSF, IL-8 IL-6, IL-1β, and IL-18)were generated and the correlationswere validatedbyapplication of IL-8and TNF-α-neutralising antibodies. Thedata reveal that IL-8 is crucial for the interaction between hepatocytes and macrophages in vitro.In addition, transcriptome analyses showedthat a change in the ratio between macrophages and hepatocytes may triggerpro-inflammatory signalling pathways of the acute phase responseand the complement system(release of, e.g., certaincyto-and chemokines).Using diclofenac and LPS showed that the release of cytokines is increasingwith higher ratios of MDMs. Altogether we coulddemonstratethat the current co-culture system is better suited to mirror thein vivosituation when compared to previously established co-culturesystems composed of HepG2and differentiated THP-1cells.Further, our data reveal that the cytokine IL-8 is crucial for the interaction between hepatocytes and macrophages in vitro.

ORGANISM(S): Homo sapiens

PROVIDER: GSE156627 | GEO | 2021/03/19

REPOSITORIES: GEO

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Project description:Progression and relapse-free survival of ovarian carcinoma are associated with the abundance of immunosuppressed CD163highCD206high tumor-associated macrophages (TAMs) and high levels of polyunsaturated fatty acids (PUFAs), in particular arachidonic acid (AA), in the tumor microenvironment. In the present study, we have investigated whether both associations are functionally linked. Methods: The effect of PUFAs on cytokine-mediated pro-inflammatory signal transduction was studied in primary monocyte-derived macrophages (MDMs) by transcriptomics, bioinformatics, phosphoprotein analysis of signal transduction proteins and MS-based proteomics of lipid rafts. Results: Pathway analysis of transcriptional profiles revealed that high CD163 and CD206/MRC1 expression in TAMs is strongly associated with an inhibition of cytokine-triggered signal transduction. This is mirrored by an impairment of the transcriptional response to interferon-beta (IFNbeta), IFNgamma and IL-6 in monocyte-derived macrophages (MDMs) by AA. This AA-mediated inhibition of pro-inflammatory signaling is caused by dysfunctions of the cognate receptors, as indicated by the inhibition by PUFAs of JAK1, JAK2, STAT1 and STAT3 phosphorylation, with the strongest inhibitory effects exerted by AA and its non-metabolizable analog ETYA. AA/ETYA treatment of MDMs results in altered composition of lipid rafts, including reduced amounts of the interferon receptor IFNAR1, STAT1 and other immune-regulatory proteins. The AA-mediated inhibition of IFN-triggered STAT1 phosphorylation was reversed by water-soluble cholesterol, known to prevent the perturbation of lipid raft structure by PUFAs. Conclusion: Our data suggest that AA, and to a lesser degree other PUFAs, impair pro-inflammatory signaling in macrophages, at least in part by altering the structure of lipid rafts, and thereby contribute to the reeducation of tumor-associated macrophages. Our findings also suggest that the pharmacologic restoration of lipid raft functions in TAM may be a promising strategy for the development of new therapeutic approaches.

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Novel indirect co-culture of immortalized hepatocytes with monocyte derived macrophages is supported by pro-inflammatory cytokine networks

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