Drug-induced liver injury (DILI) represents one of the major causes why drugs have to be withdrawn from the market. In this study, we describe a new interaction between drug-exposed hepatocytes and natural killer (NK) cells. In a previous genome-wide expression analysis of primary human hepatocytes that had been exposed to clinically relevant concentrations of 148 drugs, we found that several activating ligands for NK cell receptors were regulated by various drugs (e.g., valproic acid, ketoconazole, promethazine, isoniazid). Especially expression of the activating NKG2D ligands (MICA, MICB and ULBPs) and the NKp30 ligand B7-H6 were upregulated in primary human hepatocytes upon exposure to many different drugs. Using the human hepatocyte cell lines Huh7 and HepG2, we confirmed that protein levels of activating NK cell ligands were elevated after drug exposure. Hepatocyte cell lines or primary human hepatocytes co-cultivated with NK cells caused enhanced NK cell activation after pretreatment with drugs at in vivo relevant concentrations compared to solvent controls. Enhanced NK cell activation was evident by increased cytotoxicity against hepatocytes and interferon (IFN)-γ production. NK cell activation could be blocked by specific antibodies against activating NK cell receptors. These data support the hypothesis that NK cells can modulate drug-induced liver injury by direct interaction with hepatocytes resulting in cytotoxicity and IFN-γ production.Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Calcium phosphate nanoparticles (CaP-NPs) are biodegradable carriers that can be functionalized with biologically active molecules. As such, they are potential candidates for delivery of therapeutic molecules in cancer therapies. In this context, it is important to explore whether CaP-NPs impair the natural or therapy-induced immune cell activity against cancer cells. Therefore, in this study, we have investigated the effects of different CaP-NPs on the anti-tumor activity of natural killer (NK) cells using different ovarian cancer (OC) cell line models. We explored these interactions in coculture systems consisting of NK cells, OC cells, CaP-NPs, and therapeutic Cetuximab antibodies (anti-EGFR, ADCC-inducing antibody). Our experiments revealed that aggregated CaP-NPs can serve as artificial targets, which activate NK cell degranulation and impair ADCC directed against tumor targets. However, when CaP-NPs were properly dissolved by sonication, they did not cause substantial activation. CaP-NPs with SiO2-SH-shell induced some activation of NK cells that was not observed with polyethyleneimine-coated CaP-NPs. Addition of CaP-NPs to NK killing assays did not impair conjugation of NK with OC and subsequent tumor cytolytic NK degranulation. Therapeutic antibody coupled to functionalized CaP-NPs maintained substantial levels of antibody-dependent cellular cytotoxic activity. Our study provides a cell biological basis for the application of functionalized CaP-NPs in immunologic anti-cancer therapies.
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