title: The Impact of Acute Matriptase Inhibition in Hepatic Inflammatory Models.
abstract: Purpose. Dysfunction of matriptase-2 can be involved in iron regulatory disorder via downregulation of hepcidin expression. In the present study, we investigated the effects of 3-amidinophenylalanine-derived matriptase inhibitors on porcine hepatic inflammatory cell models. Methods. Hepatocyte-Kupffer cell cocultures (ratio of 2 : 1 and 6 : 1) were treated with four structurally related matriptase inhibitors at 50 μM. Cell cytotoxicity and relative expressions of IL-6 and IL-8 and the levels of hepcidin were determined by MTS and porcine-specific ELISA. The extracellular H2O2 contents were analyzed by Amplex Red method. Results. Matriptase inhibitors at 50 µM for 24 h did not increase cell death rate. The elevated ROS production observed after short-term application of inhibitor MI-441 could be correlated with lowered hepcidin expression. MI-460 could significantly enhance hepcidin levels in the supernatants of cocultures (by 62.21 ± 26.8% in hepatocyte-Kupffer cell, 2 : 1, and by 42.6 ± 14.3% in hepatocyte-Kupffer cell, 6 : 1, cocultures, resp.). No significant changes were found in IL-6 and IL-8 levels in cocultures exposed to matriptase inhibitors. Conclusions. Based on in vitro findings, administration of MI-460 via modulation of hepcidin expression without cytotoxic and oxidative stress inducing properties might be a reliable alternative to treat iron overload in human and veterinary clinical practice.
authors.affiliation: Department of Pharmacology and Toxicology, University of Veterinary Medicine, István u. 2, Budapest 1078, Hungary.
authors.forename: Judit
authors.identifier: 0000-0001-8396-9367
authors.initials: J
authors.lastname: Pomothy
authors.affiliation: Department of Pharmacology and Toxicology, University of Veterinary Medicine, István u. 2, Budapest 1078, Hungary.
authors.forename: Gergely
authors.initials: G
authors.lastname: Szombath
authors.affiliation: Department of Pharmacology and Toxicology, University of Veterinary Medicine, István u. 2, Budapest 1078, Hungary.
authors.forename: Patrik
authors.initials: P
authors.lastname: Rokonál
authors.affiliation: Department of Physiology and Biochemistry, University of Veterinary Medicine, István u. 2, Budapest 1078, Hungary.
authors.forename: Gábor
authors.initials: G
authors.lastname: Mátis
authors.affiliation: Department of Physiology and Biochemistry, University of Veterinary Medicine, István u. 2, Budapest 1078, Hungary.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Neogrády
authors.affiliation: Faculty of Pharmacy, Institute of Pharmaceutical Chemistry, Philipps University Marburg, Marbacher Weg 6, 35037 Marburg, Germany.
authors.forename: Torsten
authors.identifier: 0000-0001-6523-4754
authors.initials: T
authors.lastname: Steinmetzer
authors.affiliation: Department of Pharmacology and Toxicology, University of Veterinary Medicine, István u. 2, Budapest 1078, Hungary.
authors.forename: Erzsébet
authors.identifier: 0000-0002-1561-9469
authors.initials: E
authors.lastname: Pászti-Gere
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D064451:Hepcidins / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008107:Liver Diseases / Q000378:metabolism*; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D010649:Phenylalanine / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism*; D013552:Swine
chemical_list: D064451:Hepcidins; D015850:Interleukin-6; D016209:Interleukin-8; D017382:Reactive Oxygen Species; D010649:Phenylalanine; D006861:Hydrogen Peroxide; D012697:Serine Endopeptidases; C485595:matriptase