The Impact of Acute Matriptase Inhibition in Hepatic Inflammatory Models

الملخص EN

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.