Early Heme Oxygenase 1 Induction Delays Tumour Initiation and Enhances DNA Damage Repair in Liver Macrophages of Mdr2 Mice

Overview

Journal Sci Rep

Specialty Science

Date 2018 Nov 4

PMID 30389969

Citations 7

Authors

Roja Barikbin

Laura Berkhout

Julia Bolik

Dirk Schmidt-Arras

Thomas Ernst

Harald Ittrich

Gerhard Adam

Ann Parplys

Christian Casar

Till Krech

Khalil Karimi

Gabriele Sass

Gisa Tiegs

Affiliations

Soon will be listed here.

Abstract

Multi drug resistance protein 2 knockout mice (Mdr2) are a mouse model of chronic liver inflammation and inflammation-induced tumour development. Here we investigated the kinetics of early heme oxygenase 1 (HO-1) induction on inflammation, tumour development, and DNA damage in Mdr2 mice. HO-1 was induced by intraperitoneal injection of cobalt protoporphyrin IX (CoPP) twice weekly for 9 consecutive weeks. Immediately after HO-1 induction, liver function improved and infiltration of CD4 and CD8 T cells was reduced. Furthermore, we observed increased p38 activation with concomitant reduction of Cyclin D1 expression in aged Mdr2 mice. Long-term effects of HO-1 induction included increased CD8 T cell infiltration as well as delayed and reduced tumour growth in one-year-old animals. Unexpectedly, DNA double-strand breaks were detected predominantly in macrophages of 65-week-old Mdr2 mice, while DNA damage was reduced in response to early HO-1 induction in vivo and in vitro. Overall, early induction of HO-1 in Mdr2 mice had a beneficial short-term effect on liver function and reduced hepatic T cell accumulation. Long-term effects of early HO-1 induction were increased CD8 T cell numbers, decreased proliferation as wells as reduced DNA damage in liver macrophages of aged animals, accompanied by delayed and reduced tumour growth.

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