Early heme oxygenase 1 induction delays tumour initiation and enhances DNA damage repair in liver macrophages of Mdr2 −/− mice

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.