Early heme oxygenase 1 induction delays tumour initiation and enhances DNA damage repair in liver macrophages of Mdr2 mice
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Early heme oxygenase 1 induction delays tumour initiation and enhances DNA damage repair in liver macrophages of Mdr2 mice. / Barikbin, Roja; Berkhout, Laura; Bolik, Julia; Schmidt-Arras, Dirk; Ernst, Thomas; Ittrich, Harald; Adam, Gerhard; Parplys, Ann; Casar, Christian; Krech, Till; Karimi, Khalil; Sass, Gabriele; Tiegs, Gisa.
In: SCI REP-UK, Vol. 8, No. 1, 02.11.2018, p. 16238.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Early heme oxygenase 1 induction delays tumour initiation and enhances DNA damage repair in liver macrophages of Mdr2 mice
AU - Barikbin, Roja
AU - Berkhout, Laura
AU - Bolik, Julia
AU - Schmidt-Arras, Dirk
AU - Ernst, Thomas
AU - Ittrich, Harald
AU - Adam, Gerhard
AU - Parplys, Ann
AU - Casar, Christian
AU - Krech, Till
AU - Karimi, Khalil
AU - Sass, Gabriele
AU - Tiegs, Gisa
PY - 2018/11/2
Y1 - 2018/11/2
N2 - 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.
AB - 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.
KW - Journal Article
U2 - 10.1038/s41598-018-33233-0
DO - 10.1038/s41598-018-33233-0
M3 - SCORING: Journal article
C2 - 30389969
VL - 8
SP - 16238
JO - SCI REP-UK
JF - SCI REP-UK
SN - 2045-2322
IS - 1
ER -
