title: Bone marrow-derived c-jun N-terminal kinase-1 (JNK1) mediates liver regeneration.
abstract: Liver regeneration is controlled by a complex network of signaling molecules, and a prominent role for c-jun N-terminal kinase has been suggested during this process. In the present study, we aimed to characterize and define the cell-type-specific contribution of JNK1 activation during liver regeneration. We used hepatocyte-specific JNK1 knockout mice (JNK1(Δhepa)) using the cre/lox-P system. We performed partial hepatectomy (PH) in WT, JNK1(Δhepa) and JNK1(-/-) animals and investigated time-points up to 72 h after PH. Additionally, bone marrow transplantation experiments were conducted in order to identify the contribution of hematopoietic cell-derived JNK1 activation for liver regeneration. Our results show that liver regeneration was significantly impaired in JNK1(-/-) compared to JNK1(Δhepa) and WT animals. These data were evidenced by lower BrdU incorporation and decreased cell cycle markers such as Cyclin A, Cyclin D, E2F1 and PCNA 48 h after PH in JNK1(-/-) compared with JNK1(Δhepa) and WT livers. In JNK1(-/-) mice, our findings were associated with a reduced acute phase response as evidenced by a lower activation of the IL-6/STAT3/SAA-1 cascade. Additionally, CD11b(+)Ly6G(+)-cells were decreased in JNK1(-/-) compared with JNK1(Δhepa) and WT animals after PH. The transplantation of bone marrow-derived JNK1(-/-) into WT recipients caused significant reduction in liver regeneration. Interestingly, the transplantation of JNK1(-/-) into mice lacking JNK1 in hepatocytes only partially delayed liver regeneration. In summary, we provide evidence that (1) JNK1 in hematopoietic cells is crucial for liver regeneration, and (2) a synergistic function between JNK1 in hepatocytes and hematopoietic-derived cells is involved in the hepatic regenerative response.
authors.affiliation: Department of Internal Medicine III, University Hospital, RWTH Aachen University, Germany.
authors.forename: Frederik M
authors.initials: FM
authors.lastname: Schaefer
authors.affiliation: Department of Internal Medicine III, University Hospital, RWTH Aachen University, Germany.
authors.forename: Jin
authors.initials: J
authors.lastname: Peng
authors.affiliation: Department of Internal Medicine III, University Hospital, RWTH Aachen University, Germany.
authors.forename: Wei
authors.initials: W
authors.lastname: Hu
authors.affiliation: Department of Internal Medicine III, University Hospital, RWTH Aachen University, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Drvarov
authors.affiliation: Department of Internal Medicine III, University Hospital, RWTH Aachen University, Germany.
authors.forename: Yulia A
authors.initials: YA
authors.lastname: Nevzorova
authors.affiliation: Department of Internal Medicine III, University Hospital, RWTH Aachen University, Germany; General Surgery department of Affiliated ZhongDa Hospital of Southeast University, Nanjing, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Zhao
authors.affiliation: Department of Internal Medicine III, University Hospital, RWTH Aachen University, Germany.
authors.forename: Malika Al
authors.initials: MA
authors.lastname: Masaoudi
authors.affiliation: Howard Hughes Medical Institute and University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Davis
authors.affiliation: Department of Internal Medicine III, University Hospital, RWTH Aachen University, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Trautwein
authors.affiliation: Department of Internal Medicine III, University Hospital, RWTH Aachen University, Germany. Electronic address: fcubero@ukaachen.de.
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Cubero
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000201:enzymology*; D008115:Liver Regeneration / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D048055:Mitogen-Activated Protein Kinase 8
keywords: Hepatocyte; Immune cells; JNK1; Partial hepatectomy; STAT3