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(Deltahepa)) using the cre/lox-P system. We performed partial hepatectomy (PH) in WT, JNK1(Deltahepa) 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(Deltahepa) 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(Deltahepa) 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(Deltahepa) 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.