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.

IL-1R1 deficiency impairs liver regeneration after 2/3 partial hepatectomy in aged mice

“…The role of JNK2 is elusive. Sabapathy et al (2004) indicated that the loss of JNK2 contribute to cell proliferation; other study, however, demonstrated JNK2 seems dispensable (Schaefer et al, 2015) or no role in LR (Das et al, 2011). In our experiment, the delayed JNK1 phosphorylation perhaps results in reduced LR at the last two time points in IL-1R1 KO mice.…”

Hepatocyte Mitogen‐Activated Protein Kinase Kinase 7 Contributes to Restoration of the Liver Parenchyma Following Injury in Mice

“…(26) While it has been reported that mice with genetic deletion of JNK1 demonstrate decreased hepatocyte proliferation following PH, (27) this might be explained by the lack of bone marrow-derived cells with JNK1 activity, which mediate liver regeneration. (28) Tissue repair processes following CCl 4 injury were delayed in MKK7 KO mice which had increased areas of residual fibrinogen-positive necrotic tissues after 4 days. This delay in tissue repair could induce protracted wound repair reactions in chronic CCl 4 injury, causing more intense liver fibrosis, as well as more enhanced regenerative proliferation of hepatocytes, in MKK7 KO mice than in control mice.…”

“…( 26 ) While it has been reported that mice with genetic deletion of JNK1 demonstrate decreased hepatocyte proliferation following PH, ( 27 ) this might be explained by the lack of bone marrow–derived cells with JNK1 activity, which mediate liver regeneration. ( 28 )…”

Identification of the Potential Molecular Mechanisms Linking RUNX1 Activity with Nonalcoholic Fatty Liver Disease, by Means of Systems Biology

“…Its activation can be induced by TNF-α and JNK mechanisms [ 75 , 76 ] and can lead to the up-regulation of TNF-α, IL-6 and neutrophil gelatinase-associated lipocalin (LCN-2), contributing to IR-related processes in NAFLD [ 48 , 73 , 77 , 78 ]. In addition, the transcription factor AP-1 aggravates IR by inflammation-related processes, inducing the expression of IL-6 [ 79 , 80 ] and TNF-α [ 72 ]. TNF-α could be importantly contributing to the development of IR by inhibition and degradation of the IRS mediated by a serine phosphorylation through different mechanisms: (1) SOCS3 is induced by the NFκB/JNK-mediated activation of TNF-α and IL-6 [ 81 ], or via CEBPA activation [ 82 ], inducing ubiquitin-mediated degradation of IRS1 and IRS2 [ 83 ]; (2) MTOR can be activated by TNF-α or PKCβ pathways [ 84 , 85 ] due to hyperglycemia, leading to phosphorylation of multiple serine residues in IRS1 and IRS2 with their further degradation; (3) JNK1 promotes IRS1 and IRS2 serine phosphorylation [ 86 , 87 ].…”