B-Cell Activating Factor Enhances Hepatocyte-Driven Angiogenesis via B-Cell CLL/Lymphoma 10/Nuclear Factor-KappaB Signaling during Liver Regeneration

Abstract

B-cell activating factor (BAFF) is found to be associated with the histological severity of nonalcoholic steatohepatitis (NASH). BAFF was also found to have a protective role in hepatic steatosis via down regulating the expression of steatogenesis genes and enhancing steatosis in hepatocytes through BAFF-R. However, the roles of BAFF during liver regeneration are not well defined. In this study, C57/B6 mice with 70% partial hepatectomy were used as a liver regeneration model. BAFF expression was determined by enzyme immunoassay, and anti-BAFF-neutralizing antibodies were administered to confirm the effects of BAFF on liver regeneration. Western blotting, immunohistochemistry, and florescence staining determined the expression of B-cell CCL/lymphoma 10 (BCL10). The angiogenesis promoting capability was evaluated after the transfection of cells with siRNA targeting BCL10 expression, and the role of NF-κB was assessed. The results revealed that the BAFF and BCL10 levels were upregulated after partial hepatectomy. Treatment with anti-BAFF-neutralizing antibodies caused death in mice that were subjected to 70% partial hepatectomy within 72 h. In vitro, recombinant BAFF protein did not enhance hepatocyte proliferation; however, transfection with BCL10 siRNA arrested hepatocytes at the G2/M phase. Interestingly, conditioned medium from BAFF-treated hepatocytes enhanced angiogenesis and endothelial cell proliferation. Moreover, Matrix metalloproteinase-9 (MMP-9), Fibroblast growth factor 4 (FGF4), and Interleukin-8 (IL-8) proteins were upregulated by BAFF through BCL10/NF-κB signaling. In mice that were treated with anti-BAFF-neutralizing antibodies, the microvessel density (MVD) of the remaining liver tissues and liver regeneration were both reduced. Taken together, our study demonstrated that an increased expression of BAFF and activation of BCL10/NF-κB signaling were involved in hepatocyte-driven angiogenesis and survival during liver regeneration.

Noncanonical NF-κB Signaling Pathway in Liver Diseases

“…Conversely, within 72 h of undergoing 70% PHx, mice treated with anti-BAFF neutralizing antibodies died, showing reduced microvascular density in their remaining liver tissue as well as impaired liver regeneration, suggesting that BAFF-mediated signaling improved hepatocyte regeneration. 57 Moreover, compared with control mice, both Fn14 and TNF-like weak inducer of apoptosis (TWEAK) KO mice showed reduced hepatocyte and cholangiocyte proliferation after PHx. A similar phenomenon was also observed in wild-type mice treated with anti-TWEAK antibodies, 58 which indicated that the TWEAK/Fn14 signal is essential for mouse liver regeneration after PHx.…”

Progress and Prospects of Non-Canonical NF-κB Signaling Pathway in the Regulation of Liver Diseases

“…However, impaired hepatocyte replication further exacerbates chronic liver diseases. Recent studies have demonstrated that the key molecules in the non-canonical NF-κB signaling pathway regulate liver regeneration through different mechanisms [27][28][29][30][31]75]. Liver injury or partial hepatectomy (PH) induces the expression of TWEAK/Fn14, BAFF, LTα/β, and LIGHT [27,28,34,76].…”

The BAFF/NFκB axis is crucial to interactions between sorafenib‐resistant HCC cells and cancer‐associated fibroblasts

“…5 The BAFF-BAFF-R axis has also been associated with cancer progression, apoptosis, and inflammation. 6 Reducing BAFF activity by antibodies that selectively bind to BAFF-R increases drug sensitivity in cancer cells. 7 The NFκB signaling pathway is downstream of BAFF.…”

“…In hepatocytes, activated BAFF and its receptor ( BAFF‐R ) decrease the expression of steatogenesis genes and increase steatosis 5 . The BAFF–BAFF‐R axis has also been associated with cancer progression, apoptosis, and inflammation 6 . Reducing BAFF activity by antibodies that selectively bind to BAFF‐R increases drug sensitivity in cancer cells 7 .…”

“…Moreover, a permanently activated NFκB pathway and persistent nuclear expression of its downstream factor, p65, in CAFs are important in maintaining the secretion of IL6 and IL8 , and the survival of pancreatic cancer stem cells 3 . Other studies have found the balance of location (nuclear or cytoplasmic) of p65 is controlled by post‐translational modifications, and eventually affects MMP9, FGF4 , and IL8 expression 6,10 . Hepatocellular carcinoma (HCC) cells with enhanced p16/ IL6 pathways have low sensitivity to sorafenib; blocking IL6 in chemoresistant HCC cells reportedly upregulates sorafenib cytotoxicity 4 …”