Tumor Necrosis Factor–Like Weak Inducer of Apoptosis Is a Mitogen for Liver Progenitor Cells

Abstract

Liver progenitor cells (LPCs) represent the cell compartment facilitating hepatic regeneration during chronic injury while hepatocyte-mediated repair mechanisms are compromised. LPC proliferation is frequently observed in human chronic liver diseases such as hereditary hemochromatosis, fatty liver disease, and chronic hepatitis. In vivo studies have suggested that a tumor necrosis factor family member, tumor necrosis factor–like weak inducer of apoptosis (TWEAK), is promitotic for LPCs; whether it acts directly is not known. In our murine choline-deficient, ethionine-supplemented (CDE) model of chronic liver injury, TWEAK receptor [fibroblast growth factor-inducible 14 (Fn14)] expression in the whole liver is massively upregulated. We therefore set out to investigate whether TWEAK/Fn14 signaling promotes the regenerative response in CDE-induced chronic liver injury by mitotic stimulation of LPCs. Fn14 knockout (KO) mice showed significantly reduced LPC numbers and attenuated inflammation and cytokine production after 2 weeks of CDE feeding. The close association between LPC proliferation and activation of hepatic stellate cells in chronic liver injury prompted us to investigate whether fibrogenesis was also modulated in Fn14 KO animals. Collagen deposition and expression of key fibrogenesis mediators were reduced after 2 weeks of injury, and this correlated with LPC numbers. Furthermore, the injection of 2-week-CDE-treated wildtype animals with TWEAK led to increased proliferation of nonparenchymal pan cytokeratin–positive cells. Stimulation of an Fn14-positive LPC line with TWEAK led to nuclear factor kappa light chain enhancer of activated B cells (NFκB) activation and dose-dependent proliferation, which was diminished after targeting of the p50 NFκB subunit by RNA interference. Conclusion: TWEAK acts directly and stimulates LPC mitosis in an Fn14-dependent and NFκB-dependent fashion, and signaling via this pathway mediates the LPC response to CDE-induced injury and regeneration. (Hepatology 2010)

Bone marrow injection stimulates hepatic ductular reactions in the absence of injury via macrophage-mediated TWEAK signaling

“…Similar inhibition of ductular expansion in both KO scenarios is in keeping with the monogamous relation between this signal-receptor pair (31). Ductular expansion has previously been shown to be possible in the absence of Fn14 expression (17). Regarding the localization of macrophages to the biliary cells, previous data has described the recruitment of C-X-C chemokine receptor 4 (CXCR4 + ) cells to the biliary tracts via the chemokine Stromal Cell Derived Factor (SDF)-1 (32,33).…”

“…(16). We now show that exogenous TWEAK administration results in DR expansion in vivo and in addition confirm TWEAK expression by hepatic macrophages and Fn14 expression by panCK + DRs, which have been shown to mediate ductular proliferation via NFκB activation (16,17). Herein we demonstrate a direct link between macrophage TWEAK production and paracrine signaling to recipient DRs, resulting in their expansion using complimentary TWEAK/Fn14 KO models.…”

“…Cytokeratins (CK) 7 and 19, EpCAM (Epithelial Cell Adhesion Molecule), Dlk1 (Delta Like Homolog), MIC1-1C3, and Sox9 [sex determining region Y (SRY) box] are all accepted, albeit unspecific, markers of DRs, and have been used to define essential mediators, including many cytokines, which control the DR response to experimental liver injury (5,(13)(14)(15). Among the most recently identified of these paracrine signals is TNF-like weak inducer of apoptosis (TWEAK), a cytokine of the TNF family, which directly stimulates proliferation of DRs in vivo and HPCs in vitro (16,17).…”

TWEAK Inhibits TRAF2-Mediated CD40 Signaling by Destabilization of CD40 Signaling Complexes

“…Nevertheless, it appears that the TWEAK-Fn14 system is active in processes related to growth and remodeling of tissue and organs during development and tissue repair. In accordance with this, animal studies implicated the TWEAK-Fn14 system in liver progenitor cell proliferation (6,7), regulation of muscle development and muscle regeneration (8)(9)(10)(11), tumor-associated angiogenesis (12), and in various inflammationrelated pathologies including graft-versus-host disease, systemic lupus erythematosus-related nephritis (13), 2,4,6-trinitrobenzene sulfonic acid-induced colitis (14), renal and cerebral ischemia (15)(16)(17)(18), and collagen-induced arthritis (19,20).…”

Roles of Fibroblast Growth Factor-inducible 14 in Hepatocellular Carcinoma

“…Previous studies revealed, that Fn14 is also overexpressed in poorly differentiated HCC cell lines (Feng et al, 2000) and the TWEAK/Fn14 pathway promoted the proliferation of multiple HCC cell lines in vitro (Kawakita et al, 2005). A recent investigation demonstrated, that the TWEAK/ Fn14 pathway can stimulate liver progenitor cell (LPC) mitosis in the rapid growth phase during response to choline-deficient, ethionine-supplemented (CDE) dietinduced injury and re-generation in vivo (Tirnitz-Parker et al, 2010). Nonetheless, the prognostic value of Fn14 for HCC has yet to be explored and this study evaluates the clinical significance of Fn14 in HCC patients after curative resection.…”