scholarly journals Toll-like receptor 5-mediated signaling enhances liver regeneration in mice

2020 ◽  
Author(s):  
Wen Zhang ◽  
Lei Wang ◽  
Xue-Hua Sun ◽  
Xian Liu ◽  
Yang Xiao ◽  
...  
Keyword(s):  
Growth Factors ◽  
Liver Regeneration ◽  
Quantitative Pcr ◽  
Early Gene ◽  
Immediate Early ◽  
Hepatocyte Proliferation ◽  
Hepatic Lipid ◽  
Oil Red O ◽  
Tlr5 Expression

Abstract BackgroundToll-like receptor 5 (TLR5)-mediated pathways play critical roles in regulating hepatic immune response and show hepatoprotective effect in mouse models of hepatic diseases. However, the role of TLR5 in experimental models of liver regeneration has not been reported. This study aims to investigate the role of TLR5 in partial hepatectomy (PHx)-induced liver regeneration.MethodsWe performed 2/3 PHx in wild-type (WT) mice, TLR5 knockout mice, or TLR5 agonist CBLB502 treated mice as a model of liver regeneration. Bacterial flagellin content was measured by ELISA, and hepatic TLR5 expression was determined by quantitative PCR analyses and flow cytometry. To study the effects of TLR5 on hepatocyte proliferation, bromodeoxyuridine (BrdU) incorporation and proliferating cell nuclear antigen (PCNA) expression were analyzed by immunohistochemistry (IHC) staining. The effects of TLR5 during the priming phase of liver regeneration was examined by quantitative PCR analyses of immediate early gene mRNA levels, and western blot analysis of hepatic NF-κB and STAT3 activation. Cytokines and growth factors production after PHx were detected using real-time PCR analyses and cytometric bead array (CBA) assays. Oil Red O staining and hepatic lipid concentrations were analyzed to examine the effect of TLR5 on hepatic lipid accumulation after PHx.ResultsThe bacterial flagellin content in serum and liver was increased and the hepatic TLR5 expression was significantly up-regulated in WT mice upon PHx. TLR5-deficient mice exhibited reduced numbers of BrdU- and PCNA-positive cells, suppressed immediate early gene expression, and decreased cytokines and growth factors production. Moreover, PHx-induced hepatic NF-κB and STAT3 activation was inhibited in Tlr5−/− mice compared with WT mice. Consistently, the administration of CBLB502 significantly promoted PHx-mediated hepatocyte proliferation correlated with enhanced production of proinflammatory cytokines and the recruitment of macrophages and neutrophils in the liver. Besides, Tlr5−/− mice displayed significantly decreased hepatic lipid concentrations and Oil Red O positive areas compared to control mice after PHx.ConclusionWe reveal that TLR5 activation contributes to the initial events of liver regeneration after PHx. Our findings demonstrate that TLR5 signaling positively regulates liver regeneration and suggest a potential application of TLR5 agonist in promoting liver regeneration.

scholarly journals Toll-like receptor 5-mediated signaling enhances liver regeneration in mice

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Wen Zhang ◽  
Lei Wang ◽  
Xue-Hua Sun ◽  
Xian Liu ◽  
Yang Xiao ◽  
...  
Keyword(s):  
Liver Regeneration ◽  
Early Gene ◽  
Hepatocyte Proliferation ◽  
Toll Like Receptor ◽  
Hepatic Lipid ◽  
Growth Factor Production ◽  
Toll Like Receptor 5 ◽  
Oil Red O ◽  
Tlr5 Expression

Abstract Background Toll-like receptor 5 (TLR5)-mediated pathways play critical roles in regulating the hepatic immune response and show hepatoprotective effects in mouse models of hepatic diseases. However, the role of TLR5 in experimental models of liver regeneration has not been reported. This study aimed to investigate the role of TLR5 in partial hepatectomy (PHx)-induced liver regeneration. Methods We performed 2/3 PHx in wild-type (WT) mice, TLR5 knockout mice, or TLR5 agonist CBLB502 treated mice, as a model of liver regeneration. Bacterial flagellin content was measured with ELISA, and hepatic TLR5 expression was determined with quantitative PCR analyses and flow cytometry. To study the effects of TLR5 on hepatocyte proliferation, we analyzed bromodeoxyuridine (BrdU) incorporation and proliferating cell nuclear antigen (PCNA) expression with immunohistochemistry (IHC) staining. The effects of TLR5 during the priming phase of liver regeneration were examined with quantitative PCR analyses of immediate early gene mRNA levels, and with Western blotting analysis of hepatic NF-κB and STAT3 activation. Cytokine and growth factor production after PHx were detected with real-time PCR and cytometric bead array (CBA) assays. Oil Red O staining and hepatic lipid concentrations were analyzed to examine the effect of TLR5 on hepatic lipid accumulation after PHx. Results The bacterial flagellin content in the serum and liver increased, and the hepatic TLR5 expression was significantly up-regulated in WT mice after PHx. TLR5-deficient mice exhibited diminished numbers of BrdU- and PCNA-positive cells, suppressed immediate early gene expression, and decreased cytokine and growth factor production. Moreover, PHx-induced hepatic NF-κB and STAT3 activation was inhibited in Tlr5−/− mice, as compared with WT mice. Consistently, the administration of CBLB502 significantly promoted PHx-mediated hepatocyte proliferation, which was correlated with enhanced production of proinflammatory cytokines and the recruitment of macrophages and neutrophils in the liver. Furthermore, Tlr5−/− mice displayed significantly lower hepatic lipid concentrations and smaller Oil Red O positive areas than those in control mice after PHx. Conclusion We reveal that TLR5 activation contributes to the initial events of liver regeneration after PHx. Our findings demonstrate that TLR5 signaling positively regulates liver regeneration and suggest the potential of TLR5 agonist to promote liver regeneration.

scholarly journals Toll-like receptor 5-mediated signaling enhances liver regeneration in mice

2020 ◽  
Author(s):  
Wen Zhang ◽  
Lei Wang ◽  
Xue-Hua Sun ◽  
Xian Liu ◽  
Yang Xiao ◽  
...  
Keyword(s):  
Liver Regeneration ◽  
Real Time ◽  
Real Time Pcr ◽  
Early Gene ◽  
Hepatocyte Proliferation ◽  
Toll Like Receptor ◽  
Hepatic Lipids ◽  
Toll Like Receptor 5 ◽  
Oil Red O

Abstract Background Toll-like receptor 5 (TLR5)-mediated pathways play critical roles in regulating hepatic immune response and show hepatoprotective effect in mouse models of liver injury. However, the role of TLR5 in experimental models of liver regeneration has not been investigated. This study aims to determine the role of TLR5 in the partial hepatectomy (PHx)-induced liver regeneration. Methods We performed 2/3 PHx in wild-type (WT) mice, TLR5 knockout mice, or TLR5 agonist CBLB502 treated mice as an established model of liver regeneration. Bacterial flagellin content was measured by ELISA, and hepatic TLR5 expression was determined by real-time PCR analyses and flow cytometry. To study the effects of TLR5 on hepatocyte proliferation, proliferating cell nuclear antigen (PCNA) and the incorporation of bromodeoxyuridine (BrdU) were analyzed by immunohistochemistry (IHC) staining. The role of TLR5 in the priming of liver regeneration was examined by real-time PCR analyses of immediate early gene mRNA levels, as well as western blot analysis of hepatic NF-κB and STAT3 activation. Cytokines and growth factors production after PHx were detected using real-time PCR analyses and cytometric bead array (CBA) assays. Oil Red O staining and hepatic lipids concentrations were analyzed to examine the effect of TLR5 on hepatic lipid accumulation after PHx. Results The bacterial flagellin content in serum and liver was increased and the hepatic TLR5 expression was significantly up-regulated in WT mice upon PHx. TLR5-deficient mice exhibited reduced numbers of BrdU- and PCNA-positive cells, suppressed immediate early gene expression, and decreased cytokines and growth factors production. Moreover, PHx-induced NF-κB and STAT3 activation was inhibited in the liver of Tlr5−/− mice compared with WT mice. Consistently, administration of CBLB502 significantly promoted PHx-mediated hepatocyte proliferation correlated with enhanced production of proinflammatory cytokines and recruitment of macrophages and neutrophils in liver. In addition, Tlr5−/− mice displayed significantly decreased hepatic lipids concentrations and Oil Red O positive areas compared with WT mice after PHx. Conclusions We reveal that TLR5 activation is involved in the initial events of liver regeneration after PHx. Our results demonstrate that TLR5 signaling positively regulates liver regeneration and suggest a potential application of TLR5 agonist in promoting liver regeneration.

scholarly journals F4/80+ Kupffer Cell-Derived Oncostatin M Sustains the Progression Phase of Liver Regeneration through Inhibition of TGF-β2 Pathway

Molecules ◽  
2021 ◽  
Vol 26 (8) ◽  
pp. 2231
Author(s):  
Qingjun Lu ◽  
Hao Shen ◽  
Han Yu ◽  
Jing Fu ◽  
Hui Dong ◽  
...  
Keyword(s):  
Liver Regeneration ◽  
Serum Levels ◽  
Inhibitory Effect ◽  
Regenerative Process ◽  
Oncostatin M ◽  
Hepatocyte Proliferation ◽  
Initiation Phase ◽  
Distinct Role

The role of Kupffer cells (KCs) in liver regeneration is complicated and controversial. To investigate the distinct role of F4/80+ KCs at the different stages of the regeneration process, two-thirds partial hepatectomy (PHx) was performed in mice to induce physiological liver regeneration. In pre- or post-PHx, the clearance of KCs by intraperitoneal injection of the anti-F4/80 antibody (α-F4/80) was performed to study the distinct role of F4/80+ KCs during the regenerative process. In RNA sequencing of isolated F4/80+ KCs, the initiation phase was compared with the progression phase. Immunohistochemistry and immunofluorescence staining of Ki67, HNF-4α, CD-31, and F4/80 and Western blot of the TGF-β2 pathway were performed. Depletion of F4/80+ KCs in pre-PHx delayed the peak of hepatocyte proliferation from 48 h to 120 h, whereas depletion in post-PHx unexpectedly led to persistent inhibition of hepatocyte proliferation, indicating the distinct role of F4/80+ KCs in the initiation and progression phases of liver regeneration. F4/80+ KC depletion in post-PHx could significantly increase TGF-β2 serum levels, while TGF-βRI partially rescued the impaired proliferation of hepatocytes. Additionally, F4/80+ KC depletion in post-PHx significantly lowered the expression of oncostatin M (OSM), a key downstream mediator of interleukin-6, which is required for hepatocyte proliferation during liver regeneration. In vivo, recombinant OSM (r-OSM) treatment alleviated the inhibitory effect of α-F4/80 on the regenerative progression. Collectively, F4/80+ KCs release OSM to inhibit TGF-β2 activation, sustaining hepatocyte proliferation by releasing a proliferative brake.

scholarly journals Role of oxidative stress in intermittent hypoxia-induced immediate early gene activation in rat PC12 cells

2004 ◽  
Vol 557 (3) ◽  
pp. 773-783 ◽  
Author(s):  
Guoxiang Yuan ◽  
Gautam Adhikary ◽  
Andrew A. McCormick ◽  
John. J. Holcroft ◽  
Ganesh K. Kumar ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Pc12 Cells ◽  
Intermittent Hypoxia ◽  
Gene Activation ◽  
Immediate Early Gene ◽  
Early Gene ◽  
Immediate Early

FGF signalling in the early specification of mesoderm in Xenopus

Development ◽  
1993 ◽  
Vol 118 (2) ◽  
pp. 477-487 ◽  
Author(s):  
E. Amaya ◽  
P.A. Stein ◽  
T.J. Musci ◽  
M.W. Kirschner
Keyword(s):  
Dorsal Side ◽  
Dominant Negative ◽  
Early Gene ◽  
Immediate Early ◽  
Mesoderm Induction ◽  
Fgf Receptor ◽  
Muscle Formation ◽  
Fgf Signalling ◽  
Lateral Mesoderm

We have examined the role of FGF signalling in the development of muscle and notochord and in the expression of early mesodermal markers in Xenopus embryos. Disruption of the FGF signalling pathway by expression of a dominant negative construct of the FGF receptor (XFD) generally results in gastrulation defects that are later evident in the formation of the trunk and tail, though head structures are formed nearly normally. These defects are reflected in the loss of notochord and muscle. Even in embryos that show mild defects and gastrulate properly, muscle formation is impaired, suggesting that morphogenesis and tissue differentiation each depend on FGF. The XFD protein inhibits the expression of the immediate early gene brachyury throughout the marginal zone, including the dorsal side; it does not, however, inhibit the dorsal lip marker goosecoid, which is expressed in the first involuting mesoderm at the dorsal side that will underlie the head. The XFD protein also inhibits Xpo expression, an immediate early marker of ventral and lateral mesoderm. These results suggest that FGF is involved in the earliest events of most mesoderm induction that occur before gastrulation and that the early dorsal mesoderm is already composed of two cell populations that differ in their requirements for FGF.

Growth factor-induced delayed early response genes

1992 ◽  
Vol 12 (9) ◽  
pp. 3919-3929
Author(s):  
A Lanahan ◽  
J B Williams ◽  
L K Sanders ◽  
D Nathans
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Early Response ◽  
Integral Membrane Protein ◽  
Early Gene ◽  
Immediate Early ◽  
Human Macrophage ◽  
Cellular Genes ◽  
Gene Response ◽  
Early Response Genes

Growth factors induce the sequential expression of cellular genes whose products are thought to mediate long-term responses to the growth factors. In mouse 3T3 fibroblastic cells, the first genes to be expressed (immediate-early genes) are activated within minutes after the addition of platelet-derived growth factor, fibroblast growth factor, or serum. By cDNA cloning, we have identified genes that are activated after a delay of a few hours and several hours prior to serum-induced DNA replication. Activation of these delayed early response genes requires new protein synthesis, presumably the synthesis of immediate-early transcription factors described previously. Partial or complete sequencing of 13 different delayed early cDNAs, representing about 40% of the 650 primary cDNA isolates, revealed that 8 were related to known gene sequences and 5 were not. Among the former are cDNAs encoding nonhistone chromosomal proteins [HMGI(Y) and HMGI-C], adenine phosphoribosyltransferase (APRT), a protein related to human macrophage migration inhibitory factor (MIF), a protein of the major intrinsic protein (MIP) family homologous to the integral membrane protein of human erythrocytes, and cyclin CYL1. In 3T3 cells, the delayed early gene response to growth factors appears to be at least as complex as the immediate-early gene response previously described.

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