Growth Hormone Stops Excessive Inflammation After Partial Hepatectomy, Allowing Liver Regeneration and Survival Through Induction of H2‐Bl/HLA‐G (original) (raw)
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AJP: Gastrointestinal and Liver Physiology, 2013
To clarify the roles of innate immune cells in liver regeneration, here, we investigated the alteration in regenerative responses after partial hepatectomy (PH) under selective depletion of natural killer (NK) and/or NKT cells. Male, wild-type (WT; C57Bl/6), and CD1d-knockout (KO) mice were injected with anti-NK1.1 or anti-asialo ganglio- N-tetraosylceramide (GM1) antibody and then underwent the 70% PH. Regenerative responses after PH were evaluated, and hepatic expression levels of cytokines and growth factors were measured by real-time RT-PCR and ELISA. Phosphorylation of STAT3 was detected by Western blotting. Depletion of both NK and NKT cells with an anti-NK1.1 antibody in WT mice caused drastic decreases in bromodeoxyuridine uptake, expression of proliferating cell nuclear antigen, and cyclin D1, 48 h after PH. In mice given NK1.1 antibody, increases in hepatic TNF-α, IL-6/phospho-STAT3, and hepatocyte growth factor (HGF) levels following PH were also blunted significantly, wh...
Activation of Mouse Natural Killer T Cells Accelerates Liver Regeneration After Partial Hepatectomy
Gastroenterology, 2006
Activation of natural killer T cells with the synthetic ligand alpha-galactosylceramide (alpha-GalCer) induced hepatotoxicity through the tumor necrosis factor (TNF) and Fas-ligand-mediated pathway in aged mice. The aim of this study was to elucidate how alpha-GalCer-activated natural killer T cells function in hepatocyte proliferation and liver regeneration in partially hepatectomized (PHx) mice. Mice were injected with alpha-GalCer at 36 hours after 70% PHx. Hepatocyte mitosis was evaluated by either mitotic figures or proliferating cell nuclear antigen staining. The role of TNF and Fas-ligand in hepatocyte mitosis also was assessed. In PHx mice injected with alpha-GalCer, hepatocyte mitosis was greatly enhanced at 44 hours after surgery and the increase was more obvious in aged mice than in young mice. The expression of both TNF receptor 1 and Fas-ligand in liver natural killer T cells tended to increase after alpha-GalCer injection in PHx mice. Treatment of mice with anti-NK1.1 Ab 3 days before and just after hepatectomy greatly inhibited the effect of alpha-GalCer on hepatocyte mitosis and liver regeneration. Furthermore, pretreatment of PHx mice with either anti-TNF Ab or anti-FasL Ab 1 hour before alpha-GalCer injection mostly abrogated the increase in hepatocyte proliferation. alpha-GalCer injection did not accelerate hepatocyte proliferation in Fas-mutated lpr mice after PHx. CD1d-/- mice without alpha-GalCer injection showed decreased hepatocyte mitosis after PHx. Activated natural killer T cells help hepatocyte proliferation and liver regeneration after PHx via the TNF and Fas/Fas-ligand-mediated pathway.
Immune cells in liver regeneration
Oncotarget, 2015
After partial hepatectomy, hepatocytes proliferate to restore mass and function of the liver. Macrophages, natural killer (NK) cells, natural killer T (NKT) cells, dendritic cells (DC), eosinophils, gamma delta T (γδT) cells, and conventional T cells, as well as other subsets of the immune cells residing in the liver control liver regeneration, either through direct interactions with hepatocytes or indirectly by releasing inflammatory cytokines. Here, we review recent progress regarding the immune cells in the liver and their functions during liver regeneration.
Role of Vα 14 NKT cells in the development of impaired liver regeneration in vivo
Hepatology, 2003
Although we have previously demonstrated that IL-12 stimulation increases the number of hepatic natural killer (NK) T (NKT) cells and enhances liver injury during the early phase of liver regeneration, the role of NKT cells has remained unknown. We therefore evaluated the influence of NKT cells activated by IL-12 or by ␣-galactosylceramide (␣-GalCer) on murine liver regeneration using V␣ 14 NKT knockout (J␣ 281 ؊/؊ ) mice. Levels of serum alanine aminotransferase (sALT) 24 hours after partial hepatectomy were enhanced in J␣ 281 ؉/؉ but not in J␣ 281 ؊/؊ mice by both procedures.
T Cell-Derived Lymphotoxin Regulates Liver Regeneration
Gastroenterology, 2009
The ability of the liver to regenerate hepatic mass is essential to withstanding liver injury. The process of liver regeneration is tightly regulated by distinct signaling cascades involving components of the innate immune system, cytokines, and growth factors. However, the role of the adaptive immune system in regulation of liver regeneration is not well-defined. The role of adaptive immune system in liver regeneration was investigated in lymphocyte-deficient mice and in conditional lymphotoxin-deficient mice.A model of liver regeneration after 70% partial hepatectomy was used, followed by examination of liver pathology, survival, DNA synthesis, and cytokine expression.We found that mice deficient in T cells show a reduced capacity for liver regeneration following partial hepatectomy. Furthermore, surface lymphotoxin, provided by T cells, is critical for liver regeneration. Mice specifically deficient in T-cell lymphotoxin had increased liver damage and a reduced capacity to initiate DNA synthesis after partial hepatectomy. Transfer of splenocytes from wild-type but not lymphotoxin-deficient mice improved liver regeneration in T cell-deficient mice. We found that an agonistic antibody against the lymphotoxin β receptor was able to facilitate liver regeneration by reducing liver injury, increasing interleukin-6 production, hepatocyte DNA synthesis, and survival of lymphocyte-deficient (Rag) mice after partial hepatectomy.The adaptive immune system directly regulates liver regeneration via a T cell-derived lymphotoxin axis, and pharmacological stimulation of lymphotoxin β receptor might represent a novel therapeutic approach to improve liver regeneration.
Liver Regeneration and Immunity: A Tale to Tell
International Journal of Molecular Sciences
The physiological importance of the liver is demonstrated by its unique and essential ability to regenerate following extensive injuries affecting its function. By regenerating, the liver reacts to hepatic damage and thus enables homeostasis to be restored. The aim of this review is to add new findings that integrate the regenerative pathway to the current knowledge. An optimal regeneration is achieved through the integration of two main pathways: IL-6/JAK/STAT3, which promotes hepatocyte proliferation, and PI3K/PDK1/Akt, which in turn enhances cell growth. Proliferation and cell growth are events that must be balanced during the three phases of the regenerative process: initiation, proliferation and termination. Achieving the correct liver/body weight ratio is ensured by several pathways as extracellular matrix signalling, apoptosis through caspase-3 activation, and molecules including transforming growth factor-beta, and cyclic adenosine monophosphate. The actors involved in the r...
Hepatology, 2008
after partial hepatectomy (PH). It is activated upon IB phosphorylation by the IB kinase (IKK) complex comprising inhibitor of kappaB kinase 1 (IKK1), inhibitor of kappaB kinase 2 (IKK2), and nuclear factor-B essential modifier (NEMO). We studied the impact of hepatocytespecific IKK2 deletion during liver regeneration. A 70% PH was performed on IKK2 f/f (wildtype) and IKK2⌬LPCmice (hepatocyte-specific IKK2 knockout mice). PH in IKK2⌬LPC compared with IKK2 f/f mice resulted in weaker and delayed NF-B activation in hepatocytes, while nonparenchymal liver cells showed earlier NF-B activation and higher tumor necrosis factor expression. Additionally, these animals showed increased and earlier serum amyloid A and chemotactic cytokine L-1 levels followed by enhanced polymorphonuclear cell recruitment to the liver. These results correlated with earlier Jun kinase activity, c-myc expression, and matrix metalloproteinase-9 activity, suggesting earlier priming in IKK2⌬LPC mice after PH. These data preceded a more rapid cell cycle progression and earlier hepatocyte proliferation as evidenced through cyclin and 5-bromo-2-deoxyuridine analysis. Interestingly, despite faster G 1 /S progression, IKK2⌬LPC mice exhibited an enduring mitosis phase, because mitotic bodies were still observed at later stages after PH. Conclusion: We demonstrate that PH in IKK2⌬LPC mice triggers a more rapid and pronounced inflammatory response in nonparenchymal liver cells, which triggers earlier hepatocyte proliferation. (HEPATOLOGY 2008;47:
Hepatology, 2013
Nucleotides, such as adenosine triphosphate (ATP), are released by cellular injury, bind to purinergic receptors expressed on hepatic parenchymal and nonparenchymal cells, and modulate cellular crosstalk. Liver resection and resulting cellular stress initiate such purinergic signaling responses between hepatocytes and innate immune cells, which regulate and ultimately drive liver regeneration. We studied a murine model of partial hepatectomy using immunodeficient mice to determine the effects of natural killer (NK) cell-mediated purinergic signaling on liver regeneration. We noted first that liver NK cells undergo phenotypic changes post-partial hepatectomy (PH) in vivo, including increased cytotoxicity and more immature phenotype manifested by alterations in the expression of CD107a, CD27, CD11b, and CD16. Hepatocellular proliferation is significantly decreased in Rag2/ common gamma-null mice (lacking T, B, and NK cells) when compared to wildtype and Rag1-null mice (lacking T and B cells but retaining NK cells). Extracellular ATP levels are elevated post-PH and NK cell cytotoxicity is substantively increased in vivo in response to hydrolysis of extracellular ATP levels by apyrase (soluble NTPDase). Moreover, liver regeneration is significantly increased by the scavenging of extracellular ATP in wildtype mice and in Rag2/common gamma-null mice after adoptive transfer of NK cells. Blockade of NKG2D-dependent interactions significantly decreased hepatocellular proliferation. In vitro, NK cell cytotoxicity is inhibited by extracellular ATP in a manner dependent on P2Y1, P2Y2, and P2X3 receptor activation. Conclusion: We propose that hepatic NK cells are activated and cytotoxic post-PH and support hepatocellular proliferation. NK cell cytotoxicity is, however, attenuated by hepatic release of extracellular ATP by way of the activation of specific P2 receptors. Clearance of extracellular ATP elevates NK cell cytotoxicity and boosts liver regeneration. (HEPATOLOGY 2013;57:1969-1979) E xtracellular adenosine triphosphate (ATP), released actively by stressed cells or derived from necrotic cell death, serves as a potent ''danger'' signal. 1 The release of endogenous nucleotides represents a critical signal modulating cellular crosstalk, injury, and proliferation during liver regeneration. 2-5 The regenerative process is closely coordinated by way of paracrine and cell contact-dependent interactions of parenchymal and nonparenchymal cells. 6,7 Extracellular nucleotides modulate immune responses through the activation of specific P2Y (G-protein coupled) and P2X (ligand-gated ion channel) receptors that are expressed on many cell types, including natural killer (NK) cells. 8 NK cells are the major sinusoidal lymphocyte population in the human liver. A diverse range of receptors expressed on the surface of NK cells allows them to recognize and rapidly respond to damaged or stressed
P2X1 regulated IL-22 secretion by innate lymphoid cells is required for efficient liver regeneration
Hepatology (Baltimore, Md.), 2016
Paracrine signalling mediated via cytokine secretion is essential for liver regeneration after hepatic resection, yet the mechanisms of cellular crosstalk between immune and parenchymal cells are still elusive. Interleukin-22 (IL-22) is released by immune cells and mediates strong hepatoprotective functions. However, it remains unclear if IL-22 is critical for the crosstalk between liver lymphocytes and parenchymal cells during liver regeneration after partial hepatectomy. Here we found that plasma levels of IL-22 and its upstream cytokine IL-23 are highly elevated in patients after major liver resection. In a mouse model of partial hepatectomy, deletion of IL-22 was associated with significantly delayed hepatocellular proliferation and an increase of hepatocellular injury and endoplasmic reticulum stress. Using Rag1(-/-) and Rag2(-/-) γc(-/-) mice we show that the main producers of IL-22 post partial hepatectomy are conventional natural killer cells and innate lymphoid cells type 1...
Hepatology, 2005
The liver regenerates after acute injury via hepatocyte cell division; during chronic injury, when hepatocyte replication is impaired or blocked, liver progenitor oval cells mediate liver regeneration. If both regeneration options are blocked in animal models, then liver failure and death ensues. The mechanisms underlying oval cell induction, proliferation, and subsequent liver regeneration remain poorly characterized. In particular, cell-signaling pathways that distinguish the alternative pathways are unknown. This study shows that in a mouse model,