scholarly journals Regulation of liver hepcidin expression by alcohol in vivo does not involve Kupffer cell activation or TNF-α signaling

2009 ◽  
Vol 296 (1) ◽  
pp. G112-G118 ◽  
Author(s):  
Duygu Dee Harrison-Findik ◽  
Elizabeth Klein ◽  
John Evans ◽  
John Gollan
Keyword(s):  
Oxidative Stress ◽  
Kupffer Cell ◽  
Kupffer Cells ◽  
Cell Activation ◽  
Receptor Expression ◽  
Gadolinium Chloride ◽  
Iron Storage ◽  
Hepcidin Expression ◽  
Tnf Α

Alcohol downregulates hepcidin expression in the liver leading to an increase in intestinal iron transport and liver iron storage. We have previously demonstrated that alcohol-mediated oxidative stress is involved in the inhibition of hepcidin transcription by alcohol in vivo. Kupffer cells and TNF-α play a key role in alcohol-induced liver injury. The aim of this study was to define their involvement in the regulation of hepcidin expression by alcohol. Kupffer cells were inactivated or depleted by employing gadolinium chloride and liposomes containing clodronate, respectively. Rats pair fed with the alcohol-Lieber-DeCarli diet for 6 wk and mice fed with 20% ethanol in the drinking water for 1 wk were used as experimental models. Interestingly, alcohol downregulated hepcidin expression in the livers of rats and mice independent of gadolinium chloride or clodronate treatment. One week of alcohol treatment was sufficient to induce a significant increase in TNF-α levels and phosphorylation of NF-κB subunit p65. The neutralization of TNF-α by specific antibodies inhibited p65 phosphorylation. However, neither the neutralization of TNF-α nor the lack of TNF-α receptor expression reversed alcohol-induced suppression of liver hepcidin expression. The level of alcohol-induced ROS in the liver was also undiminished following Kupffer cell inactivation or depletion. Our results demonstrate that alcohol-induced Kupffer cell activation and TNF-α signaling are not involved in the suppression of liver hepcidin expression by alcohol-mediated oxidative stress in vivo. Therefore, these findings suggest that alcohol acts within hepatocytes to suppress hepcidin expression and thereby influences iron homeostasis.

Activation of human and mouse Kupffer cells by lipopolysaccharide is mediated by CD14

2002 ◽  
Vol 283 (3) ◽  
pp. G640-G645 ◽  
Author(s):  
Grace L. Su ◽  
Sanna M. Goyert ◽  
Ming-Hui Fan ◽  
Alireza Aminlari ◽  
Ke Qin Gong ◽  
...  
Keyword(s):  
Kupffer Cell ◽  
Kupffer Cells ◽  
Knockout Mice ◽  
Cell Activation ◽  
Critical Role ◽  
Dependent Manner ◽  
Liver Macrophage ◽  
Tnf Α ◽  
Presence And Absence ◽  
Lps Activation

Upregulation of CD14 in Kupffer cells has been implicated in the pathogenesis of several forms of liver injury, including alcoholic liver disease. However, it remains unclear whether CD14 mediates lipopolysaccharide (LPS) signaling in this specialized liver macrophage population. In this series of experiments, we determined the role of CD14 in LPS activation of Kupffer cells by using several complementary approaches. First, we isolated Kupffer cells from human livers and studied the effects of anti-CD14 antibodies on LPS activation of these cells. Kupffer cells were incubated with increasing concentrations of LPS in the presence and absence of recombinant human LPS binding protein (LBP). With increasing concentrations of LPS, human Kupffer cell tumor necrosis factor-α (TNF-α) production (a marker for Kupffer cell activation) increased in a dose-dependent manner in the presence and absence of LBP. In the presence of anti-human CD14 antibodies, the production of TNF-α was significantly diminished. Second, we compared LPS activation of Kupffer cells isolated from wild-type and CD14 knockout mice. Kupffer cells from CD14 knockout mice produced significantly less TNF-α in response to the same amount of LPS. Together, these data strongly support a critical role for CD14 in Kupffer cell responses to LPS.

In vivo magnetic resonance imaging study of Kupffer cell involvement in CCl4-induced hepatotoxicity in rats

1994 ◽  
Vol 72 (5) ◽  
pp. 441-446 ◽  
Author(s):  
Rheal A. Towner ◽  
Lester A. Reinke ◽  
Edward G. Janzen ◽  
Shigeto Yamashiro
Keyword(s):  
Magnetic Resonance Imaging ◽  
Magnetic Resonance ◽  
Kupffer Cell ◽  
Kupffer Cells ◽  
Methyl Palmitate ◽  
Gadolinium Chloride ◽  
Resonance Imaging ◽  
Parenchymal Cells ◽  
Trichloromethyl Radical

When carbon tetrachloride (CCl4) was administered to rats, a localized region of hepatic edema could be detected within 1 h by in vivo proton magnetic resonance imaging. However, if rats were pretreated with gadolinium chloride (GdCl3), an inhibitor of Kupffer cell function, the CCl4-induced edema was greatly decreased. Methyl palmitate, another Kupffer cell inhibitor, also decreased the degree of edema caused by the administration of CCl4. Electron micrographs of samples that were taken from regions of the liver where the edema was localized indicated formation of vacuoles and lipid droplets in parenchymal cells and enlargement of Kupffer cells, which exhibited numerous phagosomes and extensive pseudopod formation. These electron micrograph changes were also attenuated by pretreatment of the rats with GdCl3 and methyl palmitate. In vivo spin trapping and electron paramagnetic resonance experiments indicated that GdCl3 did not affect the metabolism of CCl4 to the trichloromethyl radical. The data in this report suggest that localized hepatic edema which occurs soon after administration of CCl4 involves activation of Kupffer cells, and that trichloromethyl radical production may be a separate but related process occurring in parenchymal cells. These observations support reports from other laboratories that Kupffer cells may be involved in CCl4-induced hepatotoxicity.Key words: carbon tetrachloride, hepatotoxicity, magnetic resonance imaging, gadolinium chloride, Kupffer cells.

scholarly journals Oxidative Stress and Inflammatory Modulation of Ca2+ Handling in Metabolic HFpEF-Related Left Atrial Cardiomyopathy

Antioxidants ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 860
Author(s):  
David Bode ◽  
Yan Wen ◽  
Niklas Hegemann ◽  
Uwe Primessnig ◽  
Abdul Parwani ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Metabolic Syndrome ◽  
Ejection Fraction ◽  
Left Atrial ◽  
Left Ventricular ◽  
Receptor Expression ◽  
Tnf Α ◽  
Anti Inflammatory

Metabolic syndrome-mediated heart failure with preserved ejection fraction (HFpEF) is commonly accompanied by left atrial (LA) cardiomyopathy, significantly affecting morbidity and mortality. We evaluate the role of reactive oxygen species (ROS) and intrinsic inflammation (TNF-α, IL-10) related to dysfunctional Ca2+ homeostasis of LA cardiomyocytes in a rat model of metabolic HFpEF. ZFS-1 obese rats showed features of HFpEF and atrial cardiomyopathy in vivo: increased left ventricular (LV) mass, E/e’ and LA size and preserved LV ejection fraction. In vitro, LA cardiomyocytes exhibited more mitochondrial-fission (MitoTracker) and ROS-production (H2DCF). In wildtype (WT), pro-inflammatory TNF-α impaired cellular Ca2+ homeostasis, while anti-inflammatory IL-10 had no notable effect (confocal microscopy; Fluo-4). In HFpEF, TNF-α had no effect on Ca2+ homeostasis associated with decreased TNF-α receptor expression (western blot). In addition, IL-10 substantially improved Ca2+ release and reuptake, while IL-10 receptor-1 expression was unaltered. Oxidative stress in metabolic syndrome mediated LA cardiomyopathy was increased and anti-inflammatory treatment positively affected dysfunctional Ca2+ homeostasis. Our data indicates, that patients with HFpEF-related LA dysfunction might profit from IL-10 targeted therapy, which should be further explored in preclinical trials.

Attenuation of CCl4-induced hepatic fibrosis by GdCl3treatment or dietary glycine

2001 ◽  
Vol 281 (1) ◽  
pp. G200-G207 ◽  
Author(s):  
C. A. Rivera ◽  
B. U. Bradford ◽  
K. J. Hunt ◽  
Y. Adachi ◽  
L. W. Schrum ◽  
...  
Keyword(s):  
Kupffer Cell ◽  
Kupffer Cells ◽  
Cell Activation ◽  
Transforming Growth Factor ◽  
Stellate Cell ◽  
Smooth Muscle Actin ◽  
Protein Levels ◽  
Male Wistar Rats

The role of Kupffer cells in CCl4-induced fibrosis was investigated in vivo. Male Wistar rats were treated with phenobarbital and CCl4for 9 wk, and a group of rats were injected with the Kupffer cell toxicant gadolinium chloride (GdCl3) or were fed glycine, which inactivates Kupffer cells. After CCl4alone, the fibrosis score was 3.0 ± 0.1 and collagen protein and mRNA expression were elevated, but GdCl3or glycine blunted these parameters. Glycine did not alter cytochrome P-450 2E1, making it unlikely that glycine affects CCl4metabolism. Treatment with GdCl3or glycine prevented CCl4-induced increases in transforming growth factor (TGF)-β1 protein levels and expression. CCl4treatment increased α-smooth muscle actin staining (score 3.0 ± 0.2), whereas treatment with GdCl3and glycine during CCl4exposure blocked this effect (1.2 ± 0.5); there was no staining with glycine treatment. These results support previous in vitro data and demonstrate that treatment of rats with the selective Kupffer cell toxicant GdCl3prevents stellate cell activation and the development of fibrosis.

Melatonin attenuates radiation-induced cortical bone-derived stem cells injury and enhances bone repair in postradiation femoral defect model

2021 ◽  
Author(s):  
Wei Hu ◽  
Jiawu Liang ◽  
Song Liao ◽  
Zhidong Zhao ◽  
Yuxing Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stem Cells ◽  
Flow Cytometry ◽  
Genomic Stability ◽  
Bone Defects ◽  
Self Renewal ◽  
Tnf Α ◽  
Radiation Induced ◽  
Γ Ray

Abstract Background Ionizing radiation poses a challenge to the healing of bone defects. Radiation therapy and accidental exposure to gamma-ray (γ-ray) radiation inhibit bone formation and increase the risk of fractures. Cortical bone-derived stem cells (CBSCs) are essential for osteogenic lineages, bone maintenance, and repair. This study aimed to investigate the effects of melatonin on postradiation CBSCs and bone defects. Methods CBSCs were extracted from C57/BL6 mice and were identified by flow cytometry. The effects of exogenous melatonin on the self-renewal and osteogenic capacity of postradiation CBSCs were detected in vitro. The underlying mechanisms in terms of genomic stability, apoptosis and oxidative stress-related signaling were further analyzed by western blotting, flow cytometry and immunofluorescence. Finally, the effects of melatonin on healing in postradiation bone defects were evaluated in vivo by micro-CT and immunohistochemical analysis. Results The radiation-induced reduced self-renewal and osteogenic capacity were partially reversed in postradiation CBSCs treated with melatonin. Melatonin maintained the genomic stability and apoptosis of postradiation CBSCs, and intracellular oxidative stress was decreased significantly while antioxidant-related enzymes were enhanced. Western blotting verified the anti-inflammatory effect of melatonin by downregulating the levels of IL-6 and TNF-α via extracellular regulated kinase (ERK)/nuclear factor erythroid 2-related factor 2 (NRF2)/heme oxygenase 1 (HO-1) signaling, distinct from its antioxidant effect via NRF2 signaling. In vivo experiments demonstrated that the newly formed bone in the melatonin plus Matrigel group had higher trabecular bone volume per tissue volume (BV/TV) and bone mineral density (BMD) values, and lower levels of IL-6 and TNF-α than those in the irradiation and the Matrigel groups. Conclusions This study suggested the potential of melatonin to protect CBSCs against γ-ray radiation and to assist the healing of postradiation bone defects.

scholarly journals Multiple myeloma increases nerve growth factor and other pain-related markers through interactions with the bone microenvironment

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Sam W. Z. Olechnowicz ◽  
Megan M. Weivoda ◽  
Seint T. Lwin ◽  
Szi K. Leung ◽  
Sarah Gooding ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Nerve Growth Factor ◽  
Growth Factor ◽  
Cell Activation ◽  
Cellular Interactions ◽  
Bone Microenvironment ◽  
Related Factors ◽  
Nerve Growth ◽  
Tnf Α

Abstract Interactions between multiple myeloma (MM) and bone marrow (BM) are well documented to support tumour growth, yet the cellular mechanisms underlying pain in MM are poorly understood. We have used in vivo murine models of MM to show significant induction of nerve growth factor (NGF) by the tumour-bearing bone microenvironment, alongside other known pain-related characteristics such as spinal glial cell activation and reduced locomotion. NGF was not expressed by MM cells, yet bone stromal cells such as osteoblasts expressed and upregulated NGF when cultured with MM cells, or MM-related factors such as TNF-α. Adiponectin is a known MM-suppressive BM-derived factor, and we show that TNF-α-mediated NGF induction is suppressed by adiponectin-directed therapeutics such as AdipoRON and L-4F, as well as NF-κB signalling inhibitor BMS-345541. Our study reveals a further mechanism by which cellular interactions within the tumour-bone microenvironment contribute to disease, by promoting pain-related properties, and suggests a novel direction for analgesic development.

scholarly journals Succinamide Derivatives Ameliorate Neuroinflammation and Oxidative Stress in Scopolamine-Induced Neurodegeneration

Biomolecules ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 443 ◽  
Author(s):  
Sumbal Iqbal ◽  
Fawad Ali Shah ◽  
Komal Naeem ◽  
Humaira Nadeem ◽  
Sadia Sarwar ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Neuronal Injury ◽  
Binding Affinities ◽  
Glutathione S Transferase ◽  
In Vivo Experiments ◽  
Tnf Α ◽  
And Oxidative Stress ◽  
Necrosis Factor

Oxidative stress-mediated neuroinflammatory events are the hallmark of neurodegenerative diseases. The current study aimed to synthesize a series of novel succinamide derivatives and to further investigate the neuroprotective potential of these compounds against scopolamine-induced neuronal injury by in silico, morphological, and biochemical approaches. The characterization of all the succinamide derivatives was carried out spectroscopically via proton NMR (1H-NMR), FTIR and elemental analysis. Further in vivo experiments showed that scopolamine induced neuronal injury, characterized by downregulated glutathione (GSH), glutathione S-transferase (GST), catalase, and upregulated lipid peroxidation (LPO). Moreover, scopolamine increased the expression of inflammatory mediators such as cyclooxygenase2 (COX2), nuclear factor kappa B (NF-kB), tumor necrosis factor (TNF-α), further associated with cognitive impairment. On the other hand, treatment with succinamide derivatives ameliorated the biochemical and immunohistochemical alterations induced by scopolamine, further supported by the results obtained from molecular docking and binding affinities.

scholarly journals CD4+CD25+ regulatory T cells inhibit natural killer cell functions in a transforming growth factor–β–dependent manner

2005 ◽  
Vol 202 (8) ◽  
pp. 1075-1085 ◽  
Author(s):  
François Ghiringhelli ◽  
Cédric Ménard ◽  
Magali Terme ◽  
Caroline Flament ◽  
Julien Taieb ◽  
...  
Keyword(s):  
Growth Factor ◽  
Natural Killer ◽  
Cell Activation ◽  
Transforming Growth Factor ◽  
Nk Cell ◽  
Killer Cell ◽  
Receptor Expression ◽  
Dependent Manner ◽  
Cell Functions

Tumor growth promotes the expansion of CD4+CD25+ regulatory T (T reg) cells that counteract T cell–mediated immune responses. An inverse correlation between natural killer (NK) cell activation and T reg cell expansion in tumor-bearing patients, shown here, prompted us to address the role of T reg cells in controlling innate antitumor immunity. Our experiments indicate that human T reg cells expressed membrane-bound transforming growth factor (TGF)–β, which directly inhibited NK cell effector functions and down-regulated NKG2D receptors on the NK cell surface. Adoptive transfer of wild-type T reg cells but not TGF-β−/− T reg cells into nude mice suppressed NK cell–mediated cytotoxicity, reduced NKG2D receptor expression, and accelerated the growth of tumors that are normally controlled by NK cells. Conversely, the depletion of mouse T reg cells exacerbated NK cell proliferation and cytotoxicity in vivo. Human NK cell–mediated tumor recognition could also be restored by depletion of T reg cells from tumor-infiltrating lymphocytes. These findings support a role for T reg cells in blunting the NK cell arm of the innate immune system.

Kupffer cell activation is a causal factor for hepatic insulin resistance

2010 ◽  
Vol 298 (1) ◽  
pp. G107-G116 ◽  
Author(s):  
Nicolas Lanthier ◽  
Olivier Molendi-Coste ◽  
Yves Horsmans ◽  
Nico van Rooijen ◽  
Patrice D. Cani ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Kupffer Cell ◽  
High Fat Diet ◽  
Cell Activation ◽  
Hepatic Insulin Resistance ◽  
High Fat ◽  
Short Term ◽  
Adipose Tissue Macrophages ◽  
Diet Model

Recruited adipose tissue macrophages contribute to chronic and low-grade inflammation causing insulin resistance in obesity. Similarly, we hypothesized here that Kupffer cells, the hepatic resident macrophages, play a pathogenic role in hepatic insulin resistance induced by a high-fat diet. Mice were fed a normal diet or high-fat diet for 3 days. Kupffer cell activation was evaluated by immunohistochemistry and quantitative RT-PCR. Insulin sensitivity was assessed in vivo by hyperinsulinemic-euglycemic clamp and insulin-activated signaling was investigated by Western blot. Liposome-encapsulated clodronate was injected intravenously to deplete macrophages prior to a short-term exposure to high-fat diet. Here, we characterized a short-term high-fat diet model in mice and demonstrated early hepatic insulin resistance and steatosis concurrent with Kupffer cell activation. We demonstrated that selective Kupffer cell depletion obtained by intravenous clodronate, without affecting adipose tissue macrophages, was sufficient to enhance insulin-dependent insulin signaling and significantly improve hepatic insulin sensitivity in vivo in this short-term high-fat diet model. Our study clearly shows that hepatic macrophage response participates to the onset of high-fat diet-induced hepatic insulin resistance and may therefore represent an attractive target for prevention and treatment of diet- and obesity-induced insulin resistance.

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