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.

scholarly journals Kupffer cell receptor CLEC4F is important for the destruction of desialylated platelets in mice

2021 ◽  
Author(s):  
Yizhi Jiang ◽  
Yaqiong Tang ◽  
Christopher Hoover ◽  
Yuji Kondo ◽  
Dongping Huang ◽  
...  
Keyword(s):  
Kupffer Cell ◽  
Kupffer Cells ◽  
Critical Role ◽  
Underlying Mechanism ◽  
Cell Receptor ◽  
The Body ◽  
Dependent Manner ◽  
Phagocytic Cells ◽  
Lectin Receptor

AbstractThe liver has recently been identified as a major organ for destruction of desialylated platelets. However, the underlying mechanism remains unclear. Kupffer cells, which are professional phagocytic cells in the liver, comprise the largest population of resident tissue macrophages in the body. Kupffer cells express a C-type lectin receptor, CLEC4F, that recognizes desialylated glycans with an unclear in vivo role in mediating platelet destruction. In this study, we generated a CLEC4F-deficient mouse model (Clec4f−/−) and found that CLEC4F was specifically expressed by Kupffer cells. Using the Clec4f−/− mice and a newly generated platelet-specific reporter mouse line, we revealed a critical role for CLEC4F on Kupffer cells in mediating destruction of desialylated platelets in the liver in vivo. Platelet clearance experiments and ultrastructural analysis revealed that desialylated platelets were phagocytized predominantly by Kupffer cells in a CLEC4F-dependent manner in mice. Collectively, these findings identify CLEC4F as a Kupffer cell receptor important for the destruction of desialylated platelets induced by bacteria-derived neuraminidases, which provide new insights into the pathogenesis of thrombocytopenia in disease conditions such as sepsis.

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.

scholarly journals Intestinal inflammation downregulates smooth muscle CPI-17 through induction of TNF-α and causes motility disorders

2007 ◽  
Vol 292 (5) ◽  
pp. G1429-G1438 ◽  
Author(s):  
Takashi Ohama ◽  
Masatoshi Hori ◽  
Eiichi Momotani ◽  
Yoichiro Iwakura ◽  
Fengling Guo ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Muscle Tissue ◽  
Proinflammatory Cytokines ◽  
Knockout Mice ◽  
Intestinal Inflammation ◽  
In Vivo Model ◽  
Dependent Manner ◽  
Smooth Muscle Tissue ◽  
Motility Disorders ◽  
Tnf Α

Motility disorders are frequently observed in intestinal inflammation. We previously reported that in vitro treatment of intestinal smooth muscle tissue with IL-1β decreases the expression of CPI-17, an endogenous inhibitory protein of smooth muscle serine/threonine protein phosphatase, thereby inhibiting contraction. The present study was performed to examine the pathophysiological importance of CPI-17 expression in the motility disorders by using an in vivo model of intestinal inflammation and to define the regulatory mechanism of CPI-17 expression by proinflammatory cytokines. After the induction of acute ileitis with 2,4,6,-trinitrobenzensulfonic acid, CPI-17 expression declined in a time-dependent manner. This decrease in CPI-17 expression was parallel with the reduction of cholinergic agonist-induced contraction of smooth muscle strips and sensitivity of permeabilized smooth muscle fibers to Ca2+. Among the various proinflammatory cytokines tested, TNF-α and IL-1β were observed to directly inhibit CPI-17 expression and contraction in cultured rat intestinal tissue. Moreover, both TNF-α and IL-1β inhibited CPI-17 expression and contraction of smooth muscle tissue isolated from wild-type and IL-1α/β double-knockout mice. However, IL-1β treatment failed to inhibit CPI-17 expression and contraction in TNF-α knockout mice. In β-escin-permeabilized ileal tissues, pretreatment with anti-phosphorylated CPI-17 antibody inhibited the carbachol-induced Ca2+ sensitization in the presence of GTP. These findings suggest that CPI-17 was downregulated during intestinal inflammation and that TNF-α plays a central role in this process. Downregulation of CPI-17 may play a role in motility impairments in inflammation.

scholarly journals Limited Role of Mincle in the Host Defense against Infection with Cryptococcus deneoformans

2020 ◽  
Vol 88 (11) ◽  
Author(s):  
Yuki Sato ◽  
Ko Sato ◽  
Hideki Yamamoto ◽  
Jun Kasamatsu ◽  
Tomomitsu Miyasaka ◽  
...  
Keyword(s):  
Host Defense ◽  
Early Stage ◽  
Critical Role ◽  
Yeast Cells ◽  
Dependent Manner ◽  
Th2 Response ◽  
Lectin Receptors ◽  
Cryptococcal Infection ◽  
Tnf Α

ABSTRACT Cryptococcus deneoformans is an opportunistic fungal pathogen that frequently causes fatal meningoencephalitis in patients with impaired cell-mediated immune responses such as AIDS. Caspase-associated recruitment domain 9 (CARD9) plays a critical role in the host defense against cryptococcal infection, suggesting the involvement of one or more C-type lectin receptors (CLRs). In the present study, we analyzed the role of macrophage-inducible C-type lectin (Mincle), one of the CLRs, in the host defense against C. deneoformans infection. Mincle expression in the lungs of wild-type (WT) mice was increased in the early stage of cryptococcal infection in a CARD9-dependent manner. In Mincle gene-disrupted (Mincle KO) mice, the clearance of this fungus, pathological findings, Th1/Th2 response, and antimicrobial peptide production in the infected lungs were nearly comparable to those in WT mice. However, the production of interleukin-22 (IL-22), tumor necrosis factor alpha (TNF-α), and IL-6 and the expression of AhR were significantly decreased in the lungs of Mincle KO mice compared to those of WT mice. In in vitro experiments, TNF-α production by bone marrow-derived dendritic cells was significantly decreased in Mincle KO mice. In addition, the disrupted lysates of C. deneoformans, but not those of whole yeast cells, activated Mincle-triggered signaling in an assay with a nuclear factor of activated T cells (NFAT)-green fluorescent protein (GFP) reporter cells expressing this receptor. These results suggest that Mincle may be involved in the production of Th22-related cytokines at the early stage of cryptococcal infection, although its role may be limited in the host defense against infection with C. deneoformans.

scholarly journals A novel pathway for human endothelial cell activation by antiphospholipid/anti-β2 glycoprotein I antibodies

Blood ◽  
2012 ◽  
Vol 119 (3) ◽  
pp. 884-893 ◽  
Author(s):  
Kristi L. Allen ◽  
Fabio V. Fonseca ◽  
Venkaiah Betapudi ◽  
Belinda Willard ◽  
Jainwei Zhang ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Cell Activation ◽  
Transmembrane Protein ◽  
Critical Role ◽  
Fetal Loss ◽  
Annexin A2 ◽  
Dependent Manner ◽  
Protein Protein Interactions ◽  
Endothelial Cell Activation ◽  
Signaling Complex

Abstract Antiphospholipid Abs (APLAs) are associated with thrombosis and recurrent fetal loss. These Abs are primarily directed against phospholipid-binding proteins, particularly β2GPI, and activate endothelial cells (ECs) in a β2GPI-dependent manner after binding of β2GPI to EC annexin A2. Because annexin A2 is not a transmembrane protein, the mechanisms of APLA/anti-β2GPI Ab–mediated EC activation are uncertain, although a role for a TLR4/myeloid differentiation factor 88–dependent pathway leading to activation of NF-κB has been proposed. In the present study, we confirm a critical role for TLR4 in anti-β2GPI Ab–mediated EC activation and demonstrate that signaling through TLR4 is mediated through the assembly of a multiprotein signaling complex on the EC surface that includes annexin A2, TLR4, calreticulin, and nucleolin. An essential role for each of these proteins in cell activation is suggested by the fact that inhibiting the expression of each using specific siRNAs blocked EC activation mediated by APLAs/anti-β2GPI Abs. These results provide new evidence for novel protein-protein interactions on ECs that may contribute to EC activation and the pathogenesis of APLA/anti-β2GPI–associated thrombosis and suggest potential new targets for therapeutic intervention in antiphospholipid syndrome.

Prevention of Kupffer cell-induced oxidant injury in rat liver by atrial natriuretic peptide

1999 ◽  
Vol 276 (5) ◽  
pp. G1137-G1144 ◽  
Author(s):  
Manfred Bilzer ◽  
Hartmut Jaeschke ◽  
Angelika M. Vollmar ◽  
Gustav Paumgartner ◽  
Alexander L. Gerbes
Keyword(s):  
Liver Injury ◽  
Inflammatory Response ◽  
Atrial Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Kupffer Cell ◽  
Kupffer Cells ◽  
Cell Activation ◽  
Cell Damage ◽  
Liver Cells ◽  
Atrial Natriuretic

The generation of reactive oxygen species (ROS) by activated Kupffer cells contributes to liver injury following liver preservation, shock, or endotoxemia. Pharmacological interventions to protect liver cells against this inflammatory response of Kupffer cells have not yet been established. Atrial natriuretic peptide (ANP) protects the liver against ischemia-reperfusion injury, suggesting a possible modulation of Kupffer cell-mediated cytotoxicity. Therefore, we investigated the mechanism of cytoprotection by ANP during Kupffer cell activation in perfused rat livers of male Sprague-Dawley rats. Activation of Kupffer cells by zymosan (150 μg/ml) resulted in considerable cell damage, as assessed by the sinusoidal release of lactate dehydrogenase and purine nucleoside phosphorylase. Cell damage was almost completely prevented by superoxide dismutase (50 U/ml) and catalase (150 U/ml), indicating ROS-related liver injury. ANP (200 nM) reduced Kupffer cell-induced injury via the guanylyl cyclase-coupled A receptor (GCA receptor) and cGMP: mRNA expression of the GCA receptor was found in hepatocytes, endothelial cells, and Kupffer cells, and the cGMP analog 8-bromo-cGMP (8-BrcGMP; 50 μM) was as potent as ANP in protecting from zymosan-induced cell damage. ANP and 8-BrcGMP significantly attenuated the prolonged increase of hepatic vascular resistance when Kupffer cell activation occurred. Furthermore, both compounds reduced oxidative cell damage following infusion of H2O2(500 μM). In contrast, superoxide anion formation of isolated Kupffer cells was not affected by ANP and only moderately reduced by 8-BrcGMP. In conclusion, ANP protects the liver against Kupffer cell-related oxidant stress. This hormonal protection is mediated via the GCA receptor and cGMP, suggesting that the cGMP receptor plays a critical role in controlling oxidative cell damage. Thus ANP signaling should be considered as a new pharmacological target for protecting liver cells against the inflammatory response of activated Kupffer cells without eliminating the vital host defense function of these cells.

Specific inhibition of interleukin-13 activity by a recombinant human single-chain immunoglobulin domain directed against the IL-13 receptor α1 chain

2007 ◽  
Vol 388 (3) ◽  
pp. 325-330 ◽  
Author(s):  
Stefan Knackmuss ◽  
Sebastian Krause ◽  
Kathrin Engel ◽  
Uwe Reusch ◽  
J. Christian Virchow ◽  
...  
Keyword(s):  
Cell Activation ◽  
Binding Capacity ◽  
Specific Binding ◽  
Critical Role ◽  
Target Cells ◽  
Dependent Manner ◽  
Single Chain ◽  
Interleukin 13 ◽  
Single Chain Fv ◽  
Immunoglobulin Domain

Abstract Interleukin-13 (IL-13) is a T-cell-derived pleiotropic cytokine of particular medical importance because of its critical role in the development of allergic asthma. The effects of IL-13 on its target cells are mediated through a dimeric transmembrane receptor (IL-13R), which shares the IL-4Rα subunit with the IL-4R system, but contains as a specific component the IL-13Rα1 chain. We have generated a set of single-chain Fv fragments with specific binding capacity to the extracellular domain of the human IL-13Rα1 receptor. Bacteriophage clones displaying receptor-binding antibody domains were selected from both naive and synthetic libraries by repetitive panning on recombinant and cell surface-expressed recombinant IL-13Rα1. Their specific reactivity with native human IL-13Rα1 expressed on the surface of transfected cells was demonstrated by flow cytometry. One binder that specifically interfered with cell activation by IL-13 was extensively characterized. This scFv inhibited IL-13-driven gene transcription and cell proliferation in test cell lines, as well as IL-13-induced activation of primary human monocytes in a dose-dependent manner, with an IC50 below 300 nM. This novel reagent thus constitutes a valuable tool for the further elucidation of IL-13 function in disease and offers potential therapeutic perspectives.

scholarly journals Endothelial cell activation by antiphospholipid antibodies is modulated by Krüppel-like transcription factors

Blood ◽  
2011 ◽  
Vol 117 (23) ◽  
pp. 6383-6391 ◽  
Author(s):  
Kristi L. Allen ◽  
Anne Hamik ◽  
Mukesh K. Jain ◽  
Keith R. McCrae
Keyword(s):  
Endothelial Cells ◽  
Antiphospholipid Antibodies ◽  
Transcriptional Activity ◽  
Cell Activation ◽  
Critical Role ◽  
Endothelial Activation ◽  
Dependent Manner ◽  
Endothelial Cell Activation ◽  
Proinflammatory Response ◽  
Endothelial Response

Abstract Antiphospholipid syndrome is characterized by thrombosis and/or recurrent pregnancy loss in the presence of antiphospholipid antibodies (APLAs). The majority of APLAs are directed against phospholipid-binding proteins, particularly β2-glycoprotein I (β2GPI). Anti-β2GPI antibodies activate endothelial cells in a β2GPI-dependent manner through a pathway that involves NF-κB. Krüppel-like factors (KLFs) play a critical role in regulating the endothelial response to inflammatory stimuli. We hypothesized that activation of endothelial cells by APLA/anti-β2GPI antibodies might be associated with decreased expression of KLFs, which in turn might facilitate cellular activation mediated through NF-κB. Our experimental results confirmed this hypothesis, demonstrating markedly decreased expression of KLF2 and KLF4 after incubation of cells with APLA/anti-β2GPI antibodies. Restoration of KLF2 or KLF4 levels inhibited NF-κB transcriptional activity and blocked APLA/anti-β2GPI–mediated endothelial activation despite NF-κB p65 phosphorylation. Chromatin immunoprecipitation analysis demonstrated that inhibition of NF-κB transcriptional activity by KLFs reflects sequestration of the cotranscriptional activator CBP/p300, making this cofactor unavailable to NF-κB. These findings suggest that the endothelial response to APLA/anti-β2GPI antibodies reflects competition between KLFs and NF-κB for their common cofactor, CBP/p300. Taken together, these observations are the first to implicate the KLFs as novel participants in the endothelial proinflammatory response to APLA/anti-β2GPI antibodies.

Production of superoxide and TNF-α from alveolar macrophages is blunted by glycine

1999 ◽  
Vol 277 (5) ◽  
pp. L952-L959 ◽  
Author(s):  
Michael D. Wheeler ◽  
Ronald G. Thurman
Keyword(s):  
Intracellular Calcium ◽  
Kupffer Cells ◽  
Alveolar Macrophages ◽  
Chloride Channel ◽  
Chloride Channels ◽  
Dependent Manner ◽  
Tnf Α ◽  
The Central Nervous System ◽  
Factor Α ◽  
Dose Dependent

Glycine blunts lipopolysaccharide (LPS)-induced increases in intracellular calcium concentration ([Ca2+]i) and tumor necrosis factor-α (TNF-α) production by Kupffer cells through a glycine-gated chloride channel. Alveolar macrophages, which have a similar origin as Kupffer cells, play a significant role in the pathogenesis of several lung diseases including asthma, endotoxemia, and acute inflammation due to inhaled bacterial particles and dusts. Therefore, studies were designed here to test the hypothesis that alveolar macrophages could be inactivated by glycine via a glycine-gated chloride channel. The ability of glycine to prevent endotoxin [lipopolysaccharide (LPS)]-induced increases in [Ca2+]iand subsequent production of superoxide and TNF-α in alveolar macrophages was examined. LPS caused a transient increase in intracellular calcium to nearly 200 nM, with EC50values slightly greater than 25 ng/ml. Glycine, in a dose-dependent manner, blunted the increase in [Ca2+]i, with an IC50less than 100 μM. Like the glycine-gated chloride channel in the central nervous system, the effects of glycine on [Ca2+]iwere both strychnine sensitive and chloride dependent. Glycine also caused a dose-dependent influx of radiolabeled chloride with EC50values near 10 μM, a phenomenon which was also inhibited by strychnine (1 μM). LPS-induced superoxide production was also blunted in a dose-dependent manner by glycine and was reduced ∼50% with 10 μM glycine. Moreover, TNF-α production was also inhibited by glycine and also required nearly 10 μM glycine for half-inhibition. These data provide strong pharmacological evidence that alveolar macrophages contain glycine-gated chloride channels and that their activation is protective against the LPS-induced increase in [Ca2+]iand subsequent production of toxic radicals and cytokines.

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