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PubMed2004

Differentiation and function of Kupffer cells.

Kupffer cells are the largest population of tissue macrophages. They are predominantly distributed in the lumen of hepatic sinusoids and exhibit endocytic activity against blood-borne materials entering the liver. Macrophage colony-stimulating factor and other growth factors regulate Kupffer cell differentiation in the fetal and adult period. Because of the unique attributes of tissue, Kupffer cells play essential roles not only in host defense but also in the homeostatic responses of tissue. Macrophage scavenger receptors and heme oxygenase are expressed in Kupffer cells from an early stage of ontogeny. Scavenger receptors are involved not only in the lipid metabolism but also in the bactericidal mechanism. Heme oxygenase in Kupffer cells is essential to the production of bilirubin. In this review, the developmental mechanism and functional activities of Kupffer cells are described. Evidence suggests that Kupffer cells represent a distinct cell population with unique differentiation mechanisms, metabolic functions, and responsiveness to inflammatory agents.

Aging↗
PubMed1988

Release of peptide leukotrienes from rat Kupffer cells.

Kupffer cells isolated from the normal rat liver were incubated with calcium ionophore A23187, and the levels of peptide leukotrienes (LTC4, LTD4, and LTE4) contained in the culture supernatant were determined by the combined technique of reverse-phase high-performance liquid chromatography and radioimmunoassay. In response to A23187, Kupffer cells released LTC4, LTD4, and LTE4. After 10 min-preincubation of Kupffer cells with AA861, a 5-lipoxygenase inhibitor, the generation of LTC4, LTD4, and LTE4 from A23187-stimulated Kupffer cells was significantly suppressed. Platelet activating factor (PAF), a phospholipid mediator, significantly enhanced the release of LTC4, LTD4, and LTE4 from Kupffer cells stimulated with A23187. These results suggested that Kupffer cells may participate in inflammatory and immunologic events in the liver tissue by the release of peptide leukotrienes.

Animals↗
PubMed1996

Effect of chronic ethanol feeding on nitric oxide synthesis by rat Kupffer cells.

Kupffer cells contribute to the important role of the liver defense mechanism through nitric oxide (NO) production. In this study, the effect of chronic ethanol administration on the ability of Kupffer cells to synthesize and release NO was investigated after stimulation with lipopolysaccharide (LPS). Male Wistar rats were chronically fed ethanol for 8 weeks according to the method described by DeCarli and Lieber et al. (J Nutr.91:331-336, 1967). Kupffer cells were isolated and cultured with LPS (1 micrograms/ml) for 24 hr. The levels of nitrite and nitrate, metabolites of NO, were determined in the culture medium, NO synthase (NOS) activity in Kupffer cells was determined by the method that measures conversion of [14C]arginine into [14C]citrulline. In control rats, a significant increase of nitrite and nitrate levels in culture medium was observed after LPS treatment. The magnitude of this increase was significantly smaller in chronic ethanol-fed rats. When the activity of NOS was determined, inducible NOS (iNOS) activity was higher than that of constitutive NOS, and LPS administration produced a significant elevation of iNOS activity in both control and chronic ethanol-fed rats. However, the elevation of iNOS activity by LPS stimulation was diminished by chronic ethanol administration. Distribution of iNOS in Kupffer cells as determined by an immunofluorescence method using a laser scanning confocal image system showed a lower expression of iNOS in chronic ethanol-fed rats even in the presence of LPS. These results demonstrate that the excessive production of NO by increased iNOS activity in Kupffer cells is diminished by chronic ethanol administration.

Animals↗
PubMed1996

Antigen-presenting function and B7 expression of murine sinusoidal endothelial cells and Kupffer cells.

BACKGROUND & AIMS: Inflammatory liver disease as well as rejection of liver allografts are thought to be mediated by resident antigen-presenting cells in the liver. At the same time, in vivo antigen presentation in the liver appears to be a more tolerogenic than systemic antigen challenge. The aim of this study was to show and characterize the antigen-presenting capability of sinusoidal endothelial cells and Kupffer cells. METHODS: Purified murine sinusoidal endothelial cells and Kupffer cells were studied for their ability to serve as accessory cells and antigen-presenting cells by proliferation assays. They were also studied for their expression of interleukin 1 and the B7 costimulatory molecules by Northern blotting, polymerase chain reaction, and flow cytometry. RESULTS: Both cell types expressed interleukin 1 messenger RNA and could serve equally well as accessory and antigen-presenting cells. B7-2 messenger RNA and surface expression on sinusoidal endothelial cells and on Kupffer cells was shown. Antibodies to the B7 molecules inhibited antigen presentation. Addition of interleukin 10 as a regulatory cytokine secreted by Kupffer cells was suppressive. CONCLUSIONS: Sinusoidal endothelial cells carry functional B7-2 molecules and can serve as effective antigen-presenting cells. However, antigen presentation by sinusoidal endothelial cells may be locally down-regulated by interleukin 10.

Animals↗
PubMed1988

Beta-glucuronidase and chloroacetate-esterase staining discriminates rat liver sinusoidal endothelial cells from Kupffer cells in primary culture.

Beta-glucuronidase and N-AS-D-chloroacetate esterase cytochemistry have been applied to rat liver sinusoidal endothelial cells and Kupffer cells. Both staining procedures allowed a clear-cut differentiation of either cell type. Kupffer cells which had been stained with beta-glucuronidase showed a positive reaction, whereas sinusoidal endothelial cells were completely negative. If the chloroacetate reaction was used, the former stained diffusely while the latter showed a characteristic granular staining pattern. Identity and purity of sinusoidal endothelial cells and Kupffer cells was validated by transmission and scanning electron microscopy as well as by the pattern of released eicosanoids which is characteristic for either cell type. These two staining techniques are a valuable addition to the peroxidase reaction commonly applied for differentiation.

Animals↗
PubMed1985

In vitro antiviral properties of endotoxin-activated rat Kupffer cells.

Kupffer cells isolated from the liver of normal rats were checked for their antiviral activities. The intrinsic antiviral effect against vaccinia virus was high whether the cells were activated in vitro with endotoxin or not. The expression of the extrinsic antiviral activity measured by mixing isolated Kupffer cells with vaccinia-virus-infected target cells was remarkably enhanced by prior treatment of the Kupffer cells with LPS. Interferon was shown to be not responsible for that inhibitory activity. Different experimental data suggest that the virus replication in the target cells is blocked at a late stage in the replication cycle.

Animals↗
PubMed2001

Induction of Fas and Fas ligand expression on malignant glioma cells by Kupffer cells, a potential pathway of antiliver metastases.

Kupffer cells play an important role in controlling the growth and development of liver metastases. However, the pathway of Kupffer cells against tumor metastases is not clear. In the present study, we set up an experimental model to investigate the mechanisms on how Kupffer cells kill tumor cells which metastasize to the liver. Malignant glioma cells were cocultured with Kupffer cells or treated with culture medium collected from lipopolysaccharide (LPS)-activated Kupffer cells. The results showed that the interaction between Kupffer cells and malignant glioma cells significantly stimulated the generation of tumor necrosis factoralpha (TNFalpha). TNFalpha was mainly produced by Kupffer cells, as its level in culture medium obtained from LPS-treated Kupffer cells was not significantly different from that of malignant glioma cells treated with the same medium. Both Kupffer cells and LPS/Kupffer cell-conditioned supernatants induced expression of Fas and Fas ligand on malignant glioma cells. Subsequently a significant proportion of malignant glioma cells became apoptotic, as evidenced by positive staining of annexin V and propidium iodine and an increase in cellular DNA fragmentation. Therefore, this study supports a novel pathway of Kupffer cells against liver metastases, in which tumor cells were apoptotic via the Fas-Fas ligand system induced by TNFalpha released from Kupffer cells.

Animals↗
PubMed1982

Involvement of prostaglandin E and adenosine 3', 5'-monophosphate in lipopolysaccharide-stimulated collagenase release by rat Kupffer cells.

Kupffer cells exposed to bacterial lipopolysaccharide in vitro synthesized collagenase and released the major portion of it into the extracellular space while the intracellular level of enzyme was not altered significantly. Cycloheximide prevented the appearance of collagenase in the medium indicating de novo synthesis. Indomethacin, an inhibitor of cyclooxygenase, also blocked collagenase synthesis. In line with this observation. Kupffer cells were found to synthesize substantial amounts of prostaglandin E2 when exposed to lipopolysaccharide; concomitantly, cellular cAMP levels were increased. Indomethacin was shown to abolish the stimulated cAMP formation. Addition to the culture medium of cAMP or dibutyryladenosine 3', 5'-monophosphate as well as of prostaglandin E2 or, to a lesser extent, prostaglandin E1 allowed indomethacin-inhibited cells to resume the production of collagenase. It is proposed that in rat Kupffer cells lipopolysaccharide-elicited collagenase synthesis and excretion is mediated sequentially by stimulated production of prostaglandin E2, enhanced adenylate cyclase activity and increased intracellular cAMP levels.

Animals↗
PubMed2004

Uptake characteristics of mannosylated and fucosylated bovine serum albumin in primary cultured rat sinusoidal endothelial cells and Kupffer cells.

The purpose of this study is to delineate uptake characteristics of mannosylated and fucosylated proteins in primary cultured sinusoidal endothelial cells and Kupffer cells. In cultured sinusoidal endothelial cells, uptake of mannosylated and fucosylated bovine serum albumin (BSA) was significantly inhibited by excess mannosylated and fucosylated BSAs but not by galactosylated BSA, suggesting that both glycosylated proteins might be primarily taken up via mannose receptors. In cultured Kupffer cells, uptake of fucosylated BSA was significantly inhibited by excess galactosylated BSA as well as mannosylated and fucosylated BSAs, although that of mannosylated BSA was inhibited only by mannosylated and fucosylated BSAs. This suggests that uptake of fucosylated BSA by Kupffer cells might be mediated by both Kupffer cell lectin (fucose receptor) and mannose receptor. On the other hand, in vivo hepatic uptake of fucosylated BSA was inhibited to a greater extent by GdCl3 pretreatment than that of mannosylated BSA. Based on in vitro and in vivo experiments, it was concluded that fucosylated BSA is more Kupffer cell-selective because it exhibited a lower sinusoidal endothelial cell uptake than mannosylated BSA.

Animals↗
PubMed2006

Histopathological characteristics of Ito cells and Kupffer cells in the feline liver.

The histopathological characteristics of Ito cells and Kupffer cells were investigated in the liver of 21 cats (age range: 6 months -18 years) autopsied in our laboratory during 2003. Immunohistochemical examinations were performed using antibodies against lysozyme, desmin and alpha-smooth muscle actin. No Kupffer cells reacted with the antibody against lysozyme. However, macrophages in the lung and spleen showed a positive reaction with the antibody. This finding suggests a possibility that the amount of lysozyme in the Kupffer cells of feline liver is comparatively small. On the other hand, large vacuole-laden cells were observed in the hepatic perisinusoid of some feline cases, and these cells showed a positive reaction with antibodies against desmin and alpha-smooth muscle actin. These cells could be Ito cells with large lipid vacuoles. This conclusion was supported by electron microscopic observation and oil red O staining. However, no such large vacuole-laden perisinusoidal cells were detected in the liver of young cats less than 2 years old. The present study revealed the histopathological features of Kupffer cells and Ito cells in the feline liver.

Actins↗
PubMed1998

Effect of antioxidants, resveratrol, quercetin, and N-acetylcysteine, on the functions of cultured rat hepatic stellate cells and Kupffer cells.

Effects of antioxidants, resveratrol, quercetin, and N-acetylcysteine (NAC) on the functions of cultured rat hepatic stellate cells and Kupffer cells were studied. These compounds dose-dependently suppressed serum-dependent proliferation of stellate cells as determined by [3H]thymidine and 5-bromo-2'-deoxyuridine uptake. Expression of smooth muscle alpha-actin was suppressed by a high dose of resveratrol and quercetin. These phenolic compounds also suppressed inositol phosphate metabolism, tyrosine phosphorylation, and mitogen-activated protein (MAP) kinase activation in platelet-derived growth factor/BB-stimulated stellate cells. Moreover, the phenolic compounds selectively reduced the level of cell cycle protein cyclin D1 in stellate cells. Thus, resveratrol and quercetin might inhibit stellate cell activation by perturbing signal transduction pathway and cell cycle protein expression, whereas mechanism of potent antiproliferative effect of NAC remains to be elucidated. On the other hand, kinetic analysis showed that production of nitric oxide (NO) and tumor necrosis factor alpha (TNF-alpha) by lipopolysaccharide-stimulated Kupffer cells was strongly inhibited by resveratrol and quercetin but not by NAC. Although expression of messenger RNAs for inducible NO synthase and TNF-alpha was not affected by the phenolic compounds, cellular levels of inducible NO synthase and TNF-alpha secretion were suppressed significantly, indicating the posttranscriptional process of generating these proteins might be affected predominantly by these phenolic compounds. Thus, NAC and these phenolic compounds may have therapeutic potential against liver injury by regulating functions of hepatic stellate cells and Kupffer cells.

Actins↗
PubMed1984

In vitro cytostatic properties of unactivated rat Kupffer cells.

Kupffer cells from the liver of normal rats were checked for their natural cytostatic capabilities using an in vitro target cell growth inhibition assay. A strong cytostatic effect was observed on an human tumor cell line and was shown to be exerted on various transformed or normal target cells with only small differences in their susceptibility. The inhibition of target cell proliferation was shown to depend on the effector/target cell ratio. Different experimental data suggest that an intimate membranal contact between Kupffer cells and target cells is required.

Animals↗
PubMed1980

Analysis of lectin-dependent recognition of desialylated erythrocytes by Kupffer cells.

Kupffer cells isolated from the rat liver are able to bind neuraminidase-treated rat erythrocytes via a D-galactose-specific receptor on the cell surface. Binding of desialylated erythrocytes was inhibited by several mono- and oligo-saccharides related to D-galactose, but not by unrelated sugars. However, after phosphorylation at position 6 D-glucose was as good an inhibitor as D-galactose. Two synthetic glycoproteins, D-galactosyl-albumin and, at a higher concentration, D-glucosyl-albumin, strongly inhibit cell contacts. Lectin-mediated binding of desialylated erythrocytes is dependent on the presence of Ca2'ons, but independent of ATP formation and cell motility. It is concluded that binding of desialylated erythrocytes by rat Kupffer cells is mediated by a Ca2-dependent D-galactosyl/D-glucosyl-recognition system.

Animals↗
PubMed2002

Redox regulation of cytokine expression in Kupffer cells.

Kupffer cells, resident macrophages in the liver, play a central role in the homeostatic response to liver injury. Ironically, this defensive mechanism, if dysregulated, also works against the liver in acute and chronic liver damage. Central to this response is activation of nuclear factor-kappaB (NF-kappaB), a redox-sensitive transcription factor that transactivates promoters of many inflammatory genes, including cytokines. Much research has been devoted to identification of upstream signaling for activation of NF-kappaB, but the precise mechanism by which oxidant stress participates in this signaling is yet to be determined. Clues to this key question may be attained through studies on the mechanisms of sustained and/or accentuated NF-kappaB activation in hepatic macrophages in chronic liver diseases. This article reviews the literature on redox regulation of cytokine gene expression by Kupffer cells.

Animals↗
PubMed2004

Interactions between rat colon carcinoma cells and Kupffer cells during the onset of hepatic metastasis.

Liver sinusoids harbor populations of 2 important types of immunocompetent cells, Kupffer cells (KCs) and natural killer (NK) cells, which are thought to play an important role in controlling hepatic metastasis in the first 24 hr upon arrival of the tumor cells in the liver. We studied the early interaction of KCs, NK and CC531s colon carcinoma cells in a syngeneic rat model by confocal laser scanning microscopy. Results showed a minority of KCs (19% periportal and 7% pericentral) involved in the interaction with 94% of tumor cells and effecting the phagocytosis of 92% of them. NK cell depletion decreased the phagocytosis of tumor cells by KCs by 33% over a period of 24 hr, leaving 35% of the cancer cells free, as compared to 6% in NK-positive rats. Surviving cancer cells were primarily located close to the Glisson capsule, suggesting that metastasis would initiate from this region.

Animals↗
PubMed1984

Preparation of isolated liver endothelial cells and Kupffer cells in high yield by means of an enterotoxin.

A new method for preparing non-parenchymal rat liver cells (NPC) is described. The liver cell suspension, prepared by perfusing the liver with collagenase, was treated with enterotoxin from Clostridium perfringens for 15 min. The enterotoxin made the parenchymal cells leaky, and these cells could be separated from the NPC by centrifugation in a solution containing Nycodenz (20%, w/v). During the centrifugation, the NPC floated, while the parenchymal cells sedimented. The yield of NPC per liver (200 g rat) was about 250 X 10(6) cells. The NPC were further separated into endothelial cells, Kupffer cells and stellate cells by centrifugal elutriation. This method was particularly useful for preparing endothelial cells in high yield (100 X 10(6) cells per liver). Intravenously injected formaldehyde-treated albumin was selectively taken up by the endothelial cells. Isolated endothelial cells in suspension as well as in surface culture maintained their ability to endocytose this ligand.

Animals↗
PubMed2000

Peroxisome proliferator-activated receptor alpha is restricted to hepatic parenchymal cells, not Kupffer cells: implications for the mechanism of action of peroxisome proliferators in hepatocarcinogenesis.

Peroxisome proliferators increase hepatocyte proliferation and cause liver tumors in rodents, yet the mechanism of action is not understood. Based on studies with null mice it is known that peroxisome proliferator-activated receptor-alpha (PPARalpha) is involved. There is also evidence that Kupffer cells play a central role in peroxisome proliferator-induced carcinogenesis, most likely via mechanisms involving increases in superoxide, activation of nuclear factor kappaB and production of tumor necrosis factor-alpha (TNFalpha). However, it is not known whether PPARalpha is constitutively expressed in Kupffer cells. Therefore, the expression of PPAR isoforms in rat Kupffer and parenchymal cells was examined. Kupffer cells and hepatocytes of >99% purity were isolated from rats fed either a control diet or one containing 0.1% WY-14,643 for 1 week. Protein and RNA were obtained and PPAR expression was analyzed using northern and western blots. PPARalpha, PPARbeta and PPARgamma mRNA was detected in purified hepatocytes. In Kupffer cells, mRNA encoding PPARgamma was present while transcripts for PPARalpha and PPARbeta were not detected. Immunoblots were consistent with the results found by northern analysis. Moreover, when Kupffer cells from wild-type or PPARalpha-null mice were treated with WY-14,643 in vitro, superoxide production was similar. Combined, these results show that PPARalpha is expressed in rat parenchymal cells but not in Kupffer cells. These data are consistent with the hypothesis that parenchymal cells respond to Kupffer cell-derived TNFalpha via mechanisms dependent on PPARalpha within the parenchymal cells.

Animals↗
PubMed1989

Comparison of sulphated glycosaminoglycan and hyaluronate synthesis and secretion in cultured hepatocytes, fat storing cells, and Kupffer cells.

The extracellular matrix of normal liver contains several types of proteoglycans including heparan sulphate, chondroitin sulphate isomers, dermatan sulphate, and the glycosaminoglycan, hyaluronic acid. In the present study both the synthesis and secretion as well as the pattern of radioactively labeled proteoglycans and hyaluronic acid of hepatocytes, fat-storing cells (Ito cells), and Kupffer cells maintained in monolayer cultures under mostly identical conditions were compared to assess their relative contribution to hepatic proteoglycan synthesis. Fat-storing cells were identified as the main type of cell producing and secreting proteoglycan and hyaluronic acid. More than 70% of labeled proteoglycan and hyaluronic acid were secreted into the medium. Heparan sulphate is the main type of proteoglycan in hepatocytes, whereas in the medium of fat-storing cells, chondroitin sulphate and dermatan sulphate comprise the major fractions. Hyaluronic acid was not detectable in hepatocyte cultures and found only in low amounts in the medium of Kupffer cells. The results point to a stringent quantitative and qualitative cellular compartmentation of proteoglycan synthesis in liver with fat-storing cells as the most important cell type for matrix proteoglycan and hyaluronic acid production.

Adipose Tissue↗