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

Su, Grace L.; Goyert, Sanna M.; Fan, Min; Aminlari, Alireza; Gong, Ke; Klein, Richard; Myc, Andrzej; Alarcon, William H.; Steinstraesser, Lars; Remick, Daniel G.; Wang, Stewart C.

doi:10.1152/ajpgi.00253.2001

Cited by 82 publications

(70 citation statements)

References 34 publications

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“…29 Although our inability to extend the conclusion on LPS response from bone marrow macrophages directly to liver KC represents a limitation, it has recently been shown that KC do express functional TLR4 (including CD14 and MD2) and respond to LPS in a fashion similar to other macrophage populations. 30,31 Conversely, the use of in vitro macrophage/hepatoma cell culture systems broaden the significance of our findings and allowed study of TLR4-dependent events in well-defined liver cell substitutes rather than in native liver cells that have been exposed to prolonged and often harmful ex vivo separation procedures. Although macrophage-hepatoma cell culture experiments support our hypothesis, KC-hepatocyte interactions in vivo still need to be evaluated in future studies.…”

Section: Discussionmentioning

confidence: 88%

Type I, but not type II, interferon is critical in liver injury induced after ischemia and reperfusion

et al. 2007

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We have documented the key role of toll-like receptor 4 (TLR4) activation and its signaling pathway mediated by interferon (IFN) regulatory factor 3, in the induction of inflammation leading to the hepatocellular damage during liver ischemia/reperfusion injury (IRI). Because type I IFN is the major downstream activation product of that pathway, we studied its role in comparison with IFN-␥. Groups of type I (IFNAR), type II (IFNGR) IFN receptordeficient mice, along with wild-type (WT) controls were subjected to partial liver warm ischemia (90 minutes) followed by reperfusion (1-6 hours). Interestingly, IFNAR knockout (KO) but not IFNGR KO mice were protected from IR-induced liver damage, as evidenced by decreased serum alanine aminotransferase and preservation of tissue architecture. IRtriggered intrahepatic pro-inflammatory response, assessed by tumor necrosis factor (TNF-␣), interleukin 6 (IL-6), and chemokine (C-X-C motif) ligand 10 (CXCL-10) expression, was diminished selectively in IFNAR KO mice. Consistent with these findings, our in vitro cell culture studies have shown that: (1) although hepatocytes alone failed to respond to lipopolysaccharide (LPS), when co-cultured with macrophages they did respond to LPS via macrophage-derived IFN-␤; (2) macrophages required type I IFN to sustain CXCL10 production in response to LPS. This study documents that type I, but not type II, IFN pathway is required for IR-triggered liver inflammation/damage. Type I IFN mediates potential synergy between nonparenchyma and parenchyma cells in response to TLR4 activation. (HEPATOLOGY 2008;47:199-206.) L iver ischemia/reperfusion injury (IRI) occurs in multiple clinical settings including surgical interventions, trauma, and transplantation. 1-3 The mechanisms underlying liver IRI are complex but are known to involve interactions between both nonparenchyma cells, such as Kupffer cells (KC), and parenchyma cells, such as hepatocytes. Local leukocyte sequestration and activation (neutrophils, macrophages, and T cells) leads to the formation of reactive oxygen species, secretion of pro-inflammatory cytokines/chemokines, complement activation, and vascular cell adhesion molecule activation. Because IRI develops in the absence of exogenous antigens, it has been considered as an innate immune-mediated pro-inflammatory response.It was demonstrated that the mammalian sentinel tolllike-receptor (TLR) system plays a critical role in the development of IRI. 4-7 Indeed, TLR4 activation proved essential in the induction of inflammation in a warm liver IRI mouse model. In the absence of TLR4 but not TLR2 signaling, livers were protected from IRI, and intrahepatic induction of tumor necrosis factor (TNF-␣) and interleukin 1 (IL-1␤) was abolished. 7 It was also shown, by using bone marrow chimeras, that TLR4 expression on hematopoietic rather than parenchyma cells was instrumental in promoting liver IR-mediated damage. 8 TLR4 activation triggers 2 distinct signaling pathways leading to the induction of different immune-related genes. The MyD88...

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Section: Discussionmentioning

confidence: 88%

Type I, but not type II, interferon is critical in liver injury induced after ischemia and reperfusion

et al. 2007

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“…Cell isolation was carried out using a modified version of the method described by Knook (20)(21)(22). Briefly, rats were anesthetized with an intraperitoneal injection of sodium pentobarbital.…”

Section: Isolation Of Hepatocytes and Kupffer Cellsmentioning

confidence: 99%

Lipoxin A4 exerts protective effects against experimental acute liver failure by inhibiting the NF-κB pathway

Jiang

Jiang³

et al. 2016

International Journal of Molecular Medicine

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Abstract.Although rare, acute liver failure (ALF) is associated with high levels of mortality, warranting the development of novel therapies. Nuclear factor-κB (NF-κB), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) play roles in ALF. Lipoxin A4 (LXA4) has been shown to alleviate inflammation in non-hepatic tissues. In the present study, we explored whether LXA4 exerted hepatoprotective effects in a rat model of ALF. A rat model of ALF was generated by intraperitoneal injections of D-galactosamine (300 mg/kg) and lipopolysaccharide (50 µg/kg). Animals were randomly assigned to: control group (no ALF); model group (ALF); and the groups treated with a low dose (0.5 µg/kg), medium dose (1 µg/kg), and high dose (2 µg/kg) of LXA4 (all with ALF); and pyrrolidine dithiocarbamate (PDTC)-treated group (ALF and 100 mg/kg PDTC, an inhibitor of NF-κB). Liver histology was measured using H&E staining, serum levels by ELISA, and liver mRNA expression was measured by RT-PCR for the detection of the pro-inflammatory cytokines TNF-α and IL-6. Liver cell apoptosis (as measured using the TUNEL method and examining caspase-3 activity), and Kupffer cell NF-κB activity [using an electrophoretic mobility shift assay (EMSA)] were examined. Serum levels of transaminases, TNF-α and interleukin-6 (IL-6) were substantially higher in the model group compared to controls. In the model group, significant increases in TNF-α and IL-6 mRNA expression, TUNEL-positive cells, and caspase-3 activity in the liver tissue were noted. LXA4 improved liver pathology and significantly decreased the indicators of inflammatory response and apoptosis in a dose-dependent manner. High-dose LXA4 provided better protection than PDTC. LXA4 administration significantly decreased NF-κB expression in hepatocytes and Kupffer cells. These results indicated that LXA4 inhibited NF-κB activation, reduced the secretion of pro-inflammatory cytokines, and inhibited apoptosis of liver cells, thereby exerting protective effects against ALF.

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“…5 In other forms of liver injury such as alcohol-induced injury, Kupffer cells mediate injury following activation by endogenous lipopolysaccharides (LPSs) and gut bacteria. 6,7 Because LBP has been found to be an important mediator in the LPS activation of Kupffer cells, 8,9 we sought to examine the role of LBP in acetaminophen-induced hepatotoxicity.…”

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confidence: 99%

Lipopolysaccharide-binding protein modulates acetaminophen-induced liver injury in mice

Gong

Fan

et al. 2005

Hepatology

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Acetaminophen toxicity is the most common cause of acute liver failure in the United States and Europe. Although much is known about the metabolism of acetaminophen, many questions remain regarding the pathogenesis of liver injury. In this study, we examined the role of lipopolysaccharide-binding protein (LBP), a protein important in mediating cellular response to lipopolysaccharides, by using LBP wild-type and knockout (KO) mice. We found that LBP KO mice were protected from acetaminophen-induced hepatotoxicity. At 350 mg/kg of acetaminophen, LBP KO mice had significantly less liver injury and necrosis than wild-type mice. Repletion studies in LBP KO mice using an LBP-adenoviral construct resulted in significantly more hepatic injury and necrosis after acetaminophen exposure compared with mice receiving the control adenoviral construct. In conclusion, LBP KO mice are protected from toxicity with a decrease in hepatic necrosis following acetaminophen challenge. This suggests a novel role for LBP in modulating acetaminophen-induced liver injury. Supplementary material for this article can be found on the HEPATOLOGY website

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

Cited by 82 publications

References 34 publications

Type I, but not type II, interferon is critical in liver injury induced after ischemia and reperfusion

Type I, but not type II, interferon is critical in liver injury induced after ischemia and reperfusion

Lipoxin A4 exerts protective effects against experimental acute liver failure by inhibiting the NF-κB pathway

Lipopolysaccharide-binding protein modulates acetaminophen-induced liver injury in mice

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