Effects of Hepatocyte CD14 Upregulation during Cholestasis on Endotoxin Sensitivity

Chou, Ming-Huei; Chuang, Jiin‐Haur; Eng, Hock‐Liew; Tsai, Po-Chin; Hsieh, Chih-Sung; Liu, Hsiang-Chun; Wang, Chiou-Huey; Lin, Chih-Min; Lin, Tzu-Chao

doi:10.1371/journal.pone.0034903

Cited by 11 publications

(9 citation statements)

References 35 publications

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“…In addition, CD14 has been found to be expressed in an LPS-inducible manner in Kupffer cells and sinusoidal endothelial cells (34). Consistent with our observations, a previous study revealed that hepatic CD14 upregulation led to increased endotoxin sensitivity and host proinflammatory reactions, causing organ failure and mortality in a rat model of cholestasis (34,35). In addition, it has been hypothesized that the high levels of CD14 expression observed in Kupffer cells may increase proinflammatory responses and lead to increased endotoxin-induced mortality (36).…”

Section: Discussionsupporting

confidence: 93%

Sphingosine kinase-1 mediates endotoxemia-induced hyperinflammation in aged animals

Lufrano

Jacob

Zhou

et al. 2013

Molecular Medicine Reports

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Sepsis is a serious issue in the geriatric population due to its association with high mortality rates in the elderly. The increase in mortality in the elderly correlates with inflammation. We have previously demonstrated that the inflammatory response is exacerbated in a rodent endotoxemia model of sepsis in aged rats compared with young rats. However, the molecular mediators associated with this hyperinflammatory response in aged rats have not been completely determined. Sphingosine kinase-1 (Sphk-1), an enzyme present in neutrophils and macrophages, regulates proinflammatory responses associated with endotoxemia and sepsis. To determine whether Sphk-1 is a molecular mediator associated with the observed hyperinflammatory response in aging, Sphk-1 mRNA expression was examined in hepatic tissues of young and aged rats subjected to endotoxemia. A significant increase in Sphk-1 mRNA was observed in endotoxemic aged rats compared with young rats. This increase was correlated with a significant increase in TNF-α mRNA levels in the liver. CD14 is a receptor component for lipopolysaccharide (LPS) and therefore, CD14 mRNA expression in hepatic tissues of endotoxemic young and aged rats was examined. Of note, CD14 mRNA was significantly upregulated in endotoxemic aged rats. Sphk-1 mRNA expression was significantly elevated in LPS-treated Kupffer cells and this increase correlated with an increase in CD14 mRNA expression. Results of the present study indicated that increased Sphk-1 expression in the liver in response to endotoxemia mediates the hyperinflammatory state observed in aged animals.

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Section: Discussionsupporting

confidence: 93%

Sphingosine kinase-1 mediates endotoxemia-induced hyperinflammation in aged animals

Lufrano

Jacob

Zhou

et al. 2013

Molecular Medicine Reports

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“…LPS binds to TLR4 and transduces subsequent signals that lead to upregulation of the inflammatory response (2,18). As was observed in previous studies, we demonstrated an upregulation of TLR4 in the liver after 1 wk of BDL (4,16,18). Immunostaining revealed strong TLR4 expression along the sinusoid in the BDL group (Fig.…”

Section: Discussionsupporting

confidence: 86%

Inhibition of Toll-like receptor 4 suppresses liver injury induced by biliary obstruction and subsequent intraportal lipopolysaccharide injection

Oya

Yokoyama

Kokuryo

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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Oya S, Yokoyama Y, Kokuryo T, Uno M, Yamauchi K, Nagino M. Inhibition of Toll-like receptor 4 suppresses liver injury induced by biliary obstruction and subsequent intraportal lipopolysaccharide injection. Am J Physiol Gastrointest Liver Physiol 306: G244 -G252, 2014. First published December 19, 2013 doi:10.1152/ajpgi.00366.2013The objective of this study was to elucidate the role of Toll-like receptor 4 (TLR4) in liver injury induced by biliary obstruction and subsequent intraportal lipopolysaccharide (LPS) infusion in rats. Biliary obstruction often leads to the development of bacterial translocation. Rats were subjected to either a sham operation (Sham group) or bile duct ligation for 7 days (BDL group). Seven days after each operation, LPS (0.5 g) was injected through the ileocecal vein. In other experiments, rats that had undergone BDL were pretreated, before LPS challenge, with internal biliary drainage (Drainage group); intravenous TAK-242, a TLR4 inhibitor (TAK group); or intravenous GdCl3, a Kupffer cell deactivator (GdCl3 group). The expression of the TLR4 protein and the number of Kupffer cells in the liver were significantly increased in the BDL group compared with the Sham group. These changes were normalized after biliary drainage. The expression of TLR4 colocalized with Kupffer cells, which was confirmed by double immunostaining. Serum levels of liver enzymes and proinflammatory cytokines after intraportal LPS injection were significantly higher in the BDL group than in the Sham group. However, pretreatment with TAK-242 or GdCl 3 strongly attenuated these changes to levels similar to those seen with biliary drainage. These results imply that blocking TLR4 signaling effectively attenuates liver damage to the same level as that observed with biliary drainage in rats with BDL and subsequent intraportal LPS infusion. TAK-242 treatment may be used for patients who are susceptible to liver damage by biliary obstruction and endotoxemia. bile duct ligation; bacterial translocation; TAK-242; biliary drainage; Kupffer cell PATIENTS WITH CHOLANGIOCARCINOMA or pancreatic head cancer often develop biliary obstruction. Biliary obstruction leads to impaired intestinal barrier function and the translocation of enteric bacteria to the systemic circulation (10, 26, 31). Thus, patients with biliary obstruction are susceptible to septic complications not only with cholangiovenous reflux but also with increased bacterial translocation (BT) from the gut to the systemic circulation (1,11,21). Severe liver damage has been shown using a model of biliary obstruction [bile duct ligation (BDL)] followed by endotoxin challenge by duodenal, intravenous, or intraperitoneal lipopolysaccharide (LPS) administration (2, 6, 18). However, no study has ever administered LPS through portal circulation (which mimics the conditions of BT) in BDL rats.A previous report demonstrated that intraportal LPS administration induces severe liver injury via Toll-like receptor 4 (TLR4) activation on Kupffer cells and the production of excessive a...

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“…Third, using liver biopsy as the ‘gold standard’ for assessing the accuracy of sCD14 has important limitations associated with sampling errors, as well as intra- and inter-observer variability, which are at least partly linked to the biopsy size [32]. Finally, serum sCD14 levels may increase in other conditions such as cholestasis, biliary atresia, and ischemia reperfusion injury [35]–[36]. However, these are extremely unusual conditions.…”

Section: Discussionmentioning

confidence: 99%

Soluble CD14 Levels Reflect Liver Inflammation in Patients with Nonalcoholic Steatohepatitis

et al. 2013

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Background & AimsLiver inflammation is a risk factor for the progression of nonalcoholic fatty liver disease (NAFLD). However, the diagnosis of liver inflammation is very difficult and invasive liver biopsy is still the only method to reliably detect liver inflammation. We previously reported that overexpression of CD14 in Kupffer cells may trigger the progression to nonalcoholic steatohepatitis (NASH) via liver inflammation following hyper-reactivity to low-dose lipopolysaccharide. Therefore, the aim of this study was to investigate the relationship between soluble type of CD14 (sCD14) and histological features in patients with NAFLD.MethodsOur cohort consisted of 113 patients with liver biopsy-confirmed NAFLD and 21 age-matched healthy controls. Serum sCD14 levels were measured by an enzyme-linked immunosorbent assay.ResultsSerum sCD14 levels were significantly associated with diagnosis of NASH and the area under the receiver operator characteristic curve (AUROC) to distinguish between not NASH and NASH was 0.802. Moreover, serum sCD14 levels were significantly associated with the disease activity based on NAFLD activity score and hepatic CD14 mRNA expression, which is correlated with membrane CD14 (mCD14) expression, in patients with NAFLD. In multiple regression analysis, the serum sCD14 levels were independently associated with liver inflammation. The AUROC to distinguish between mild and severe liver inflammation in patients with NAFLD was 0.752.ConclusionsWe found that serum sCD14 levels increased significantly with increasing liver inflammation grade in patients with NAFLD, reflecting increased hepatic CD14 expression. Serum sCD14 is a promising tool to predict the worsening of liver inflammation, and may offer a potential biomarker for evaluation of therapeutic effects in NAFLD.

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Effects of Hepatocyte CD14 Upregulation during Cholestasis on Endotoxin Sensitivity

Cited by 11 publications

References 35 publications

Sphingosine kinase-1 mediates endotoxemia-induced hyperinflammation in aged animals

Sphingosine kinase-1 mediates endotoxemia-induced hyperinflammation in aged animals

Inhibition of Toll-like receptor 4 suppresses liver injury induced by biliary obstruction and subsequent intraportal lipopolysaccharide injection

Soluble CD14 Levels Reflect Liver Inflammation in Patients with Nonalcoholic Steatohepatitis

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