Obstructive jaundice in rats results in exaggerated hepatic production of tumor necrosis factor-alpha and systemic and tissue tumor necrosis factor-alpha levels after endotoxin

O'Neil, Stephen; Hunt, J.; Filkins, James P.; Gamelli, Richard L.

doi:10.1016/s0039-6060(97)90019-2

Cited by 41 publications

(26 citation statements)

References 11 publications

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“…After BDL, TFF3 mRNA expression in IL-6 ϩ/ϩ mice livers was down-regulated and remained at low levels until 3 weeks (data not shown), consistent with the up-regulation of TNF-␣, HGF, and TGF-␤ during this time, as reported in previous studies. 6,19,20 However, between 7 and 12 weeks after BDL, TFF3 mRNA levels in the IL-6 ϩ/ϩ mice livers returned to near baseline levels (Figure 6A). In contrast, IL-6 Ϫ/Ϫ mice livers showed a slight, but statistically significant up-regulation of TFF3 mRNA between 3 to 7 weeks compared to baseline levels in the IL-6 Ϫ/Ϫ mice.…”

Section: Dynamic Changes Of Tff3 Expression After Bdl and Impaired Exmentioning

confidence: 97%

“…Isolating the BECs in culture also removes potential confounding paracrine influences of other growth factors and cytokines that are produced by peribiliary stromal and hematopoietic cells after BDL in vivo. 6,19,20 Examples include TNF-␣, HGF, and TGF-␤, which are not produced or differentially regulated by BECs under this condition (data not shown), but can significantly decrease TFF3 expression. 21 Finally however, the dynamic regulation of TFF3 mRNA and protein expression was studied in relationship to STAT3 and MAPK signaling, in vivo, using a chronic BDL model in IL-6 ϩ/ϩ and IL-6 Ϫ/Ϫ mice.…”

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confidence: 88%

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Regulation and Function of Trefoil Factor Family 3 Expression in the Biliary Tree

Nozaki

Lunz

Specht

et al. 2004

The American Journal of Pathology

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Microarray analysis identified trefoil factor family 3 (TFF3) as a gene expressed in biliary epithelial cells (BECs), regulated by interleukin (IL)-6, and potentially involved in biliary pathophysiology. We therefore studied the regulation and function of BEC TFF3, in vitro and in vivo in IL-6 ؉/؉ and IL-6 ؊/؊ mice subjected to chronic bile duct ligation for 12 weeks. In vitro studies showed that IL-6 wild-type (IL-6 ؉/؉ ) BECs expressed higher TFF3 mRNA and protein levels than IL-6-deficient (IL-6 ؊/؊ ) BECs. BEC TFF3 expression is dependent primarily on signal transducer and activator of transcription (STAT3) signaling, but the reciprocal negative regulation known to exist between the intracellular IL-6/gp130 signaling pathways, STAT3 and mitogen-activated protein kinase (MAPK), importantly contributes to BEC TFF3 expression. Specifically blocking STAT3 activity with a dominant-negative molecule or treatment with a growth factor such as hepatocyte growth factor, which increases MAPK signaling, decreases BEC TFF3 expression. In contrast, specifically blocking MAPK activity with PD98059 significantly increased BEC TFF3 expression. Higher BEC TFF3 levels in IL-6 ؉/؉ BECs were associated with significantly better migration than IL-6 ؊/؊ BECs in a wound-healing assay and defective IL-6 ؊/؊ BEC migration was reversed with exogenous TFF3. In vivo, hepatic TFF3 mRNA and protein expression was limited to BECs and dependent significantly on STAT3 signaling, but was influenced by other factors present after bile duct ligation. Com-

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Section: Dynamic Changes Of Tff3 Expression After Bdl and Impaired Exmentioning

confidence: 97%

mentioning

confidence: 88%

Regulation and Function of Trefoil Factor Family 3 Expression in the Biliary Tree

Nozaki

Lunz

Specht

et al. 2004

The American Journal of Pathology

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“…Numerous experimental studies have demonstrated a profound proinflammatory response following endotoxin challenge, which is marked by an increased production of tumor necrosis factor (TNF)-␣, interleukin (IL)-1, and IL-6 in animals with biliary obstruction (9,14,17,18,28). This proinflammatory milieu is associated with increased markers of end organ injury [aspartate aminotransferase (AST) and creatinine] and death (14), and blockade of this response through the administration of gadolinium chloride has been shown to suppress the systemic proinflammatory response leading to improved survival (18,24).…”

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confidence: 99%

LPS-binding protein mediates LPS-induced liver injury and mortality in the setting of biliary obstruction

Minter¹,

Bi²,

Ben-Josef³

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

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GL. LPS-binding protein mediates LPS-induced liver injury and mortality in the setting of biliary obstruction. Am J Physiol Gastrointest Liver Physiol 296: G45-G54, 2009. First published October 23, 2008 doi:10.1152/ajpgi.00041.2008.-It is generally accepted that low levels of lipopolysaccharide (LPS)-binding protein (LBP) augment the cell's response to LPS, whereas high levels of LBP have been shown to inhibit cell responses to LPS. Clinical studies and in vitro work by our group have demonstrated that, in the setting of liver disease, increased or acute-phase levels of LBP may actually potentiate rather than inhibit an overwhelming proinflammatory response. Therefore, in the present studies we sought to determine the role of acute-phase LBP in mediating morbidity and mortality in animals challenged with LPS in the setting of biliary obstruction. Using LBP-deficient mice and LBP blockade in wild-type mice, we demonstrate that high levels of LBP are deleterious in the setting of cholestasis. Following biliary obstruction and intraperitoneal LPS challenge, hepatic injury, hepatic neutrophil infiltration, and mortality were significantly increased in animals with an intact LBP acute-phase response. Kupffer cell responses from these animals demonstrated a significant increase in several inflammatory mediators, and Kupffer cell-associated LBP appears to be responsible for these differences, at least in part. Our results indicate that the role of LBP signaling in inflammatory conditions is complex and heterogeneous, and elevated levels of LBP are not always protective. Increased LBP production in the setting of cholestatic liver disease appears to be deleterious and may represent a potential therapeutic target for preventing overwhelming inflammatory responses to LPS in this setting.

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“…9 In addition, cholestasis is associated with enhanced susceptibility toward endotoxin-induced toxicity. [9][10][11][12][13][14] Endotoxin exerts its biological effects by activating immunocompetent cells such as monocytes and macrophages. After exposure to endotoxin, these cells readily release various inflammatory mediators such as the cytokines tumor necrosis factor (TNF) and interleukin-1 (IL-1), 15 which leads to an inflammatory response.…”

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Interleukin-1 receptor type I gene-deficient bile duct-ligated mice are partially protected against endotoxin

et al. 2002

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Cholestatic liver injury is associated with an increased susceptibility toward endotoxininduced toxicity. To determine the role of interleukin 1 (IL-1) herein, extrahepatic cholestasis was induced by bile duct ligation (bdl) in IL-1 receptor type I gene-deficient (IL-1R ؊/؊ ) mice, which are unresponsive to IL-1␣ and IL-1␤, and normal IL-1R ؉/؉ mice. Bdl elicited increases in hepatic IL-1␣ and IL-1␤ messenger RNA (mRNA) and protein. Hepatocellular injury at 2 weeks after bdl was similar in IL-1R ؊/؊ and IL-1R ؉/؉ mice as shown by clinical chemistry and histopathology. Administration of endotoxin to cholestatic mice at 2 weeks after bdl was associated with enhanced cytokine release, more severe liver damage, and occurrence of death when compared with sham-operated mice. Endotoxin effects in shamoperated IL-1R ؊/؊ and IL-1R ؉/؉ mice were largely similar, but cholestatic IL-1R ؊/؊ mice were better protected against toxic effects of endotoxin, as reflected by lowered cytokine release, less profound liver injury, and reduced mortality. These data indicate that IL-1␣ and IL-1␤ are produced in the liver after bdl, but that these cytokines do not play a significant role in cholestatic liver damage; however, endogenous IL-1 activity is an important denominator of enhanced endotoxin sensitivity that is observed during cholestasis induced by bdl. S urgery in jaundiced patients with periampullary tumors carries an increased risk of postoperative complications. 1 Whereas in experienced centers, postoperative mortality has been reduced from 20% to 5%, morbidity remains as high as 50%. 2,3 Most complications have a septic etiology and are considered to be related with translocation of endotoxin from the intestinal lumen into the portal and systemic circulation where an inflammatory cascade is triggered. 4,5 Potential causes of translocation of endotoxin include lack of bile salts in the intestinal lumen resulting in increased bacterial translocation, 6,7 decreased function of the resident macrophages of the liver (the Kupffer cells) leading to inadequate interception of endotoxin, 6-8 and changes in plasma concentrations of lipoproteins which bind endotoxin. 9 In addition, cholestasis is associated with enhanced susceptibility toward endotoxin-induced toxicity. [9][10][11][12][13][14] Endotoxin exerts its biological effects by activating immunocompetent cells such as monocytes and macrophages. After exposure to endotoxin, these cells readily release various inflammatory mediators such as the cytokines tumor necrosis factor (TNF) and interleukin-1 (IL-1), 15 which leads to an inflammatory response. The Kupffer cells are also capable of releasing these cytokines in response to endotoxin. 16,17 IL-1␣ and IL-1␤ are pleiotropic proinflammatory cytokines that are considered to play a proximal role in initiation and regulation of the inflammatory cascade triggered in response to endotoxins or bacteremia. 15,18 Both IL-1␣ and IL-1␤ can interact with two specific cell surface receptors, the type I and type II IL-1 receptor (IL-1R), of ...

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Obstructive jaundice in rats results in exaggerated hepatic production of tumor necrosis factor-alpha and systemic and tissue tumor necrosis factor-alpha levels after endotoxin

Cited by 41 publications

References 11 publications

Regulation and Function of Trefoil Factor Family 3 Expression in the Biliary Tree

Regulation and Function of Trefoil Factor Family 3 Expression in the Biliary Tree

LPS-binding protein mediates LPS-induced liver injury and mortality in the setting of biliary obstruction

Interleukin-1 receptor type I gene-deficient bile duct-ligated mice are partially protected against endotoxin

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