Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cell-mediated immunity and macrophage activity, especially that of Kupffer cells, are impaired during cholestasis. Some evidence exists that bile acids play a role in these immune defects. The purpose of this study was to evaluate the effects of individual bile acids on immunity and to determine whether monocytes could be a target. We assessed the effects of chenodeoxycholic acid, an endogenous bile acid, ursodeoxycholic acid, which has been shown to partially correct the immunological abnormalities observed in primary biliary cirrhosis, and their tauroconjugates on the production of interleukin-1, interleukin-6 and tumor necrosis factor-alpha. Chenodeoxycholic acid had a dose-dependent inhibitory effect on interleukin-1 (inhibitory concentration 50% = 60 mumol/L), interleukin-6 (inhibitory concentration 50% = 80 mumol/L) and tumor necrosis factor-alpha (inhibitory concentration 50% = 80 mumol/L) production; inhibition was almost complete at 250 mumol/L. In contrast, ursodeoxycholic acid had lesser or minimal inhibitory effects (inhibitory concentration 50% = 100 mumol/L for interleukin-1 and above 200 mumol/L for interleukin-6 and tumor necrosis factor-alpha). The inhibitory effects of taurochenodeoxy-cholic acid and tauroursodeoxycholic acid were similar to those of chenodeoxycholic acid and ursodeoxycholic acid, respectively. Ursodeoxycholic acid did not reverse the chenodeoxycholic acid-induced inhibition of interleukin-6 or tumor necrosis factor-alpha production. In conclusion, chenodeoxycholic acid exerts strong inhibitory effects on monocyte activity in vitro, whereas the effects of ursodeoxycholic acid are minor.
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PMID:Differential effects of chenodeoxycholic and ursodeoxycholic acids on interleukin 1, interleukin 6 and tumor necrosis factor-alpha production by monocytes. 150 15

The potential effects of cytokines on hepatocellular transport functions remain undefined. Interleukin-6 (IL-6) is a cytokine that is produced in sepsis, hepatitis, and other inflammatory conditions often associated with cholestasis. Using cultured rat hepatocytes, we have investigated the effects of IL-6 on hepatocellular bile salt uptake. Because hepatocyte Na(+)-K(+)-adenosinetriphosphatase (ATPase) produces the electrochemical gradient that drives sodium-dependent bile salt contransport, we also examined the effects of IL-6 on Na(+)-K(+)-ATPase activity. Hepatocytes cultured for 20 h in media containing IL-6 exhibited a dose-dependent noncompetitive inhibition of [3H]taurocholate uptake, which was maximal at an IL-6 dose of 100 U/ml. IL-6 treatment had no effect on hepatocyte sodium-independent taurocholate uptake. Northern blotting of RNA from cultured hepatocytes revealed that IL-6 had no effect on steady-state RNA levels of the Na(+)-taurocholate transporter (Ntcp). Hepatocytes incubated with IL-6 for 20 h, however, exhibited a 55% decrease in hepatocyte Na(+)-K(+)-ATPase activity. This effect also was dose dependent, with maximal inhibition occurring at an IL-6 dose of 100 U/ml. Similar treatment with IL-6 did not influence hepatocyte Mg(2+)-ATPase activity. The inhibition of Na(+)-K(+)-ATPase activity induced by IL-6 provides a putative mechanism for the observed inhibition of sodium-dependent taurocholate uptake. Since modulation of bile salt transport and Na(+)-K(+)-ATPase activity occurred at IL-6 concentrations comparable to the serum levels observed in patients with severe inflammatory states, these findings have potential pathophysiological relevance for the cholestasis of sepsis and other inflammatory disorders.
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PMID:Interleukin-6 inhibits hepatocyte taurocholate uptake and sodium-potassium-adenosinetriphosphatase activity. 781 Jun 56

Metallothioneins (MT) are ubiquitous found in eukaryotic organism. MT have a potential for metal-storage and protect the cells against stress. On the genomic level, proinflammatory cytokines like interleukin-6 and transition metals like copper cause induction of MT. Therefore, an estimation of MT in liver-biopsies from patients with different diseases probably could help in identifying acute-phase reactions and processes which lead to increased copper. We investigated paraffin embedded liver biopsies from 170 patients and 13 control biopsies from cases of sudden death. Tissue was stained with a primary antibody against MT and a peroxidase technique was used to make results visible. A grading was performed using an immunoreactive score (IRS from 0-24) and by computer-aided measurement of the optical density (OD) of the stained tissue slides. Patients with cholestasis (IRS: 12.1 +/- 2.8, n = 11), autoimmune (10.6 +/- 3.1, n = 7) or inflammatory bowel diseases (IBD) (13.3 +/- 5.1, n = 4) and lymphoma (9.8 +/- 5.8, n = 21) showed marked increases in MT compared to the controls (5.2 +/- 2.8, n = 13). Patients with chronic hepatitis B or C or chronic alcoholic abuse had no elevation of MT. Furthermore, no correlation was found between histological damage and amount of MT except in cases of cholestasis, in which increased MT was observed. Results by OD confirmed the findings. In summary, we were able to demonstrate a clear increase of MT content in liver-biopsies in proinflammatory and cholestatic conditions. Marked elevation in patients with systemic diseases (like autoimmune-, IBD and lymphoma) seems to be best explained by an acute-phase induction of MT by proinflammatory cytokines. This could help in identifying these conditions in liver biopsies.
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PMID:Metallothionein in liver-biopsies from patients with different diseases. 1248 63

Hydrophobic bile acids, which are known to be cytotoxic for hepatocytes, are retained in high amount in the liver during cholestasis. Thus, we have investigated the effects of bile acids with various hydrophobicities on biliary epithelial cells. Biliary epithelial cells were cultured in the presence of tauroursodeoxycholate (TUDC), taurocholate (TC), taurodeoxycholate (TDC), taurochenodeoxycholate (TCDC), or taurolithocholate (TLC). Cell proliferation, viability, apoptosis and secretion of monocyte chemotactic protein-1 (MCP-1) and of interleukin-6 (IL-6) were studied. Cell proliferation was increased by TDC, and markedly decreased by TLC in a dose dependent manner (50-500 microM). Cell viability was significantly decreased by TLC and TCDC at 500 microM. TLC, TDC and TCDC induced apoptosis at high concentrations. The secretion of MCP-1 and IL-6 was markedly stimulated by TC. TUDC had no significant effect on any parameter. These findings demonstrate that hydrophobic bile acids were cytotoxic and induced apoptosis of biliary epithelial cells. Furthermore, TC, a major biliary acid in human bile, stimulated secretion of cytokines involved in the inflammatory and fibrotic processes occurring during cholestatic liver diseases.
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PMID:Effects of bile acids on biliary epithelial cells: proliferation, cytotoxicity, and cytokine secretion. 1252 37

A variety of hepatobiliary abnormalities occur in inflammatory bowel diseases (IBDs). The role of tight junction (TJ) in hepatobiliary complications have been well described. The purpose of this study was to investigate the role of inducible nitric oxide (NOS) in alteration of hepatocyte TJ paracellular barrier and in the rapid transcytotic vesicular pathway modification associated with intestinal inflammation. To address this question, we used an experimental model of colitis, induced by dinitrobenzene sulfonic acid (DNBS). When compared to DNBS-treated iNOS wild-type (WT) mice, DNBS-treated iNOS knock out mice (iNOSKO) mice experienced a significant less rate of the extent and severity of the histological signs of colon injury. Colon levels of the pro-inflammatory cytokines tumour necrosis factor, interleukin-1beta and interleukin-6 were also significantly reduced in iNOS-KO mice in comparison to wild-type mice. Liver histology from iNOSKO and wild-type mice iNOSWT did not show any parenchymal and portal tract inflammation at 4 days after DNBS administration. Serum total bilirubin and alanine aminotransferase, were significantly reduced in DNBS-iNOSKO mice vs DNBS-iNOSKO mice. Therefore, we found an increase of tight junctional permeability to lanthanum nitrate (molecular weight, 433) in the livers from DNBS-treated IL-10WT mice, lanthanum accumulated throughout the junctional area up to the most apical region bordering the lumen. Absence of a functional iNOS gene in iNOSKO mice resulted in a significant reduction of apical diffusion of lanthanum after DNBS-induced colitis. Immunofluorescent labeling of frozen liver sections from DNBS-iNOSWT mice showed a significant alteration of the immunolocalization for claudin-1 and zonula occludens (ZO)-1. In contrast, a significant reduced alteration in the localization of the immunosignals for claudin-1 and ZO-1 was observed in the liver from iNOSKO mice after DNBS administration. In conclusion, we suggest that the iNOS may represent an important pathophysiological mechanism of hepatobiliary injuries and cholestasis observed in patients with IBD.
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PMID:Role of iNOS in hepatocyte tight junction alteration in mouse model of experimental colitis. 1283 36

Cholestasis develops during inflammatory conditions characterized by the release of cytokines like interleukin-6 (IL-6), which is the major player in the hepatic acute-phase response. However, the exact contribution of IL-6 to transporter down-regulation is unclear. Therefore, we compared wild-type and IL-6-deficient mice after IL-6-injection and induction of an aseptic (turpentine-injection) or septic (LPS-injection) acute-phase response. Down-regulation of basolateral (Ntcp, Oatp1, and Mrp3) and canalicular (Mrp2, Bsep) transporter mRNA occurred after treatment with IL-6, turpentine, and LPS. In IL-6-deficient mice, turpentine failed to decrease mRNA-levels of basolateral and canalicular transporters, whereas LPS-mediated down-regulation of Ntcp, Mrp3, and Mrp2 was abolished at later time points (24 h). In conclusion, induction of an aseptic and septic acute-phase response leads to the down-regulation of basolateral and canalicular organic anion transporters. IL-6 is required for transporter down-regulation during aseptic inflammation. Furthermore, IL-6 also contributes to transporter regulation during LPS-induced cholestasis at more delayed time points.
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PMID:Interleukin-6 regulates hepatic transporters during acute-phase response. 1531 96

We report here the case of a patient suffering from hemophagocytic syndrome (HPS) associated with bile ductopenia. A 24-year old man was admitted after suffering fever, sore throat and general malaise for 7 days and jaundice for 2 days. Clinical studies showed hepatic dysfunction with hyperbilirubinemia. Epstein-Barr viral DNA from two bone marrow samples was detected. Bone marrow aspiration disclosed findings of HPS. Liver biopsy showed centrilobular cholestasis with lack of interlobular bile duct. Repeated therapeutic plasma exchange was effective for decreasing serum bilirubin and interleukin-6 levels. The patient received liver transplantation, however, he finally died of alveolar hemorrhage resulting from disseminated intravascular coagulation and acute rejection.
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PMID:Effect of plasma exchange on the circulating IL-6 levels in a patient with fatal hemophagocytic syndrome associated with bile ductopenia. 1655 42

We investigated the protective role of aminoguanidine (AG) in rat liver injury induced by chronic biliary obstruction. Secondary biliary cirrhosis was induced by bile duct ligation for 14 days. Swiss albino rats were divided into three groups: Common bile duct ligated (CBDL) rats; Group A, CBDL rats treated with AG as Group B and simple laparotomy group known as the Sham group; Group C. Group B received 200 mg/kg of AG intraperitoneally daily throughout 14 days. The present data showed decreased gama glutamyl transferase (GGT), aspartate aminotransferase (AST), bilirubin and alanine aminotransferase (ALT) levels in the AG treated rats, when compared with CBDL rats (p < 0.05). In the AG treated rats, tissue levels of malondialdehyde (MDA) were significantly lower than that in CBDL rats (p < 0.001). Although the levels of glutathione (GSH) in AG treated rats were higher and myeloperoxidase (MPO) were lower than that in CBDL rats, the difference was not statistically significant (p > 0.05). The levels of interleukin-1alpha (IL-1alpha) and tumor necrosis factor-alpha (TNF-alpha) were significantly lower and although the levels of interleukin-6 (IL-6) were lower in AG treated rats than that in CBDL rats, the difference was not statistically significant. Administration of AG in the rats with biliary obstruction resulted in inhibition of ductular proliferation and portal inflammation. The present study demonstrates that intraperitoneal administration of AG in CBDL rats maintains antioxidant defenses, reduces liver oxidative and cytokine damage and ductular proliferation and portal inflammation. This effect of AG may be useful in the preservation of liver injury in cholestasis.
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PMID:The effect of aminoguanidine against cholestatic liver injury in rats. 1689 51

We investigated the effect of caffeic acid phenethyl ester in rat ileum injury induced by chronic biliary obstruction. Swiss albino rats were divided into three groups: Group 1, sham (n = 7); Group 2, common bile duct ligation (n = 7); and Group 3, common bile duct ligation plus caffeic acid phenethyl ester (n = 7). In the caffeic acid phenethyl ester-treated rats, ileum tissue levels of malondialdehyde and myeloperoxidase were significantly lower than those of the bile duct-ligated rats (P < 0.001). The levels of tumor necrosis factor-alpha, interleukin-6, and interleukin-1alpha in the caffeic acid phenethyl ester group were significantly lower than those in the bile duct ligation group (P < 0.03, P < 0.01, and P < 0.02 respectively). The present study demonstrates that intraperitoneal administration of caffeic acid phenethyl ester in bile duct-ligated rats reduces intestinal oxidative stress. This effect may be useful in the preservation of intestinal damage in cholestasis.
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PMID:The effect of caffeic acid phenethyl ester on bacterial translocation and intestinal damage in cholestatic rats. 1698 3

Interleukin-6 (IL-6) is a major regulator of the acute phase reaction in the liver and is thought to mediate protective effects in response to hepatotoxins. In this study, the influence of bile acids on IL-6 signal transduction was analyzed. It was shown that hydrophobic bile acids such as glycochenodeoxycholate (GCDC) inhibited IL-6-induced tyrosine phosphorylation of signal transducer and activator of transcription (STAT) 3 in hepatocytes and in perfused rat liver. This inhibition was accompanied by GCDC-mediated downregulation of glycoprotein (gp) 130 expression, whereas gp130 and suppressor of cytokine signaling 3 messenger RNA and gp80 protein levels remained unaffected. The GCDC-induced downregulation of gp130 protein expression was insensitive to inhibition of proteasomal or lysosomal protein degradation but turned out to be sensitive to inhibition of caspase-3 or caspase-8 activity. Accordingly, treatment of cell extracts with active recombinant caspase-3 led to a decay of immunoreactive gp130. Moreover, activation of caspases by CD95 ligand or hyperosmotic stress also resulted in a downregulation of gp130 levels. This indicates that caspase activation antagonizes IL-6 signaling by decay of gp130 levels. However, caspase inhibition did not prevent GCDC-dependent inhibition of IL-6-induced STAT3 activation, which turned out to be at least partially sensitive to suppression of p38(MAPK) activation. In conclusion, hydrophobic bile acids compromise IL-6 signaling through both a caspase-mediated downregulation of gp130 and a p38(MAPK)-dependent inhibition of STAT3 phosphorylation. This may contribute to bile acid-induced hepatotoxicity in cholestasis through counteracting the known hepatoprotective effects of IL-6.
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PMID:Bile acids inhibit interleukin-6 signaling via gp130 receptor-dependent and -independent pathways in rat liver. 1705 37


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