Interleukin-6 regulates hepatic transporters during acute-phase response

Siewert, Elmar; Dietrich, Christoph G.; Lammert, Frank; Heinrich, Peter C.; Matern, Siegfried; Gartung, Carsten; Geier, Andreas

doi:10.1016/j.bbrc.2004.07.102

Cited by 92 publications

(84 citation statements)

References 35 publications

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“…Here, we found that multiple cytokines were activated by inflammatory perturbations, including significant and prolonged activation of TNF-a. In agreement with our findings, inflammatory cytokines downregulated the expression of bile canalicular transporters in the short term, including Abcc2, Abcb11, and other genes (16)(17)(18), although not Slco1b1 (19). Here, we found that downregulation of canalicular transporters can continue in the long term during ongoing activation of inflammatory cells and local release of relevant cytokines.…”

Section: Discussionsupporting

confidence: 92%

Adenosine Triphosphate–Binding Cassette Subfamily C Member 2 Is the Major Transporter of the Hepatobiliary Imaging Agent ^99mTc-Mebrofenin

Bhargava¹,

Joseph²,

Ananthanarayanan³

et al. 2009

J Nucl Med

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The organic anion 99m Tc-N-[2- [(3-bromo-2,4,6-trimethylphenyl)amino]-2-oxoethyl]-N-(carboxymethyl)-glycine ( 99m Tc-mebrofenin) and its analogs are widely used for hepatobiliary imaging. Identification of the mechanisms directing bile canalicular transport of these agents will provide insights into the basis of their hepatic handling for assessing perturbations. Methods: We performed studies in animals, including healthy Fischer 344 rats or rats treated with carbon tetrachloride or intrasplenic cell transplantation and healthy Wistar rats or HsdAMC:TR-Abcc2 mutant rats in Wistar background. Onset of hepatic inflammation was verified by analysis of carbon uptake in Kupffer cells. Hepatic clearance of 99m Tc-mebrofenin was studied with dynamic imaging, and fractional retention of peak hepatic mebrofenin activity after 60 min was determined. Changes in the expression of bile canalicular transporters were analyzed by real-time polymerase chain reaction and Western blots. Results: Carbon tetrachloride and cell transplantation produced hepatic inflammation with activation of Kupffer cells, resulting in a rapid decline in the expression of the bile canalicular transporters Abcb4, Abcb11, and Abcc2. Among these transporters, decreased expression of Abcc2 was most prominent, and this decline persisted for 4 wk. Next, we examined 99m Tc-mebrofenin excretion in HsdAMC:TR-Abcc2 mutant rats (in which Abcc2 expression is naturally inactivated), compared with their healthy counterparts. In healthy HsdRccHan:WIST rats, only 23% 6 3% of the peak 99m Tc-mebrofenin activity was retained after 60 min. By contrast, in HsdAMC:TR-Abcc2 mutant rats, 73% 6 5% of the peak 99m Tc-mebrofenin activity was retained (P , 0.001). Moreover, the administration of cyclosporin A markedly inhibited 99m Tc-mebrofenin excretion in healthy rats, with no further effect on already impaired 99m Tc-mebrofenin excretion in HsdAMC:TR-Abcc2 mutant rats. Hepatic excretion of 99m Tc-mebrofenin was largely dependent on Abcc2. This molecular basis of 99m Tc-mebrofenin excretion will advance studies of pathophysiologic mechanisms in hepatic Abcc2 pathways.

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Section: Discussionsupporting

confidence: 92%

Adenosine Triphosphate–Binding Cassette Subfamily C Member 2 Is the Major Transporter of the Hepatobiliary Imaging Agent ^99mTc-Mebrofenin

Bhargava¹,

Joseph²,

Ananthanarayanan³

et al. 2009

J Nucl Med

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“…Hypozincemia is a frequent finding in acute and chronic inflammatory and infectious disease. The correlation of elevated plasma IL-6 with low plasma zinc to gastrointestinal disease occurrence in children with Down's syndrome is an example of such reports (10). Because hypozincemia is an IL-6-dependent physiologic effect, the response may vary in individuals with single-nucleotide polymorphisms in the promoter region of IL-6, which influences IL-6 production and function (33,34).…”

Section: Discussionmentioning

confidence: 99%

“…Cytokine induction by LPS is more complex, involving TNF␣ and IL-1␣, in addition to IL-1␤, leptin, and IL-6 (9). Nevertheless, IL-6 is viewed as the main proinflammatory cytokine regulating acute-phase genes (10). Recently, the hypoferremia of inflammation induced in mice by turpentine was demonstrated to be produced by IL-6 through induction of hepcidin synthesis in the liver (11).…”

mentioning

confidence: 99%

Interleukin-6 regulates the zinc transporter Zip14 in liver and contributes to the hypozincemia of the acute-phase response

Liuzzi

Lichten²,

Rivera³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

495

395

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Infection and inflammation produce systemic responses that include hypozincemia and hypoferremia. The latter involves regulation of the iron transporter ferroportin 1 by hepcidin. The mechanism of reduced plasma zinc is not known. Transcripts of the two zinc transporter gene families (ZnT and Zip) were screened for regulation in mouse liver after turpentine-induced inflammation and LPS administration. Zip14 mRNA was the transporter transcript most up-regulated by inflammation and LPS. IL-6 knockout (IL-6 ؊/؊ ) mice did not exhibit either hypozincemia or the induction of Zip14 with turpentine inflammation. However, in IL-6 ؊/؊ mice, LPS produced a milder hypozincemic response but no Zip14 induction. Northern analysis showed Zip14 up-regulation was specific for the liver, with one major transcript. Immunohistochemistry, using an antibody to an extracellular Zip14 epitope, showed both LPS and turpentine increased abundance of Zip14 at the plasma membrane of hepatocytes. IL-6 produced increased expression of Zip14 in primary hepatocytes cultures and localization of the protein to the plasma membrane. Transfection of mZip14 cDNA into human embryonic kidney cells increased zinc uptake as measured by both a fluorescent probe for free Zn 2؉ and 65 Zn accumulation, as well as by metallothionein mRNA induction, all indicating that Zip14 functions as a zinc importer. Zip14 was localized in plasma membrane of the transfected cells. These in vivo and in vitro experiments demonstrate that Zip14 expression is up-regulated through IL-6, and that this zinc transporter most likely plays a major role in the mechanism responsible for hypozincemia that accompanies the acute-phase response to inflammation and infection.endotoxemia ͉ inflammation ͉ hepatic ͉ Slc39a14 ͉ knockout mice

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“…In this sense, it has been suggested that proinflammatory cytokines, such as IL-1␤, TNF␣, and IL-6, may contribute to altered expression of hepatic drug transporters occurring during inflammation (61). Indeed, administration of IL-1␤, TNF␣, or IL-6 to rodents resulted in reduced expression of various sinusoidal or canalicular drug transporters (62)(63)(64). Moreover, as recently reported (65), exposure of primary human hepatocytes to 100 ng/ml TNF␣ or 10 ng/ml IL-6 for 48 h was found to down-regulate mRNA levels of major sinusoidal influx transporters, including sodium-taurocholate cotransporting polypeptide (NTCP), Oatp1, organic cation transporter 1 (OCT1), and organic anion transporter 2 (65).…”

Section: Discussionmentioning

confidence: 99%

Intertissue Flow of Glutathione (GSH) as a Tumor Growth-promoting Mechanism

Obrador

Benlloch

Pellicer

et al. 2011

Journal of Biological Chemistry

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B16 melanoma F10 (B16-F10) cells with high glutathione (GSH) content show high metastatic activity in vivo.An intertissue flow of GSH, where the liver is the main reservoir, can increase GSH content in metastatic cells and promote their growth. We have studied here possible tumor-derived molecular signals that could activate GSH release from hepatocytes. GSH efflux increases in hepatocytes isolated from mice bearing liver or lung metastases, thus suggesting a systemic mechanism. Fractionation of serum-free conditioned medium from cultured B16-F10 cells and monoclonal antibody-induced neutralization techniques facilitated identification of interleukin (IL)-6 as a tumor-derived molecule promoting GSH efflux in hepatocytes. IL-6 activates GSH release through a methionine-sensitive/organic anion transporter polypeptide 1-and multidrug resistance protein 1-independent channel located on the sinusoidal site of hepatocytes. Specific siRNAs were used to knock down key factors in the main signaling pathways activated by IL-6, which revealed a STAT3-dependent mechanism. Our results show that IL-6 (mainly of tumor origin in B16-F10-bearing mice) may facilitate GSH release from hepatocytes and its interorgan transport to metastatic growing foci.Glutathione (L-␥-glutamyl-L-cysteinyl-glycine; GSH), 2 the most prevalent non-protein thiol in mammalian cells, is involved in many cellular functions (1, 2). GSH in cancer cells is particularly relevant in the regulation of 1) carcinogenic mechanisms; 2) sensitivity against cytotoxic drugs, ionizing radiation, and some cytokines; 3) DNA synthesis; and 4) cell proliferation and death (3,4).Early studies on the organ distribution of metastatic cells showed that less than 0.1% of circulating cells survive to cause secondary metastatic growth (5). The liver is a common site for metastasis development, and, as previously shown, a high percentage of circulating cancer cells are mechanically trapped in the liver microvasculature (6). Interaction of metastatic cancer cells with the hepatic sinusoidal endothelium and Kupffer cells activates local release of proinflammatory cytokines, which then may act as molecular signals promoting cancer cell adhesion, invasion, and proliferation (3, 7). Direct in vitro lysis of metastatic tumor cells by cytokine-activated murine vascular endothelial cells has also been shown (8).From the original subcutaneous B16 melanoma tumor, spontaneously originated in C57BL/6J mice, and using sequential in vitro-in vivo growing cycles, I. J. Fidler (9) obtained 10 different cell variants (F1-F10) with increasing metastatic potentials. The B16-F10 line showed the highest metastatic activity and became a classical model widely used in metastasis research. Recent results identified the existence of a natural defense mechanism against cancer metastasis whereby the arrest of tumor cells in the liver induces endogenous NO and H 2 O 2 release, leading to sinusoidal tumor cell killing and reduced hepatic metastasis formation (3, 10). We have shown that GSH protects circulati...

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Interleukin-6 regulates hepatic transporters during acute-phase response

Cited by 92 publications

References 35 publications

Adenosine Triphosphate–Binding Cassette Subfamily C Member 2 Is the Major Transporter of the Hepatobiliary Imaging Agent ^99mTc-Mebrofenin

Adenosine Triphosphate–Binding Cassette Subfamily C Member 2 Is the Major Transporter of the Hepatobiliary Imaging Agent ^99mTc-Mebrofenin

Interleukin-6 regulates the zinc transporter Zip14 in liver and contributes to the hypozincemia of the acute-phase response

Intertissue Flow of Glutathione (GSH) as a Tumor Growth-promoting Mechanism

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Interleukin-6 regulates hepatic transporters during acute-phase response

Cited by 92 publications

References 35 publications

Adenosine Triphosphate–Binding Cassette Subfamily C Member 2 Is the Major Transporter of the Hepatobiliary Imaging Agent 99mTc-Mebrofenin

Adenosine Triphosphate–Binding Cassette Subfamily C Member 2 Is the Major Transporter of the Hepatobiliary Imaging Agent 99mTc-Mebrofenin

Interleukin-6 regulates the zinc transporter Zip14 in liver and contributes to the hypozincemia of the acute-phase response

Intertissue Flow of Glutathione (GSH) as a Tumor Growth-promoting Mechanism

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Product

Resources

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Adenosine Triphosphate–Binding Cassette Subfamily C Member 2 Is the Major Transporter of the Hepatobiliary Imaging Agent ^99mTc-Mebrofenin

Adenosine Triphosphate–Binding Cassette Subfamily C Member 2 Is the Major Transporter of the Hepatobiliary Imaging Agent ^99mTc-Mebrofenin