scholarly journals ORF3 protein of hepatitis E virus interacts with the Bβ chain of fibrinogen resulting in decreased fibrinogen secretion from HuH-7 cells

2009 ◽  
Vol 90 (6) ◽  
pp. 1359-1370 ◽  
Author(s):  
Ruchi Ratra ◽  
Anindita Kar-Roy ◽  
Sunil K. Lal
Keyword(s):  
Acute Phase ◽  
Acute Phase Response ◽  
Mammalian Cells ◽  
Hepatitis E Virus ◽  
Hepatitis E ◽  
Phase Response ◽  
Northern Hybridization ◽  
Specific Gene ◽  
Mrna Levels ◽  
Orf3 Protein

The ORF3 protein of hepatitis E virus (HEV), the precise cellular functions of which remain obscure, was used in a yeast two-hybrid screen to identify its cellular binding partners. One of the identified interacting partners was fibrinogen Bβ protein. The ORF3–fibrinogen Bβ interaction was verified by co-immunoprecipitation and fluorescence resonance energy transfer in mammalian cells. Fibrinogen is a hepatic acute-phase protein and serves as a central molecule that maintains host homeostasis and haemostasis during an acute-phase response. Metabolic labelling of ORF3-transfected HuH-7 cells showed that secreted as well as intracellular levels of fibrinogen were decreased in these cells compared with vector-transfected controls. Northern hybridization and RT-PCR analyses revealed that the mRNA levels of all three chains of fibrinogen, Aα, Bβ and γ, were transcriptionally downregulated in ORF3-transfected cells. The constitutive expression of fibrinogen genes can be significantly upregulated by interleukin (IL)-6, an important mediator of liver-specific gene expression during an acute-phase response. Transcription of fibrinogen genes after IL-6 stimulation was less in ORF3-expressing cells compared with controls. This report adds one more biological function to, and advances our understanding of, the cellular role of the ORF3 protein of HEV. The possible implications of these findings in the virus life cycle are discussed.

Tissue-specific gene expression of prolactin receptor in the acute-phase response induced by lipopolysaccharides

2004 ◽  
Vol 287 (4) ◽  
pp. E750-E757 ◽  
Author(s):  
Ana M. Corbacho ◽  
Giuseppe Valacchi ◽  
Lukas Kubala ◽  
Estibaliz Olano-Martín ◽  
Bettina C. Schock ◽  
...  
Keyword(s):  
Acute Phase ◽  
Acute Phase Response ◽  
Prolactin Receptor ◽  
Phase Response ◽  
Specific Gene ◽  
Mrna Levels ◽  
Tissue Specific ◽  
Specific Regulation

Acute inflammation can elicit a defense reaction known as the acute-phase response (APR) that is crucial for reestablishing homeostasis in the host. The role for prolactin (PRL) as an immunomodulatory factor maintaining homeostasis under conditions of stress has been proposed; however, its function during the APR remains unclear. Previously, it was shown that proinflammatory cytokines characteristic of the APR (TNF-α, IL-1β, and IFNγ) induced the expression of the PRL receptor (PRLR) by pulmonary fibroblasts in vitro. Here, we investigated the in vivo expression of PRLR during lipopolysaccharide (LPS)-induced APR in various tissues of the mouse. We show that PRLR mRNA and protein levels were downregulated in hepatic tissues after intraperitoneal LPS injection. Downregulation of PRLR in the liver was confirmed by immunohistochemistry. A suppressive effect on mRNA expression was also observed in prostate, seminal vesicle, kidney, heart, and lung tissues. However, PRLR mRNA levels were increased in the thymus, and no changes were observed in the spleen. The proportion of transcripts for the different receptor isoforms (long, S1, S2, and S3) in liver and thymus was not altered by LPS injection. These findings suggest a complex tissue-specific regulation of PRLR expression in the context of the APR.

scholarly journals The Hepatitis E Virus ORF3 Protein Modulates Epidermal Growth Factor Receptor Trafficking, STAT3 Translocation, and the Acute-Phase Response

2008 ◽  
Vol 82 (14) ◽  
pp. 7100-7110 ◽  
Author(s):  
Vivek Chandra ◽  
Anindita Kar-Roy ◽  
Sudha Kumari ◽  
Satyajit Mayor ◽  
Shahid Jameel
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Acute Phase ◽  
Acute Phase Response ◽  
Hepatitis E Virus ◽  
Growth Factor Receptor ◽  
Hepatitis E ◽  
Orf3 Protein ◽  
Epidermal Growth

ABSTRACT The hepatitis E virus (HEV) causes acute viral hepatitis, but its characterization is hampered by the lack of an efficient in vitro infection system that can be used to study the effects of HEV proteins on cellular processes. Previous studies suggest that the viral ORF3 protein (pORF3) is essential for infection in vivo and is likely to modulate the host response. Here, we report that pORF3 localizes to early and recycling endosomes and causes a delay in the postinternalization trafficking of epidermal growth factor receptor (EGFR) to late endosomes/lysosomes. The cytoplasmic phosphorylated signal transducer and activator of transcription 3 (pSTAT3) proteins require growth factor receptor endocytosis for their translocation from the cytoplasm to nucleus. Consequently, lower levels of pSTAT3 were found in the nuclei of ORF3-expressing Huh7 human hepatoma cells stimulated with EGF. This results in downregulation of the acute-phase response, a major determinant of inflammation in the host. We propose that through its effects on EGFR trafficking, pORF3 prolongs endomembrane growth factor signaling and promotes cell survival. The effects on STAT3 translocation would result in a reduced inflammatory response. Both of these events are likely to contribute positively to viral replication.

Gene expression in regenerating and acute-phase rat liver

1990 ◽  
Vol 259 (3) ◽  
pp. G340-G347 ◽  
Author(s):  
J. Milland ◽  
A. Tsykin ◽  
T. Thomas ◽  
A. R. Aldred ◽  
T. Cole ◽  
...  
Keyword(s):  
Vitamin D ◽  
Rat Liver ◽  
Acute Phase ◽  
Acute Phase Response ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Binding Protein ◽  
Ornithine Transcarbamylase ◽  
Phase Response ◽  
Mrna Levels ◽  
Vitamin D Binding Protein

The integration of growth and the acute-phase response is investigated by comparing the mRNA levels in rat liver during acute inflammation with those after partial hepatectomy. Northern analysis is carried out for the mRNAs for thiostatin, alpha 2-macroglobulin, alpha 1-antitrypsin, inter-alpha-trypsin inhibitor subunit 1, haptoglobin, ceruloplasmin, transferrin, vitamin D-binding protein, alpha 1-acid glycoprotein, beta-fibrinogen, apolipoproteins A-IV and E, albumin, transthyretin, alpha 2-HS-glycoprotein, retinol-binding protein, beta-tubulin, c-myc protooncogene, glyceraldehyde-3-phosphate dehydrogenase, phosphoenolpyruvate carboxykinase, ornithine transcarbamylase, and alcohol dehydrogenase. The acute-phase response dominates during the first 18 h. Changes in mRNA levels related to growth of the liver become important thereafter, and the capacity for an acute-phase response of plasma protein synthesis becomes greatly reduced. The early increase in the level of ceruloplasmin mRNA observed during inflammation is abolished during regeneration, and that of vitamin D-binding protein mRNA is converted into a decrease. The mRNAs levels of glyceraldehyde-3-phosphate dehydrogenase increase, and those for phosphoenolpyruvate carboxykinase decrease during regeneration. Ornithine transcarbamylase mRNA levels are found to exhibit negative acute-phase regulation. The pattern of transcriptional regulation is similar during inflammation and regeneration.

scholarly journals Suppression of DHEA sulfotransferase (Sult2A1) during the acute-phase response

2004 ◽  
Vol 287 (4) ◽  
pp. E731-E738 ◽  
Author(s):  
Min Sun Kim ◽  
Judy Shigenaga ◽  
Art Moser ◽  
Carl Grunfeld ◽  
Kenneth R. Feingold
Keyword(s):  
Acute Phase ◽  
Acute Phase Response ◽  
Hormone Receptors ◽  
Mrna Level ◽  
Pregnane X Receptor ◽  
Phase Response ◽  
Farnesoid X Receptor ◽  
Bile Acid Metabolism ◽  
Mrna Levels ◽  
Dependent Manner

The acute-phase response (APR) induces alterations in lipid metabolism, and our data suggest that this is associated with suppression of type II nuclear hormone receptors that are key regulators of fatty acid, cholesterol, and bile acid metabolism. Recently, the farnesoid X receptor (FXR), constitutive androstane receptor (CAR), and pregnane X receptor (PXR) were found to regulate DHEA sulfotransferase (Sult2A1), which plays an important role in DHEA sulfation and detoxification of bile acids. Because FXR, PXR, and CAR are suppressed during the APR, we hypothesized that Sult2A1 is downregulated during the APR. To induce the APR, mice were treated with LPS, which will then trigger the release of various cytokines, and the mRNA levels of Sult2A1 and the sulfate donor 3′-phosphoadenosine 5′-phosphosulfate synthase 2 (PAPSS2), as well as the enzyme activity of Sult2A1, were determined in the liver. We found that mRNA levels of Sult2A1 decrease in a time- and dose-dependent manner during the LPS-induced APR. Similar changes were observed in the mRNA levels of PAPSS2, the major synthase of PAPS in the liver. Moreover, hepatic Sult2A1 activity and serum levels of DHEA-sulfate (DHEA-S) were significantly decreased in LPS-treated animals. These results suggest that decreased levels or activities of FXR, PXR, and CAR during the APR could contribute to decreases in Sult2A1, resulting in decreased sulfation of DHEA and lower circulating level of DHEA-S. Finally, we found that both TNF and IL-1 caused a significant decrease in the mRNA level of Sult2A1 in Hep3B human hepatoma cells, suggesting that the proinflammatory cytokines TNF and IL-1 mediate the inhibitory effect of LPS on Sult2A1 mRNA level. Our study provides a possible mechanism by which infection and inflammation are associated with altered steroid metabolism and cholestasis.

In vivo regulation of plasma platelet-activating factor acetylhydrolase during the acute phase response

1999 ◽  
Vol 277 (1) ◽  
pp. R94-R103 ◽  
Author(s):  
Riaz A. Memon ◽  
John Fuller ◽  
Arthur H. Moser ◽  
Kenneth R. Feingold ◽  
Carl Grunfeld
Keyword(s):  
Mrna Expression ◽  
Acute Phase ◽  
Acute Phase Response ◽  
Platelet Activating Factor ◽  
Phase Response ◽  
Mrna Levels ◽  
Potent Inducer ◽  
Platelet Activating Factor Acetylhydrolase ◽  
Infection And Inflammation ◽  
Lps Treatment

Plasma platelet-activating factor acetylhydrolase (PAF-AH) hydrolyzes PAF and oxidized phospholipids and is associated with lipoproteins in the circulation. Endotoxin [lipopolysaccharide (LPS)], a potent inducer of the acute phase response (APR), produces marked changes in several proteins that play important roles in lipoprotein metabolism. We now demonstrate that LPS produces a 2.5- to 3-fold increase in plasma PAF-AH activity in Syrian hamsters. The plasma PAF-AH activity is found in the high-density lipoprotein (HDL) fraction and is increased threefold with LPS treatment despite a decrease in plasma HDL levels, indicating that plasma PAF-AH activity is increased per HDL particle. LPS markedly increased PAF-AH mRNA levels in liver, spleen, lung, and small intestine. The maximal increase in plasma PAF-AH activity and mRNA expression in liver and spleen is seen 24 h after LPS treatment. Both tumor necrosis factor and interleukin-1 modestly increased plasma PAF-AH activity and mRNA levels in liver and spleen, suggesting that they may partly mediate the effect of LPS on PAF-AH. Surgical removal of spleen had no effect on basal or LPS-induced plasma PAF-AH activity, suggesting that spleen per se may not contribute to plasma PAF-AH activity. Finally, LPS, turpentine and zymosan increased plasma PAF-AH activity in mice and/or rats, indicating that multiple APR inducers upregulate plasma PAF-AH and this effect is consistent across different rodent species. Taken together, our results indicate that plasma PAF-AH activity and mRNA expression is markedly upregulated during the host response to infection and inflammation. An increase in plasma PAF-AH may enhance the degradation of PAF as well as alter the structure and function of HDL during infection and inflammation.

Paraoxonase activity in the serum and hepatic mRNA levels decrease during the acute phase response

1998 ◽  
Vol 139 (2) ◽  
pp. 307-315 ◽  
Author(s):  
Kenneth R Feingold ◽  
Riaz A Memon ◽  
Arthur H Moser ◽  
Carl Grunfeld
Keyword(s):  
Acute Phase ◽  
Acute Phase Response ◽  
Phase Response ◽  
Mrna Levels ◽  
Paraoxonase Activity

LPS and cytokines regulate extra hepatic mRNA levels of apolipoproteins during the acute phase response in Syrian hamsters

1997 ◽  
Vol 1344 (3) ◽  
pp. 210-220 ◽  
Author(s):  
Ingibjörg Hardardóttir ◽  
Jean Sipe ◽  
Arthur H Moser ◽  
Christopher J Fielding ◽  
Kenneth R Feingold ◽  
...  
Keyword(s):  
Acute Phase ◽  
Acute Phase Response ◽  
Phase Response ◽  
Mrna Levels ◽  
Syrian Hamsters

Regulation of urea synthesis during the acute-phase response in rats

2013 ◽  
Vol 304 (7) ◽  
pp. G680-G686 ◽  
Author(s):  
Karen Louise Thomsen ◽  
Niels Jessen ◽  
Andreas Buch Møller ◽  
Niels Kristian Aagaard ◽  
Henning Grønbæk ◽  
...  
Keyword(s):  
Acute Phase ◽  
Acute Phase Response ◽  
Urea Cycle ◽  
Acute Phase Proteins ◽  
Phase Response ◽  
Mrna Levels ◽  
Urea Synthesis ◽  
Cycle Enzyme ◽  
Tnf Α ◽  
Urea Cycle Enzyme

The acute-phase response is a catabolic event involving increased waste of amino-nitrogen (N) via hepatic urea synthesis, despite an increased need for amino-N incorporation into acute-phase proteins. This study aimed to clarify the regulation of N elimination via urea during different phases of the tumor necrosis factor-α (TNF-α)-induced acute-phase response in rats. We used four methods to study the regulation of urea synthesis: We examined urea cycle enzyme mRNA levels in liver tissue, the hepatocyte urea cycle enzyme proteins, the in vivo capacity of urea-N synthesis (CUNS), and known humoral regulators of CUNS at 1, 3, 24, and 72 h after TNF-α injection (25 μg/kg iv rrTNF-α) in rats. Serum acute-phase proteins and their liver mRNA levels were also measured. The urea cycle enzyme mRNA levels acutely decreased and then gradually normalized, whereas the urea cycle enzyme proteins remained essentially unchanged over time. The CUNS rose after 3 h and then normalized. The acute-phase response was fully activated at 24 h with markedly increased serum levels of the acute-phase proteins. TNF-α acutely upregulated the CUNS. Later, despite the fully established 24-h acute-phase response and the decreased activity of the urea cycle enzyme genes, there was no change in the urea cycle enzyme proteins or the CUNS. Thus in no phase after the initiation of the acute-phase response was in vivo urea synthesis orchestrated in combination with acute-phase protein synthesis so as to limit N waste.

scholarly journals Activation of plasminogen activator inhibitor implicates protease InhA in the acute-phase response to Bacillus anthracis infection

2009 ◽  
Vol 58 (6) ◽  
pp. 737-744 ◽  
Author(s):  
Myung-Chul Chung ◽  
Shelley C. Jorgensen ◽  
Taissia G. Popova ◽  
Jessica H. Tonry ◽  
Charles L. Bailey ◽  
...  
Keyword(s):  
Bacillus Anthracis ◽  
Plasminogen Activator ◽  
Acute Phase ◽  
Acute Phase Response ◽  
Plasminogen Activator Inhibitor ◽  
Phase Response ◽  
Strong Increase ◽  
Mrna Levels ◽  
Activator Inhibitor ◽  
Pai 1

Anthrax is a zoonotic disease caused by Bacillus anthracis. The infection is associated with inflammation and sepsis, but little is known about the acute-phase response during disease and the nature of the bacterial factors causing it. In this study, we examined the levels of the acute-phase proteins (APPs) in comparative experiments using mice challenged with spores and a purified B. anthracis protease InhA as a possible factor mediating the response. A strong increase in the plasma levels of APPs such as haptoglobin and serum amyloid A was observed during infection. Protein and mRNA levels of plasminogen activator inhibitor (PAI)-1 in the liver were also increased concurrently with bacterial dissemination at 72 h post-infection. Similar effects were observed at 6 h post injection with InhA. Induction of hepatic transforming growth factor-β1, a PAI-1 inducer, was also found in the liver of InhA-injected mice. PAI-1 elevation by InhA resulted in an increased level of urokinase-type plasminogen activator complex with PAI-1 and a decreased level of D-dimers indicating inhibition of blood fibrinolysis. These results reveal an acute liver response to anthrax infection and provide a plausible pathophysiological link between the host inflammatory response and the pro-thrombotic haemostatic imbalance in the course of disease through PAI-1 induction in the liver.

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