Heat shock inhibits the acute phase response in primary rat hepatocytes

2000 ◽  
Vol 57 (6) ◽  
pp. 637
Author(s):  
J.E Gosnell ◽  
W.J Welch ◽  
H.W Harris
Keyword(s):  
Heat Shock ◽  
Acute Phase ◽  
Acute Phase Response ◽  
Rat Hepatocytes ◽  
Phase Response ◽  
Primary Rat Hepatocytes

scholarly journals Decreased expression levels of rat liver glutathione S-transferase A2 and albumin during the acute phase response are mediated by HNF1 (hepatic nuclear factor 1) and IL6DEX-NP

2004 ◽  
Vol 377 (3) ◽  
pp. 763-768 ◽  
Author(s):  
Richard WHALEN ◽  
Susan H. VOSS ◽  
Thomas D. BOYER
Keyword(s):  
Acute Phase ◽  
Acute Phase Response ◽  
Rat Hepatocytes ◽  
Phase Response ◽  
Negative Regulator ◽  
Nuclear Factor ◽  
Hepatic Nuclear Factor 1 ◽  
Nuclear Factor 1

The acute phase response is characterized by positive and negative regulation of many liver proteins including GSTs (glutathione S-transferases) and albumin. The expression of albumin and some GSTs are dependent on HNF1 (hepatic nuclear factor 1). Interleukin 6 plus dexamethasone induce a nuclear protein (IL6DEX-NP) in rat hepatocytes in vitro that binds to a promoter element adjacent to the HNF1 site of rGSTA2 and decreases its expression. We determined how HNF1 and IL6DEX-NP regulate rGSTA2 and albumin expression in rats during the acute phase response after LPS (lipopolysaccharide) treatment. Expression of rGSTA2 and albumin mRNA decreased 3 h after LPS treatment and remained low for 48 h. Transcription rates showed a similar pattern but albumin transcription was less affected. HNF1 and IL6DEX-NP binding to the rGSTA2 promoter was present in control livers but was absent at 3 and 6 h after LPS. By 12 h, HNF1 and IL6DEX-NP binding to the rGSTA2 promoter reappeared and increased to above normal at 48 h. The patterns of HNF1 and IL6DEX-NP binding to the albumin promoter were similar. Affinity of IL6DEX-NP for the albumin promoter was less than that for the rGSTA2 promoter and changes in the transcription rates were consistent with the difference. Early decreases in rGSTA2 and albumin during the acute phase response are due to decreased binding of HNF1. Later persistent decreases in transcriptional rate of rGSTA2 and to a lesser extent albumin are due to increased IL6DEX-NP binding. IL6DEX-NP appears to be an important negative regulator of gene expression in vitro and in vivo.

scholarly journals The influence of glucocorticoid on the fibrinogen messenger RNA content of rat liver in vivo and in hepatocyte suspension culture

1984 ◽  
Vol 220 (3) ◽  
pp. 631-637 ◽  
Author(s):  
H M G Princen ◽  
H J Moshage ◽  
H J W de Haard ◽  
P J van Gemert ◽  
S H Yap
Keyword(s):  
Acute Phase ◽  
Acute Phase Response ◽  
Messenger Rna ◽  
Acute Phase Proteins ◽  
Rat Hepatocytes ◽  
Phase Response ◽  
Control Value ◽  
Hepatocyte Suspension

The plasma concentration of fibrinogen, one of the major acute-phase proteins produced by the liver, increases during the acute-phase response as a result of enhanced synthesis in liver. Since adrenal-cortical hormones have been thought to have a key role in the regulation of the fibrinogen synthesis, fibrinogen-polypeptide mRNA sequences were determined in the present study, by using a specific complementary-DNA probe, in RNA fractions obtained from rat hepatocytes exposed to glucocorticoids in vitro (hepatocyte suspension cultures) and in vivo. Maximal induction of the fibrinogen-polypeptide mRNA (to 400% of the control value) was found in vitro at 0.1 microM-dexamethasone after 9 h of incubation. The same magnitude of induction was obtained with 20 microM-cortisol or 60 microM-corticosterone. In contrast with the findings in vitro, no induction of the fibrinogen-polypeptide mRNA was observed in the liver at various times after injection of different doses of glucocorticoids into rats. These results suggest that more complex regulatory mechanisms are involved and that glucocorticoids are not the sole regulatory factors in vivo in the enhanced synthesis of fibrinogen during the acute-phase response.

scholarly journals Mechanism of negative regulation of rat glutathione S-transferase A2 by the cytokine interleukin 6

2002 ◽  
Vol 365 (1) ◽  
pp. 229-237 ◽  
Author(s):  
Susan H. VOSS ◽  
Richard WHALEN ◽  
Thomas D. BOYER
Keyword(s):  
Acute Phase ◽  
Interleukin 6 ◽  
Acute Phase Response ◽  
Culture Media ◽  
Rat Hepatocytes ◽  
Phase Response ◽  
Negative Regulator ◽  
Glutathione S Transferase ◽  
Mobility Shift ◽  
Nuclear Factor 1

A decrease in concentration of some liver proteins, including the detoxification enzyme glutathione S-transferase A2 (rGSTA2), occurs during the acute-phase response. Interleukin 6 (IL-6) with dexamethasone (DEX) decreases transcription of rGSTA2 in rat hepatocytes. The promoter region that mediates suppression of rGSTA2 was localized to 150bp. These 150bp were divided and used for electrophoretic mobility-shift assays. Induction of a protein that specifically bound to an oligonucleotide from this region required new protein synthesis and IL-6 with DEX in the culture media. The protein bound to part of the hepatocyte nuclear factor 1 (HNF1) site but was different from and did not displace HNF1. A core sequence, TGATT, was required for binding. The protein also bound to an HNF1 site in the albumin promoter. We hypothesize that IL-6 along with DEX induced a novel protein that decreased transcription of rGSTA2 and possibly albumin by interfering with the transactivating function of HNF1. The protein may be an important negative regulator of transcription during the acute-phase response.

Prostaglandins E2 and F2α are not involved in the monocytic-product (interleukin-1)-induced stimulation of hepatic fibrinogen synthesis in rats

1988 ◽  
Vol 74 (5) ◽  
pp. 477-483 ◽  
Author(s):  
J. C. W. M. Holtslag ◽  
H. J. Moshage ◽  
J. F. van Pelt ◽  
J. A. G. M. Kleuskens ◽  
F. W. J. Gribnau ◽  
...  
Keyword(s):  
Acute Phase ◽  
Acute Phase Response ◽  
Second Messengers ◽  
Interleukin 1 ◽  
Rat Hepatocytes ◽  
Phase Response ◽  
Mrna Content ◽  
Stimulation Of

1. Monocytic products, especially interleukin-1 (IL-1), play an important role in the acute-phase response. Prostaglandins have been shown to act as second messengers in several physiological alterations of the acute-phase response, such as fever, muscle wasting and immunoregulation. The present study was undertaken to determine the role of prostaglandins in the monocytic-product-induced stimulation of the hepatic synthesis of fibrinogen, a well-known acute-phase protein. 2. Prostaglandin (PG) E2, PGF2α and 16,16-dimethyl-PGE2 did not stimulate fibrinogen synthesis and fibrinogen polypeptide mRNA content when administered intraperitoneally to rats or when added to monolayer cultures of rat hepatocytes. 3. Cyclo-oxygenase inhibitors did not abolish the stimulation of fibrinogen synthesis and its mRNA content induced by monocytic products in vivo or in vitro. 4. These findings indicate that the enhanced synthesis of fibrinogen induced by monocytic products (including IL-1) during the acute-phase response is not mediated by prostaglandins or other products of the cyclo-oxygenase pathway of arachidonic acid.

Febrile-range temperature but not heat shock augments the acute phase response to interleukin-6 in human hepatoma cells

2006 ◽  
Vol 290 (5) ◽  
pp. G903-G911 ◽  
Author(s):  
Stephen J. Wigmore ◽  
Kenneth C. H. Fearon ◽  
James A. Ross ◽  
Stephen J. McNally ◽  
William J. Welch ◽  
...  
Keyword(s):  
Heat Treatment ◽  
Protein Synthesis ◽  
Heat Shock ◽  
Acute Phase ◽  
Acute Phase Response ◽  
Acute Phase Protein ◽  
Phase Response ◽  
Human Hepatoma ◽  
Human Hepatoma Cells ◽  
Phase Protein

The relationship between the stress protein response and the acute phase response (APPR) was studied in human hepatoma cells to investigate the hierarchy of regulation of these survival responses. Huh-7 cells were subjected to heat treatment (febrile-range temperature 40°C or heat shock 43°C) followed by recovery at 37°C in the presence or absence of IL-6 given either before or after heat treatment. The effects on total, fractional, and acute phase protein synthesis were then analyzed by metabolic labeling, ELISA, real-time PCR, Northern blot analysis, and activation of an α1-antitrypsin reporter plasmid. Cell energetics were studied under the same conditions using an index of mitochondrial activity and measurement of cellular ATP levels. Febrile-range temperature (40°C) augmented acute phase protein production when cells had been pretreated with IL-6. Pretreatment of cells with IL-6 also prevented heat shock-induced suppression of α1-antichymotrypsin (ACT) but not transferrin. mRNA expression of ACT and α1-antitrypsin reporter activation studies was consistent with transcriptional regulation of these proteins. Expression of mRNA transcripts for transferrin was increased despite protein expression being reduced by heat shock. The effects of heat shock on acute phase protein synthesis can be modified by preincubation with IL-6, whereas addition of this ligand after heat treatment has no effect on the suppressive effect of heat on the APPR. The mechanism of this action appears to be transcriptionally regulated in the case of ACT, but in the case of transferrin, it may be mediated by another process such as posttranslational modification.

Activation of activating protein 1 during hepatic acute phase response

1993 ◽  
Vol 264 (1) ◽  
pp. G95-G103 ◽  
Author(s):  
M. Hattori ◽  
A. Tugores ◽  
J. K. Westwick ◽  
L. Veloz ◽  
H. L. Leffert ◽  
...  
Keyword(s):  
Acute Phase ◽  
Acute Phase Response ◽  
Rat Hepatocytes ◽  
Binding Activity ◽  
Phase Response ◽  
Mobility Shift ◽  
Necrosis Factor Alpha ◽  
Western Blots ◽  
Adult Rat ◽  
Nuclear Extracts

During an acute phase response following inflammatory stimuli, specific changes occur in the synthesis and secretion of many hepatic proteins. Because the expression of differentiated function requires the coordinated regulation of many genes, we investigated the activity of general and tissue-specific transcription factors using a rat liver model of the acute phase response induced by Freund's adjuvant. Nuclear extracts and RNAs were prepared throughout a 48-h posttreatment period. Mobility shift assays revealed increased binding activity by nuclear factor-kappa B, interleukin-6 (IL-6) responsive element binding protein, and activating protein 1 (AP-1). Two AP-1 complexes were induced during the acute phase response, and correlation between their presence and transcription activity was demonstrated by transfection studies. Elevated binding activity of AP-1 also correlated with elevated levels of c-jun, junD, junB, and c-fos mRNAs. Western blots showed elevated hepatic levels of c-Jun but not c-Fos proteins during the acute phase response. In addition, IL-6, tumor necrosis factor-alpha, and IL-1 beta, cytokine regulators of the acute phase response, stimulated expression of an AP-1 responsive reporter gene introduced by DNA-mediated transfection into adult rat hepatocytes in primary culture. These findings demonstrate the complexity of AP-1 hepatic transcription factor responses to humoral regulators with direct hepatocellular effects.

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