An In Vitro and In Vivo Study of Cytokines in the Acute-Phase Response Associated with Bisphosphonates

ABSTRACT Regulation of a number of aspects of the acute-phase response, including induction of fever and activation of the hypothalamo-pituitary-adrenal axis, occurs within the hypothalamus. The acute-phase response appears to be co-ordinated by the inflammatory cytokine interleukin-1 (IL-1). A number of studies using hybridization techniques to measure IL-1 gene expression and immunocyto-chemistry to localize immunoactive IL-1 have established the concept that the central nervous system, and in particular the hypothalamus, is a site of IL-1 production, and that levels increase in response to inflammatory stimuli. In this report we present data on the levels of IL-1β produced in the rat hypothalamus using quantitative immunoassay techniques. Bacterial endotoxin, administered to rats in vivo, evoked increases in hypothalamic IL-1β levels which were significant within 1 h, and reached maximum levels at 5–10 h. The response to endotoxin was dose-related, and levels reached in hypothalamic extracts corresponded to intra-hypothalamic levels of the order of 20 ng/ml. During short-term in-vitro culture of rat hypothalami, endotoxin stimulated a dose-related increase in both the synthesis and the secretion of IL-1β, which reached similar levels to those seen after in-vivo stimulation. Hypothalami obtained from animals stimulated with endotoxin in vivo did not, however, show any evidence of persistent stimulation of IL-1β production when subsequently cultured in vitro. These data support the concept that production of hypothalamic IL-1 is an essential step in regulating the activity of the hypothalamus during the acute-phase response, and provide for the first time quantitative data on the magnitude, dose—response relationships and time-courses of rat hypothalamic IL-1β production in vivo and in vitro.

Download Full-text

In vitro release of ?1-acid glycoprotein RNA sequences shows fidelity with the acute phase response in vivo

Molecular Biology Reports ◽

10.1007/bf00419737 ◽

1986 ◽

Vol 11 (3) ◽

pp. 163-172 ◽

Cited By ~ 7

Author(s):

G. A. Clawson ◽

J. Button ◽

C. H. Woo ◽

Yu-Cheng Liao ◽

E. A. Smuckler

Keyword(s):

Acute Phase ◽

Acute Phase Response ◽

In Vitro Release ◽

Phase Response ◽

Rna Sequences ◽

Acid Glycoprotein ◽

Vitro Release

Download Full-text

Chylomicron-bound LPS inhibits activation of the acute phase response in vitro and in vivo

Journal of Surgical Research ◽

10.1016/j.jss.2003.08.106 ◽

2003 ◽

Vol 114 (2) ◽

pp. 303

Author(s):

J.S. Chang ◽

D.H. Lee ◽

A.E. Falor ◽

F. Kasravi ◽

H.W. Harris

Keyword(s):

Acute Phase ◽

Acute Phase Response ◽

Phase Response

Download Full-text

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

Biochemical Journal ◽

10.1042/bj20031256 ◽

2004 ◽

Vol 377 (3) ◽

pp. 763-768 ◽

Cited By ~ 11

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.

Download Full-text

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

Biochemical Journal ◽

10.1042/bj2200631 ◽

1984 ◽

Vol 220 (3) ◽

pp. 631-637 ◽

Cited By ~ 17

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.

Download Full-text

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

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00522.2003 ◽

2004 ◽

Vol 287 (4) ◽

pp. E750-E757 ◽

Cited By ~ 20

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.

Download Full-text

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

Clinical Science ◽

10.1042/cs0740477 ◽

1988 ◽

Vol 74 (5) ◽

pp. 477-483 ◽

Cited By ~ 5

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.

Download Full-text

Hormonal and metabolic response to recombinant human tumor necrosis factor in rat: in vitro and in vivo

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1988.255.2.e206 ◽

1988 ◽

Vol 255 (2) ◽

pp. E206-E212

Author(s):

R. S. Warren ◽

H. F. Starnes ◽

N. Alcock ◽

S. Calvano ◽

M. F. Brennan

Keyword(s):

Tumor Necrosis Factor ◽

Trace Metal ◽

Acute Phase ◽

Acute Phase Response ◽

Tumor Necrosis ◽

Metabolic Response ◽

Zinc Transport ◽

Necrosis Factor

Tumor necrosis factor (TNF; cachectin) has been implicated as a mediator of the toxic manifestations of overwhelming bacterial infection as well as the chronic catabolic state of cancer cachexia. We have examined the acute metabolic and hormonal response after administration of recombinant human TNF in the rat. TNF given by intraperitoneal injection produced dose- and time-related increases in hepatic amino acid uptake, decreases in serum trace metal concentrations, and a pattern of endocrine hormone alterations characteristic of the acute phase response to tissue injury. In vitro zinc transport studies by rat hepatocytes cultured in the presence of TNF alone, or in combination with recombinant human interleukin 1, another mediator of the acute phase response, demonstrated that neither monokine was capable of directly stimulating zinc transport into cells. These findings suggest that TNF may function as an endogenous mediator of the early metabolic response to sepsis and that the trace metal changes induced by TNF in vivo may occur through a secondary mechanism.

Download Full-text

Epigenetic Modulation by Apabetalone Counters Cytokine-Driven Acute Phase Response In Vitro, in Mice and in Patients with Cardiovascular Disease

Cardiovascular Therapeutics ◽

10.1155/2020/9397109 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12

Author(s):

Sylwia Wasiak ◽

Dean Gilham ◽

Emily Daze ◽

Laura M. Tsujikawa ◽

Christopher Halliday ◽

...

Keyword(s):

Cardiovascular Disease ◽

Acute Phase ◽

Acute Phase Response ◽

Phase Response ◽

Serum Amyloid ◽

Cytokine Signaling ◽

Serum Amyloid P ◽

Gene And Protein Expression ◽

Amyloid P

Chronic systemic inflammation contributes to cardiovascular disease (CVD) and correlates with the abundance of acute phase response (APR) proteins in the liver and plasma. Bromodomain and extraterminal (BET) proteins are epigenetic readers that regulate inflammatory gene transcription. We show that BET inhibition by the small molecule apabetalone reduces APR gene and protein expression in human hepatocytes, mouse models, and plasma from CVD patients. Steady-state expression of serum amyloid P, plasminogen activator inhibitor 1, and ceruloplasmin, APR proteins linked to CVD risk, is reduced by apabetalone in cultured hepatocytes and in humanized mouse liver. In cytokine-stimulated hepatocytes, apabetalone reduces the expression of C-reactive protein (CRP), alpha-2-macroglobulin, and serum amyloid P. The latter two are also reduced by apabetalone in the liver of endotoxemic mice. BET knockdown in vitro also counters cytokine-mediated induction of the CRP gene. Mechanistically, apabetalone reduces the cytokine-driven increase in BRD4 BET occupancy at the CRP promoter, confirming that transcription of CRP is BET-dependent. In patients with stable coronary disease, plasma APR proteins CRP, IL-1 receptor antagonist, and fibrinogen γ decrease after apabetalone treatment versus placebo, resulting in a predicted downregulation of the APR pathway and cytokine targets. We conclude that CRP and components of the APR pathway are regulated by BET proteins and that apabetalone counters chronic cytokine signaling in patients.

Download Full-text