Corticotrophin-releasing factor as a mediator of the acute-phase response in rats, mice and rabbits

1993 ◽  
Vol 136 (2) ◽  
pp. 207-216 ◽  
Author(s):  
P. M. Hagan ◽  
S. Poole ◽  
A. F. Bristow
Keyword(s):  
Protein Synthesis ◽  
Acute Phase ◽  
Acute Phase Response ◽  
Acute Phase Proteins ◽  
Acute Phase Protein ◽  
Phase Response ◽  
Interleukin 1Β ◽  
Corticotrophin Releasing Factor ◽  
Phase Protein

ABSTRACT The acute-phase response involves a number of separate physiological components, including induction of acute-phase protein synthesis by the liver. This response can be induced in vivo by administration of the endogenous leucocytic mediator interleukin-1β. A number of in-vivo effects of interleukin-1β have been reported to be mediated by corticotrophin-releasing factor (CRF), including activation of the hypothalamo-pituitary-adrenal axis and induction of fever, and in this report we have examined a possible involvement of CRF in mediating interleukin-1β-induced acute-phase protein synthesis. Interleukin-1β stimulated the elevation of species-specific plasma acute-phase proteins in rats, mice and rabbits. Co-injection of interleukin-1β with the specific CRF receptor antagonist α-helical-CRF9–41 NH2 abolished or attenuated acute-phase protein synthesis induced by interleukin-1β in all three species for up to 12 h after injection. The inhibitory effect of α-helical-CRF9–41NH2 was reduced or absent 24 h after injection. Neutralizing anti-CRF antisera had no effect on acute-phase protein synthesis in the mouse and, paradoxically, potentiated acute-phase protein synthesis induced by interleukin-1β in the rat. These results indicate a possible mediatory role for CRF in regulation of acute-phase protein synthesis, and suggest that CRF may mediate induction of acute-phase protein synthesis by a different mechanism from that involved in regulation of corticotrophin secretion. Journal of Endocrinology (1993) 136, 207–216

Ciliary neurotrophic factor is catabolic and shares with IL-6 the capacity to induce an acute phase response

1996 ◽  
Vol 271 (1) ◽  
pp. R185-R190 ◽  
Author(s):  
N. J. Espat ◽  
T. Auffenberg ◽  
J. J. Rosenberg ◽  
M. Rogy ◽  
D. Martin ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Acute Phase ◽  
Neurotrophic Factor ◽  
Acute Phase Response ◽  
Acute Phase Protein ◽  
Ciliary Neurotrophic Factor ◽  
Phase Response ◽  
Phase Protein

Ciliary neurotrophic factor (CNTF), a member of the interleukin-6 (IL-6) superfamily, has recently been shown to induce several inflammatory responses when administered to healthy animals, including induction of fever and a hepatic acute phase protein response. In the present report, 250 micrograms.kg body wt-1.day-1 of recombinant rat CNTF or murine IL-6 were repeatedly administered to healthy mice over a 7-day period in an effort to compare biological responses. In addition to its in vivo capacity to elicit a hepatic acute phase response, administration of CNTF, but not IL-6, produced profound anorexia and lean tissue wasting in mice. In C57B1/6 mice, 7 days of CNTF administration led to a 21% loss in carcass protein content, resulting from carcass protein breakdown rates being increased 218% over freely fed controls (both P < 0.01). Protein synthesis rates in carcass protein were also increased in CNTF-treated mice compared with both freely fed animals and mice pair-fed equivalent quantities of food. In contrast, administration of equivalent quantities of murine IL-6 had no effect on food intake or body weight in mice, although IL-6 produced a similar hepatic acute phase response, as determined by increases in serum amyloid P and seromucoid fraction and increases in total hepatic protein synthesis. However, when CNTF was coincubated with extensor digitorum longus muscles from juvenile rats in vitro, rates of total muscle and myofibrillar protein degradation and muscle protein synthesis were unchanged. We conclude that CNTF can regulate in vivo both skeletal muscle remodeling as well as the distant anorexia and hepatic acute phase protein responses. In the case of skeletal muscle, these actions are both indirect and independent of the associated anorexia. These properties of CNTF are distinct from IL-6, which when administered to the mouse at these doses is neither anorexigenic nor cachexia producing.

scholarly journals The acute-phase response in (NZB X NZW)F1 and MRL/l MICE.

1982 ◽  
Vol 156 (4) ◽  
pp. 1268-1273 ◽  
Author(s):  
C Rordorf ◽  
H P Schnebli ◽  
M L Baltz ◽  
G A Tennent ◽  
M B Pepys
Keyword(s):  
Acute Phase ◽  
Acute Phase Response ◽  
Acute Phase Proteins ◽  
Acute Phase Protein ◽  
Phase Response ◽  
Serum Amyloid ◽  
Human Rheumatoid Arthritis ◽  
Amyloid A ◽  
Serum Amyloid A Protein ◽  
Phase Protein

The acute-phase plasma protein response to disease activity in murine models of autoimmune lupus-like disease was investigated by measurement of the concentration of serum amyloid P component (SAP) in NZB X W and MRL/l mice. The levels of SAP, which is a major acute-phase protein in mice, did not rise at all in response to progression of disease in NZB X W mice between the ages of 1 and 9 mo. This resembles the behavior of acute-phase proteins such as C-reactive protein and serum amyloid A protein in human systemic lupus erythematosus, and just as in human lupus, where the occurrence of intercurrent microbial infection can stimulate an acute-phase response, so injection of bacterial lipopolysaccharide or casein into the NZB X W mice stimulated "normal" acute-phase SAP production. In marked contrast, MRL/l mice developed greatly increased levels of SAP, which correlated closely with progression of their pathology as they aged. The disease profile of the MRL/l strain includes rheumatoid factors and spontaneous polyarthritis and their SAP response resembles the behavior of acute phase proteins in human rheumatoid arthritis. Different patterns of acute-phase response in different autoimmune disorders may thus be a reflection of the genetic predisposition to particular diseases and/or contribute to their pathogenesis. The existence of animal counterparts for the various clinical patterns of human acute-phase protein production will assist in experimental investigation of the underlying mechanisms and of the biological role of the acute-phase response.

scholarly journals Induction and Modulation of Acute-Phase Response by Protein Malnutrition in Rats: Comparative Effect of Systemic and Localized Inflammation on Interleukin-6 and Acute-Phase Protein Synthesis

1998 ◽  
Vol 128 (2) ◽  
pp. 166-174 ◽  
Author(s):  
Saı̈d Lyoumi ◽  
Fabienne Tamion ◽  
Jean Petit ◽  
Pierre Déchelotte ◽  
Claudine Dauguet ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Acute Phase ◽  
Interleukin 6 ◽  
Acute Phase Response ◽  
Acute Phase Protein ◽  
Protein Malnutrition ◽  
Phase Response ◽  
Comparative Effect ◽  
Phase Protein

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.

Acute-phase response of human hepatocytes: Regulation of acute-phase protein synthesis by interleukin-6

Hepatology ◽  
1990 ◽  
Vol 12 (5) ◽  
pp. 1179-1186 ◽  
Author(s):  
José V. Castell ◽  
Maria José Gómez-lechón ◽  
Martina David ◽  
Ricardo Fabra ◽  
Ramón Trullenque ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Acute Phase ◽  
Interleukin 6 ◽  
Acute Phase Response ◽  
Acute Phase Protein ◽  
Human Hepatocytes ◽  
Phase Response ◽  
Phase Protein

scholarly journals Acute-phase response factor, a nuclear factor binding to acute-phase response elements, is rapidly activated by interleukin-6 at the posttranslational level

1993 ◽  
Vol 13 (1) ◽  
pp. 276-288
Author(s):  
U M Wegenka ◽  
J Buschmann ◽  
C Lütticken ◽  
P C Heinrich ◽  
F Horn
Keyword(s):  
Transcriptional Regulation ◽  
Acute Phase ◽  
Interleukin 6 ◽  
Acute Phase Response ◽  
Acute Phase Protein ◽  
Phase Response ◽  
Response Factor ◽  
Nuclear Factor ◽  
Response Elements ◽  
Phase Protein

Interleukin-6 (IL-6) is known to be a major mediator of the acute-phase response in liver. We show here that IL-6 triggers the rapid activation of a nuclear factor, termed acute-phase response factor (APRF), both in rat liver in vivo and in human hepatoma (HepG2) cells in vitro. APRF bound to IL-6 response elements in the 5'-flanking regions of various acute-phase protein genes (e.g., the alpha 2-macroglobulin, fibrinogen, and alpha 1-acid glycoprotein genes). These elements contain a characteristic hexanucleotide motif, CTGGGA, known to be required for the IL-6 responsiveness of these genes. Analysis of the binding specificity of APRF revealed that it is different from NF-IL6 and NF-kappa B, transcription factors known to be regulated by cytokines and involved in the transcriptional regulation of acute-phase protein genes. In HepG2 cells, activation of APRF was observed within minutes after stimulation with IL-6 or leukemia-inhibitory factor and did not require ongoing protein synthesis. Therefore, a preexisting inactive form of APRF is activated by a posttranslational mechanism. We present evidence that this activation occurs in the cytoplasm and that a phosphorylation is involved. These results lead to the conclusions that APRF is an immediate target of the IL-6 signalling cascade and is likely to play a central role in the transcriptional regulation of many IL-6-induced genes.

scholarly journals Acute-phase response factor, a nuclear factor binding to acute-phase response elements, is rapidly activated by interleukin-6 at the posttranslational level.

1993 ◽  
Vol 13 (1) ◽  
pp. 276-288 ◽  
Author(s):  
U M Wegenka ◽  
J Buschmann ◽  
C Lütticken ◽  
P C Heinrich ◽  
F Horn
Keyword(s):  
Transcriptional Regulation ◽  
Acute Phase ◽  
Interleukin 6 ◽  
Acute Phase Response ◽  
Acute Phase Protein ◽  
Phase Response ◽  
Response Factor ◽  
Nuclear Factor ◽  
Response Elements ◽  
Phase Protein

Interleukin-6 (IL-6) is known to be a major mediator of the acute-phase response in liver. We show here that IL-6 triggers the rapid activation of a nuclear factor, termed acute-phase response factor (APRF), both in rat liver in vivo and in human hepatoma (HepG2) cells in vitro. APRF bound to IL-6 response elements in the 5'-flanking regions of various acute-phase protein genes (e.g., the alpha 2-macroglobulin, fibrinogen, and alpha 1-acid glycoprotein genes). These elements contain a characteristic hexanucleotide motif, CTGGGA, known to be required for the IL-6 responsiveness of these genes. Analysis of the binding specificity of APRF revealed that it is different from NF-IL6 and NF-kappa B, transcription factors known to be regulated by cytokines and involved in the transcriptional regulation of acute-phase protein genes. In HepG2 cells, activation of APRF was observed within minutes after stimulation with IL-6 or leukemia-inhibitory factor and did not require ongoing protein synthesis. Therefore, a preexisting inactive form of APRF is activated by a posttranslational mechanism. We present evidence that this activation occurs in the cytoplasm and that a phosphorylation is involved. These results lead to the conclusions that APRF is an immediate target of the IL-6 signalling cascade and is likely to play a central role in the transcriptional regulation of many IL-6-induced genes.

scholarly journals Canine Acute Phase Response: Relationship between Serum Cytokine Activity and Acute Phase Protein in Dogs.

1994 ◽  
Vol 56 (3) ◽  
pp. 487-492 ◽  
Author(s):  
Kazuto YAMASHITA ◽  
Toru FUJINAGA ◽  
Toru MIYAMOTO ◽  
Mitsuyoshi HAGIO ◽  
Yasuharu IZUMISAWA ◽  
...  
Keyword(s):  
Acute Phase ◽  
Acute Phase Response ◽  
Acute Phase Protein ◽  
Phase Response ◽  
Response Relationship ◽  
Serum Cytokine ◽  
Phase Protein

scholarly journals Interleukin-6 Downregulates Factor XII Production by Human Hepatoma Cell Line (HepG2)

Blood ◽  
1997 ◽  
Vol 90 (4) ◽  
pp. 1501-1507
Author(s):  
Franca Citarella ◽  
Angelina Felici ◽  
Mieke Brouwer ◽  
John Wagstaff ◽  
Antonio Fantoni ◽  
...  
Keyword(s):  
Acute Phase ◽  
Acute Phase Response ◽  
Acute Phase Proteins ◽  
Acute Phase Protein ◽  
Hepatoma Cell ◽  
Hepatoma Cell Line ◽  
Factor Xii ◽  
Human Hepatoma Cell ◽  
Phase Protein ◽  
Hepatoma Cell Line Hepg2

Involvement of the contact system of coagulation in the pathogenesis of various inflammatory diseases is suggested by reduced plasma levels of factor XII (Hageman factor) and prekallikrein generally considered to result from activation of the contact system. However, in many of these diseases patients develop an acute-phase response and, therefore, an alternative explanation for the decreased levels of factor XII could be the downregulation of factor XII gene expression in the liver as described for negative acute-phase proteins. We report here that interleukin-6 (IL-6), the principal cytokine mediating the synthesis of most acute-phase proteins in the liver, downregulates the production of factor XII by the human hepatoma cell line HepG2 by up to 75%. The decrease in protein secretion correlated with an equivalent decrease of factor XII mRNA likely indicating a pretranslational control of factor XII gene expression by IL-6. Downregulation of factor XII production by IL-6 in vitro parallelled that of transthyretin, a known negative acute-phase protein. Moreover, we show that, in patients developing an acute-phase response after immunotherapy with IL-2, plasma levels of factor XII correlate (r = .76, P < .0001) with those of transthyretin. Taken together, these results suggest that factor XII behaves as a negative acute-phase protein.

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.

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