Interleukin-6 inhibits corticosteroid-binding globulin synthesis by human hepatoblastoma-derived (Hep G2) cells
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Corticosteroid-binding globulin (CBG) belongs to the superfamily of serine proteinase inhibitors which include alpha 1-antitrypsin, alpha 1-antichymotrypsin, and T4-binding globulin. Interleukin-6 (IL-6), the main mediator of the acute phase phenomenon, increases alpha 1-antitrypsin and alpha 1-antichymotrypsin synthesis and decreases T4-binding globulin synthesis by human hepatoblastoma-derived (Hep G2) cells. This effect is predominantly at a transcriptional level. When Hep G2 cells were exposed to different concentrations of IL-6 for variable time intervals, IL-6 caused a dose- and time-dependent decrease in the amount of [35S]methionine-labeled CBG immunoprecipitated in the culture medium. This effect could be greatly reduced by preincubation of IL-6 with its neutralizing antibody and reversed by removing the cytokine from the culture medium. The secretion rate of CBG was not affected by cell exposure to IL-6. CBG mRNA steady state levels were reduced; changes in mRNA were quantitatively similar to changes in secreted protein. Nuclear run-off assays failed to show a change in the rate of transcription of the CBG gene. These data indicate that IL-6 diminishes CBG synthesis by Hep G2 cells acting at a posttranscriptional level, presumably through a reduced stability of mRNA. In view of the role of IL-6 in the inflammatory process and other acute phase phenomena, these data suggest that its effects on CBG synthesis might influence the bioavailability of cortisol indirectly and play a role in regulating the homeostatic process during these conditions.Keywords:
Hepatoblastoma
Transcortin
Vitamin D-binding protein
Immunological and binding methods have been used to demonstrate that acute inflammation induced in the pregnant mouse by a single sc turpentine injection elicits plasma protein responses in the fetal as well as in the maternal compartment. The maternal response involves, along with the classical pattern of positive and negative acute phase reactants seen in the inflammatory nonpregnant animal, a highly specific approximately 2-fold increase of alpha-fetoprotein (AFP) concentrations. In addition, the high pregnancy-associated corticosteroid binding globulin (CBG) levels drop dramatically (2-3 times) in response to inflammation. The fetal response is characterized by small (10-25%) but statistically significant declines of AFP, CBG, and albumin concentrations, without any increase in levels of the positive classical acute phase reactants. The divergent responses of the estrophilic mouse AFP on the two sides of the placental barrier result in a 3- to 4-fold enrichment of the maternal serum vs. an approximately 20% impoverishment of the fetal serum in high affinity estrogen binding sites. The similar decrease in levels of CBG in mother and fetus leads to marked losses of high affinity corticosteroid sites for both. Neither the affinity constants for the estrogen-AFP interactions nor those for the corticosterone-CBG interactions are affected by inflammation. This is the first report of AFP as a positive marker of acute inflammation, of AFP as a pregnancy-specific inflammatory reactant in the mouse, and of a plasma protein response of the fetus in utero to an inflammatory stress undergone by the mother.
Transcortin
Corticosterone
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Transcortin
Corticosterone
Steroid hormone
Sex steroid
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Hepatoblastoma is a rare malignant tumor. One case of hepatoblastoma per 1 million of children under the age of 15 is diagnosed annually in the Republic of Kazakhstan (RK), which corresponds to 5–6 cases per year. In 90% of cases the tumor is diagnosed in children under the age of 5 and has two peaks of incidence: the first peak at birth or within the first month of life, and the second peak between the ages of 16 and 18 months. The cases involving patients older than 5 years are extremely rare. The paper reports the case of female patient, who was diagnosed with hepatoblastoma in the age not typical for malignant neoplasms of this type. The review of hepatoblastoma epidemiology, possible risk factors, clinical manifestations, diagnosis and treatment methods is provided in this issue.
Hepatoblastoma
Liver tumor
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The approximate association constants of the plasma vitamin D binding globulin (Gc-globulin) for 25-hydroxycholecalciferol (25(OH)D3) and the plasma 25(OH)D3 binding capacities were measured in samples from 123 patients with a variety of disorders. No gross differences in binding affinities were observed between different groups of patients and controls. Many patients, however, had moderately reduced, and several had grossly reduced, plasma binding capacities. The changes in Gc-globulin relative to some other proteins are also described in detail in three patients during the course of their illness. Gc-globulin concentration and hence plasma vitamin D binding capacity can undergo rapid and marked changes during illness.
Vitamin D-binding protein
Alpha globulin
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Corticosterone
Steroid hormone
Sex steroid
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Corticosteroids exert inhibitory effects on wound healing. They circulate, largely bound to corticosteroid-binding globulin, and the plasma concentrations of this protein determine their bioavailability. The amount of corticosteroid-binding globulin in wounds and the related effects of burn injury are not known. We have therefore measured corticosteroid-binding globulin in serum and wound fluid obtained from subcutaneously implanted sponges, retrieved 1, 3, and 10 days after insertion in rats. The effect of burning was studied by comparing rats that had a small scald burn with sham-burned control rats. In serum, corticosteroid-binding globulin levels were lower in burned rats than in control animals: the difference was 22%, 28%, and 37% for days 1, 3, and 10, respectively (p < 0.05 for each comparison), and values at day 1 were lower than at days 3 and 10 in control rats (p < 0.05) but not in burned rats. In wound fluid, corticosteroid-binding globulin levels were lower in burned rats than in control animals: the difference was 23%, 24%, and 34% for days 1, 3, and 10, respectively (p < 0.01 for all comparisons), and the values were significantly higher (p < 0.05) at day 1 when compared with values at day 10 in both groups. We therefore conclude that a small burn injury has significant effects on levels of corticosteroid-binding globulin on serum and wound fluid corticosteroid-binding globulin. The decreased concentration of wound fluid corticosteroid-binding globulin at day 10 versus day 1, with a concomitant increase in serum corticosteroid-binding globulin, suggests an accelerated degradation of the protein within the wound; this phenomenon is exaggerated by the burn injury. This is supported by Western blot analysis, which revealed the appearance of a small polypeptide that reacts with an antiserum against rat corticosteroid-binding globulin in wound fluid at day 10.
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Scalding
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AVARIETY of extracellular binding proteins enhance the solubility of steroid hormones in biological fluids and facilitate their transport from steroidogenic tissues to target cells (1). In mammals, albumin is quantitatively the most important of these proteins and provides a large reservoir of loosely bound hormone that may be released within some target tissues (2). Two albumin-related proteins, vitamin D binding protein and α-fetoprotein, also appear to have arisen by duplication of a common ancestral gene (3) and are characterized by higher affinities and specificities for steroid ligands. The molecular composition and structure of the vitamin D binding protein have already been described in detail (4), and this review will concentrate on the molecular properties of two other biologically important classes of extracellular steroid binding proteins: corticosteroid binding globulin (CBG) and the sex-steroid binding proteins; sex hormone binding globulin (SHBG) and androgen binding protein (ABP). These proteins are far less abundant than those of the albumin superfamily, but they bind biologically active steroid hormones with remarkably high affinity and specificity. As a result, they not only transport steroid hormones but also modulate steroid bioavailability (5), and may participate directly in the delivery of steroids to certain cells by interaction with plasma membrane receptors (6). Indeed, it is becoming increasingly obvious that their activities may be attributed to unique structural properties; a greater understanding of which may help define their physiological importance.
Vitamin D-binding protein
Transcortin
Steroid hormone
Androgen-binding protein
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Exposing rats to a single session of inescapable tail shock (IS) reduces corticosteroid binding globulin (CBG) 24 h later (Fleshner et al., Endocrinology 136: 5336-5342, 1995). The present experiments examined whether reductions in CBG are differentially affected by controllable vs. identical uncontrollable tail shock, are mediated by IS-induced glucocorticoid elevation, or reflect IS-induced activation of the acute phase response and whether IS produces fever. The results demonstrate that 1) equivalent reductions in CBG are observed in response to escapable tail shock or yoked IS, 2) IS-induced CBG reduction is not blocked by adrenalectomy in rats that receive basal corticosteroid replacement or by pretreatment with RU-38486, and 3) IS appears to activate the acute phase response, since IS reduces serum levels of an acute-phase negative reactant (CBG), increases serum levels of acute-phase positive reactants (haptoglobin and alpha 1-acid glycoprotein), and increases core body temperature 20-24 h later.
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Basal (medicine)
Haptoglobin
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The current study aimed to investigate the influence of acute stress by shearing procedures on hematological parameters, serum cortisol concentration and serum protein electrophoretic pattern in Comisana sheep. A total of 20 not pregnant and not lactating adult ewes, aged 3−4 years old and with a mean bodyweight of 55.50 ± 3.50 kg, were enrolled in the study. From each animal, blood samples were collected before shearing (TPRE) and 5 (TPOST5) and 60 (TPOST60) minutes after the end of the shearing procedure in order to assess the values of hematological parameters, serum cortisol, total proteins and protein fractions, including albumin, α-, β1-, β2- and γ-globulins. According to statistical analysis results, albumin values were lower at TPOST60 than TPOST5 (p < 0.01), whereas α- and β2-globulins and the A/G ratio were higher at TPOST60 with respect to TPRE (p < 0.01) and TPOST5 (p < 0.01). A higher serum concentration of cortisol was found at TPOST5 and TPOST60 than TPRE (p < 0.01), and at TPOST60 than TPOST5 (p < 0.01). The serum cortisol values were negatively correlated with the serum values of albumin, β1-globulins and A/G ratio at TPOST60, and positively correlated with α- and β2-globulins at TPOST5 and TPOST60. The decrease in the albumin concentration and the increase in the α- and β2-globulins observed in ewes after shearing with respect to the baseline values suggests an acute phase response in shorn ewes. Additionally, the correlation found between the serum cortisol concentration and the serum protein fractions confirmed the immunomodulatory effect of this hormone, emphasizing the linkage between the endocrine and immune systems during an acute stress condition.
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Serum Albumin
Shearing (physics)
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ABSTRACT The influence of age, sex and strain on the serum concentration of transcortin (corticosteroid-binding globulin) and vitamin D-binding protein (DBP) in mice was investigated. The effect of age was studied in two strains, C57BL/6JPfd and BALB/c m HeAPfd. The concentration of transcortin and DBP increased with age. In young animals the concentration of each protein showed a significant strain difference, which disappeared in older mice for DBP, but not for transcortin. In 7-day-old animals, no sex difference was observed for either protein, but in older animals a clear sex difference was found for transcortin. Adult males tended to have somewhat higher levels of DBP than adult females, but this difference was significant only on day 70. The variation in transcortin and DBP levels was further investigated in a large number of mouse strains. The DBP concentration did not markedly vary among strains (5·98–9·65 μmol/l in males and 5·08–8·85 μmol/l in females). Transcortin, however, showed marked strain variations, ranging from 0·72 to 2·06 μmol/l in males and from 1·02 to 4·55 μmol/l in females and there was a significant correlation ( r = 0·66, n = 26, P <0·001) between the mean transcortin levels in males and females of different strains. Interstrain variation was much higher than intrastrain variation or variation among related strains, suggesting that the transcortin concentration is largely controlled by genetically determined factors. There was a significant correlation ( r = 0·82, n = 9, P <0·01) between the mean corticosterone and transcortin concentrations (measured at 21.00 h). Consequently, differences in the free corticosterone levels in the serum of various mouse strains were smaller than the differences in the total corticosterone concentrations. The affinity of transcortin for corticosterone was similar in all but one strain; however, transcortin of the RIIIS/J strain showed a lower affinity for corticosterone. J. Endocr. (1986) 109, 141–147
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Vitamin D-binding protein
Serum concentration
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