Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.16.3.1 (ceruloplasmin)
5,074 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The body's protective responses to infection, wounding, trauma, and malignancy include the acute-phase reaction, which is modulated by various cytokines and their cellular receptors. During the acute-phase reaction, levels of specific proteins synthesized by the liver increase in the plasma. Little information is available about the extrahepatic synthesis of plasma proteins during the acute-phase reaction. The study described here analyzes the tissue-specific expression of genes encoding the plasma proteins albumin (ALB), alpha 1-antitrypsin (AAT), transferrin (TF), haptoglobin (HP), ceruloplasmin (CP), serum amyloid A (SAA), alpha 1-acid glycoprotein (AGP) and alpha 2-HS-glycoprotein (AHSG) during the acute-phase reaction in C57B1 mice. The acute-phase reaction was induced by intraperitoneal injections of bacterial lipopolysaccharide (LPS). During the acute-phase reaction, genes encoding CP, SAA, AGP, and HP demonstrate unique extrahepatic tissue specific patterns of expression in kidney, spleen, thymus, heart, brain, lung, testis, and epididymis. Different temporal patterns of HP gene expression also were observed in lung and thymus after induction by LPS. The function of extrahepatic synthesis of plasma proteins is not yet understood; however, a local provision of specific plasma proteins in mammalian tissues may offer the host a source of functionally important proteins during periods of stress.
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PMID:Extrahepatic expression of plasma protein genes during inflammation. 175 24

Because a number of different cytokines have been reported to regulate the synthesis of human, murine, and rat acute phase proteins (APP), we studied the effect of cytokines on production of several major human APP in a single system, the human hepatoma cell line Hep 3B. Conditioned medium (CM) prepared from human blood monocytes activated with LPS in the presence of dexamethasone led to substantial induction of serum amyloid A (SAA) and C-reactive protein (CRP) synthesis whereas the defined cytokines IL-1 beta, TNF alpha, and medium from a human keratinocyte cell line (COLO-16), containing hepatocyte-stimulating factor activity, failed to induce these two major APP. Induction of SAA and CRP was accompanied by an increase in concentration of their specific mRNA. Size fractionation of CM from activated monocytes by fast protein liquid chromatography indicated that SAA- and CRP-inducing activity eluted as a single peak with a Mr of approximately 18 kDa. alpha 1-Antitrypsin, which also failed to respond to IL-1 beta or TNF alpha, was induced by both CM and medium from COLO-16 cells. The induction of AT by CM was accompanied by an increase in specific mRNA. Induction of ceruloplasmin and alpha 1-antichymotrypsin and decrease in the synthesis of albumin was achieved by both CM and IL-1 beta. Ceruloplasmin and albumin responded in a comparable fashion to both TNF alpha and medium from COLO-16 cells; the response of ACT to these cytokines was not evaluated. These results indicate that human SAA and CRP are induced in Hep 3B cells by products of activated monocytes but not by IL-1 beta, TNF-alpha, or some hepatocyte-stimulating factor preparations and that a group of heterogeneous mechanisms are involved in the induction of the various human APP.
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PMID:Heterogeneous nature of the acute phase response. Differential regulation of human serum amyloid A, C-reactive protein, and other acute phase proteins by cytokines in Hep 3B cells. 245 96

We defined the acute phase behaviour of a number of rabbit plasma proteins in studies (in vivo) and studied the effects of monokine preparations on their synthesis by rabbit primary hepatocyte cultures. Following turpentine injection, increased serum levels of C-reactive protein, serum amyloid A protein, haptoglobin, ceruloplasmin, and decreased concentrations of albumin were observed. In contrast to what is observed in man, concentrations of alpha 2-macroglobulin and transferrin were increased. Co-culture of primary hepatocyte cultures with lipopolysaccharide-activated human peripheral blood monocytes or incubation with conditioned medium prepared from lipopolysaccharide-activated human or rabbit monocytes resulted in dose-dependent induction of serum amyloid A, haptoglobin, ceruloplasmin and transferrin and depression of albumin synthesis, while C-reactive protein synthesis and mRNA levels remained unchanged. A variety of interleukin-1 preparations induced dose-dependent increases in the synthesis and secretion of serum amyloid A, haptoglobin, ceruloplasmin and transferrin and decreased albumin synthesis. Human recombinant tumour necrosis factor (cachectin) induced a dose-dependent increase in synthesis of haptoglobin and ceruloplasmin. In general, human interleukin-1 was more potent than mouse interleukin-1 and tumour necrosis factor. None of the monokines we studied had an effect on C-reactive protein synthesis or mRNA levels. These data confirm that C-reactive protein, serum amyloid A, haptoglobin and ceruloplasmin display acute phase behaviour in the rabbit, and demonstrate that, in contrast to their behaviour in man, alpha 2M and transferrin are positive acute phase proteins in this species. While both interleukin-1 and tumour necrosis factor regulate biosynthesis of a number of these acute phase proteins in rabbit primary hepatocyte cultures, neither of these monokines induced C-reactive protein synthesis. Comparison of these findings with those in human hepatoma cell lines, in which interleukin-1 does not induce serum amyloid A synthesis, suggests that the effect of interleukin-1 on serum amyloid A synthesis may be indirect.
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PMID:Regulation of rabbit acute phase protein biosynthesis by monokines. 246 85

Interleukin 6 (IL6) is the new definition of a group of cytokines previously named according to their biological activity, e.g. B cell stimulatory factor 2 (BSF-2), hybridoma plasmocytoma-growth factor (HGF), interferon-beta 2 (IFN-beta 2), hepatocyte stimulating factor (HSF). It has recently been suggested that IL6 may represent the major mediator of acute-phase protein response whereas IL1 beta and TNF-alpha could play a minor role. We compared the effect of the three cytokines on hepatic protein synthesis by performing in vitro as well as in vivo experiments. Human hepatoma cells (PLC/PRF5) were exposed to each cytokine separately for 20 h, and the effect was then studied at the protein and RNA level. All three cytokines reduced albumin and increased C3 and ceruloplasmin biosynthesis. The cytokines induced the same effect at the RNA level indicating that the modulation was pretranslational. The effect of the cytokines was specific since actin gene expression was not changed; furthermore the effect was blocked by specific antibodies against the cytokines. The effect of the single cytokines was dose and time dependent, and quantitatively comparable. None of the cytokines was able to alter alpha 1-anti-trypsin synthesis. In vivo experiments with mice showed that IL1 beta and TNF-alpha both induce serum amyloid A (SAA) mRNA in the mouse liver and increase factor B (Bf) gene expression. Human recombinant IL6 induced SAA gene expression and it also had a weak positive effect on Bf gene expression after i.p. injection. These data demonstrate that the three cytokines studied are quantitatively and qualitatively comparable, and that all three are probably involved in acute-phase protein response.
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PMID:Interleukin 6, the third mediator of acute-phase reaction, modulates hepatic protein synthesis in human and mouse. Comparison with interleukin 1 beta and tumor necrosis factor-alpha. 313 37

AS101 (ammonium trichloro(dioxyethylene-0,0')tellurate) is a new synthetic compound previously described by us as having immunomodulating properties and minimal toxicity. Phase II clinical trials are currently in progress with AS101 on cancer patients. AS101 has been recently found to have both radioprotective and chemoprotective effects on hemopoiesis of irradiated mice or mice treated with various chemotherapeutic drugs. The present research was designed to study the in vivo induction of liver acute phase proteins secretion in mice or patients treated with AS101. Induction of these proteins, some of which have the capacity to scavenge free radicals, may contribute to radioprotection. We present evidence that treatment with the immunomodulator AS101 increases production of a variety of acute phase proteins. We demonstrate a significant elevation of serum amyloid A (SAA) in sera of treated mice, as well as an increase in SAA, factor B and ceruloplasmin in sera of patients treated with AS101. The same AS101 treatment was shown to decrease the amount of the negative acute phase protein, albumin. In addition we show that IL-1, IL-6 and TNF-alpha are important mediators of changes in SAA concentrations induced by AS101. Abrogation of SAA production in AS101 treated mice by any one of the anti IL-1R, IL-6R or TNF-alpha antibodies indicates that at least in mice, SAA production is not controlled by a single extracellular signal, but rather it is regulated, at the least, by all three cytokines in various combinations. A better understanding of the mechanism by which AS101 confers radioprotection will enable us to use it more effectively in the restoration of hemopoiesis in patients following radiation or suffering from overdose or accidental radiation.
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PMID:Induction of acute phase proteins in mice and humans by treatment with AS101, an immunomodulator with radioprotective properties. 753 80

alpha 2-Macroglobulin, a major acute phase reactant in many species, increases in the Richardson's ground squirrel (Spermophilus richarsonii) during hibernation at the level of both mRNA and protein. To determine if the pattern of liver gene expression known as the acute phase response is elicited as a normal part of the physiological adaptation of hibernation, acute phase reactants were identified in the Richardson's ground squirrel and were then assayed for changes in mRNA expression in the livers of active and hibernating ground squirrels. Our data demonstrate that alpha 1-antitrypsin, alpha 2-macroglobulin, ceruloplasmin, C-reactive protein, and serum amyloid A are acute phase reactants in the Richardson's ground squirrel. Of these, only alpha 2-macroglobulin (alpha 2M) mRNA increases during hibernation, demonstrating that the entire acute phase response is not elicited as a part of the adaptation for hibernation. Alternatively, data from blood clotting assays of serum from active and hibernating animals support a role for the increase in alpha 2M protein during hibernation in decreasing the coagulative properties of the blood.
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PMID:alpha 2-Macroglobulin gene expression during hibernation in ground squirrels is independent of acute phase response. 754 65

IL-6, tumour necrosis factor-alpha (TNF-alpha) and IL-1 are thought to be the key mediators of the acute phase response although much of the evidence is based on in vitro studies. It is not clear to what extent each of the acute phase proteins are regulated in vivo by each of these cytokines. The aim of this study was to examine the effects of IL-6 treatment in eight patients with cancer on the concentrations of an extensive range of positive and negative acute phase proteins. It was part of a larger investigation to assess the value of IL-6 in the management of chemotherapy-induced thrombocytopenia. IL-6 was administered by a daily subcutaneous injection for 7 days at a dose level of 1, 3, or 10 micrograms/kg/day. Increases in the positive acute phase proteins, serum amyloid A, C-reactive protein, alpha 1-acid glycoprotein, alpha 1-antichymotrypsin, haptoglobin, alpha 1-antitrypsin, fibrinogen, complement component C3, and caeruloplasmin, were observed, with the greatest incremental changes and fastest responses being seen for C-reactive protein and serum amyloid A protein. The negative acute phase proteins transferrin, transthyretin and retinol binding protein all fell to a nadir within 48-96 h after the first IL-6 injection. Increases in complement component C4 were only found in two patients, which may be related to the increase in circulating TNF-alpha concentrations found only in these patients. This study has therefore shown that IL-6 is capable of causing changes in the majority of acute phase proteins in vivo. Although secondary induction of TNF-alpha was not observed in the majority of patients examined, it is still possible however that other cytokines involved in regulation of the acute phase response, such as IL-1, may have been induced and contributed to the overall response.
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PMID:The acute phase protein response in patients receiving subcutaneous IL-6. 755 93

The availability of the IL-1R antagonist (IL-1ra) has made it possible to assess the specific contributions of IL-1 to the acute phase changes induced by complex mixtures of cytokines. We utilized IL-1ra to define the contribution of IL-1 to the effects of conditioned medium from LPS-stimulated monocytes on production of the positive acute phase proteins C-reactive protein, serum amyloid A, fibrinogen, alpha 1-protease inhibitor, complement component C3, alpha 1-antichymotrypsin, alpha 1-acid glycoprotein, and ceruloplasmin and the negative acute phase proteins albumin and transferrin in Hep 3B cells. Induction of C-reactive protein and serum amyloid A was essentially abolished, induction of complement component C3 and alpha 1-acid glycoprotein was moderately decreased and induction of fibrinogen was enhanced. In contrast, there was no significant effect of IL-1ra on induction by conditioned medium of alpha 1-protease inhibitor, alpha 1-antichymotrypsin, or ceruloplasmin. IL-1ra partially blocked the down-regulatory effects of conditioned medium on both of the negative acute phase proteins we studied--albumin and transferrin. These findings enhance our understanding of the contribution of IL-1 to the acute phase response. In addition, they indicate that IL-1ra in vivo may influence synthesis of both positive and negative acute phase proteins.
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PMID:IL-1 receptor antagonist affects the plasma protein response of Hep 3B cells to conditioned medium from lipopolysaccharide-stimulated monocytes. 768 88

The acute phase proteins (APPs) have been empirically defined as those whose plasma concentration changes following inflammatory reaction. Those proteins whose concentrations increase are referred to as positive APP, while those whose levels decline are termed negative APP. In man, positive APP are: alpha 1 acid glycoprotein, alpha 1 protease inhibitor, alpha 1 antichymotrypsin, haptoglobin, ceruloplasmin, fibrinogen, C-reactive protein, serum amyloid A. Great variability in the APP response between different species is observed. The principal functions of APP, result from the interaction of these proteins with ligands of various origins which give "protein-ligands" complexes. These complexes are cleared by the RES or by the hepatocyte. The results are protease inhibition, neutralization of toxic molecules such as hemoglobin or the superoxide anion, clearance of cell membranes and chromatin. The drop of the plasma concentration of negative APP during an inflammatory reaction carries a rise of free ligands (fatty acids, hormones, vitamins, trace elements). IL6 has been recognized as the principal regulator of most APP genes. The response of the hepatic cell to IL6 is characterized by the enhanced production of type 2 or IL6 specific APPs. The biochemical process of signal transduction is IL6--JAK2--APRF The set of APP genes regulated by IL1 type cytokines (type 1 APPs) is distinct from that regulated by IL6 type cytokine. IL1 and TNF alpha mediated stimulation of type 1 APP genes is synergistically enhanced by IL6 type cytokines. The biochemical process of signal transduction is IL1, IL6--Ras--MAP kinase--NFIL6 The targeted inflammatory proteic profile including the assay of C-reactive protein, haptoglobin and alpha 1 acid glycoprotein produces a "biological tool" to the clinician in order to manage an inflammatory response. IL6, a proteic marker for the future, connected with CRP, will be assayed during early inflammatory reaction.
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PMID:[Acute-phase proteins in inflammation]. 856 70

We previously reported that high density lipoprotein (HDL) protects against the oxidative modification of low density lipoprotein (LDL) induced by artery wall cells causing these cells to produce pro-inflammatory molecules. We also reported that enzyme systems associated with HDL were responsible for this anti-inflammatory property of HDL. We now report studies comparing HDL before and during an acute phase response (APR) in both humans and a croton oil rabbit model. In rabbits, from the onset of APR the protective effect of HDL progressively decreased and was completely lost by day three. As serum amyloid A (SAA) levels in acute phase HDL (AP-HDL) increased, apo A-I levels decreased 73%. Concomitantly, paraoxonase (PON) and platelet activating factor acetylhydrolase (PAF-AH) levels in HDL declined 71 and 90%, respectively, from days one to three. After day three, there was some recovery of the protective effect of HDL. AP-HDL from human patients and rabbits but not normal or control HDL (C-HDL) exhibited increases in ceruloplasmin (CP). This increase in CP was not seen in acute phase VLDL or LDL. C-HDL incubated with purified CP and re-isolated (CP-HDL), lost its ability to inhibit LDL oxidation. Northern blot analyses demonstrated enhanced expression of MCP-1 in coculture cells treated with AP-HDL and CP-HDL compared to C-HDL. Enrichment of human AP-HDL with purified PON or PAF-AH rendered AP-HDL protective against LDL modification. We conclude that under basal conditions HDL serves an anti-inflammatory role but during APR displacement and/or exchange of proteins associated with HDL results in a pro-inflammatory molecule.
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PMID:Anti-inflammatory HDL becomes pro-inflammatory during the acute phase response. Loss of protective effect of HDL against LDL oxidation in aortic wall cell cocultures. 867 45


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