Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

During inflammatory states, hepatocytes are induced to synthesize and secrete a group of proteins called acute-phase proteins. It has recently been shown that besides interleukin-6 (IL-6), related cytokines such as leukemia inhibitory factor, oncostation M and interleukin-11 are also mediators of the hepatic acute-phase response. All these mediators belong to the hematopoietic family of alpha-helical cytokines. Here we show that an additional member of this cytokine family, ciliary neurotrophic factor (CNTF), induces the hepatic acute-phase protein genes haptoglobin, alpha 1-antichymotrypsin, alpha 2-macroglobulin and beta-fibrinogen in human hepatoma cells (HepG2) and in primary rat hepatocytes with a time course and dose-response comparable with that of IL-6. Our next aim was to define the receptor components used by CNTF on hepatic cells. Using a cell-free binding assay we exclude that CNTF binds to the 80 kDa IL-6 receptor, a protein with significant homology to the CNTF receptor which has recently been cloned from neuroblastoma cells. In human hepatoma cells (Hep3B) which lack the leukemia inhibitory factor receptor, CNTF was not able to induce acute-phase protein synthesis, indicating that this receptor protein may be part of the functional CNTF receptor on hepatic cells.
 ...
PMID:Ciliary neurotrophic factor induces acute-phase protein expression in hepatocytes. 128 89

Animals subjected to immunostimulatory conditions exhibit reduced tissue levels of total cytochrome P450 and P450-dependent drug metabolism. We have investigated the possibility that depressed levels of two carcinogen-metabolizing cytochrome P450s may be due to decreased levels of the mRNAs encoding these enzymes by studying the effect of monocyte-derived cytokines on the induction of CYP1A1 and CYP1A2 mRNAs in isolated rat hepatocytes. Medium conditioned by activated human peripheral blood monocytes or by the U937 monocyte cell line suppressed the induction of both mRNAs by 2,3,7,8-tetrachlorodibenzo-p-dioxin, whereas beta-fibrinogen mRNA levels increased 30-40-fold. CYP1A2 mRNA induction was maximally inhibited more than CYP1A1 mRNA (approximately 95 and 65%, respectively), and lower concentrations of conditioned medium suppressed CYP1A2 mRNA induction (half-maximal at 1.9 and 3.1%, respectively). Low concentrations of recombinant interleukin-1 suppressed the inducer-dependent accumulation of both CYP1A1 and CYP1A2 mRNAs in a dose-dependent fashion (half-maximal at 2 and 0.5 units/ml, respectively), while two other monocyte-derived cytokines, interleukin-6 and transforming growth factor-beta, did not. Run-on transcription analysis demonstrated that conditioned medium and interleukin-1 rapidly suppressed the transcription rate of CYP1A1 and CYP1A2 in inducer-treated hepatocytes. The close correspondence between the reductions in CYP1A1 and CYP1A2 transcription rates and mRNA levels suggest that conditioned medium and interleukin-1 suppress the induction of these mRNAs principally through a transcriptional mechanism.
 ...
PMID:Interleukin-1 beta suppresses the induction of P4501A1 and P4501A2 mRNAs in isolated hepatocytes. 156 64

Independent of de novo protein synthesis, interleukin-1, interleukin-6, and dexamethasone caused immediate stimulation of transcriptional activity of most major acute phase plasma protein genes in the rat hepatoma H-35 cells. However, activation of alpha 2-macroglobulin and alpha 1-acid glycoprotein genes were delayed by 2-4 h and required ongoing protein synthesis. The hormones also increased transiently the transcription of the junB gene and the amounts of JunB, C/EBP, and C/EBP-like mRNA. To identify whether JunB and C/EBP have the ability to control both the early and late acute phase reactants, expression vectors for mouse C/EBP and JunB together with reporter gene constructs containing recognized hormone-specific regulatory elements were introduced into hepatoma cells. C/EBP displayed prominent transactivation activity with the interleukin-1 and glucocorticoid regulatory elements of alpha 1-acid glycoprotein, the interleukin-1 regulatory element of haptoglobin gene, and the interleukin-6 regulatory element of beta-fibrinogen. The interleukin-6 regulatory elements of the first two genes and the glucocorticoid response element of the third gene were not affected by C/EBP. These data suggest that normal hormone activation of these three acute phase reactant genes might involve, in part, C/EBP-related factors which have a broad range of specificity. H-35 cells stably transformed with a mouse C/EBP expression vector showed an elevated basal level as well as cytokine inducible expression of some but not all acute phase reactants. Cotransfected JunB resulted in reduced activity of cytokine-responsive constructs and in lower transactivation by C/EBP. JunB appears to function as a modulator of plasma protein expression during the course of acute phase response.
 ...
PMID:Transcriptional regulation through cytokine and glucocorticoid response elements of rat acute phase plasma protein genes by C/EBP and JunB. 171 61

Transforming growth factor-beta (TGF beta 1), a multipotent immunoregulatory peptide produced by human platelets, has been shown to stimulate the synthesis of fibrinogen, contrapsin, complement component C3, and alpha-1-proteinase inhibitor by murine hepatocytes cultured for 2 days in DMEM containing 1 microM insulin and dexamethasone and 0.2% BSA. In the range of 10 pg to 10 ng/ml TGF-beta 1 did not elicit any change in albumin secretion. Two main inflammatory cytokines: interleukin-6 (IL-6) and interleukin-1 (IL-1), known to stimulate two different subsets of murine acute phase plasma proteins, failed to increase contrapsin and alpha-1-proteinase inhibitor production. Epidermal growth factor (EGF) in the concentration 1 ng to 10 ng/ml effectively counteracted the stimulatory effect of TGF-beta 1 on acute phase protein production. TGF-beta 1-induced fibrinogen protein levels were associated with increased beta-fibrinogen mRNA content. TGF-beta 1 appears to be an additional physiological factor responsible for the direct stimulation of normal mouse hepatocytes to acute phase response.
 ...
PMID:Regulation of acute phase reaction by transforming growth factor beta in cultured murine hepatocytes. 172 35

Secretory products of cultured human blood monocytes contain a hepatocyte-stimulating factor which is able to induce the acute-phase proteins alpha 2-macroglobulin and fibrinogen in rat liver cells. Total RNA was isolated from unstimulated and lipopolysaccharide-stimulated human monocytes and translated in a reticulocyte lysate. The capability of the cell-free synthesized proteins to induce the acute-phase proteins alpha 2-macroglobulin and fibrinogen was assayed in rat hepatocyte primary cultures and in the rat hepatoma cell line Fao. The products translated from the mRNA of lipopolysaccharide-stimulated human monocytes induced mRNAs for alpha 2-macroglobulin and fibrinogen and therefore contain hepatocyte-stimulating factor. The translation products of unstimulated monocytes had no effect. A cDNA containing the coding sequence for interleukin-6 (B-cell stimulatory factor 2, interferon-beta 2/26-kDa protein, interleukin HP1) derived from human T-cells cloned into the transcription vector pGEM4 was transcribed in vitro. Translation of the isolated RNA in a reticulocyte lysate led to the synthesis of a protein of about 25 kDa. This cell-free synthesized interleukin-6 exhibited hepatocyte-stimulating activity measured by the induction of beta-fibrinogen mRNA in Fao cells. Using an antibody against interleukin-6, two proteins of 22 kDa and 23 kDa were immunoprecipitated from the culture medium of lipopolysaccharide-stimulated human monocytes. These two proteins were not synthesized by unstimulated monocytes. When total RNA from unstimulated human monocytes and lipopolysaccharide-stimulated human monocytes and lymphocytes was subjected to Northern analysis and hybridized with the interleukin-6 cDNA, a strong hybridization signal corresponding to an RNA of about 1300 bases was detected only in the RNA from lipopolysaccharide-stimulated human monocytes, indicating that human monocytes express the interleukin-6 gene after stimulation. The data presented in this paper strongly suggest that hepatocyte-stimulating factor from human monocytes and interleukin-6 from T-cells are identical.
 ...
PMID:Cell-free-synthesized interleukin-6 (BSF-2/IFN-beta 2) exhibits hepatocyte-stimulating activity. 245 23

Conditioned medium from human monocytes contains a partially characterized hepatocyte-stimulating factor that simultaneously elevates the mRNA levels of the acute-phase protein beta-fibrinogen and decreases albumin mRNA in rat hepatoma cells. We demonstrate that recombinant human B-cell stimulatory factor 2, which is identical to interferon-beta 2/26 kDa protein and interleukin-HP1, exhibits the same activity as hepatocyte-stimulating factor. Furthermore, a specific antibody against B-cell stimulatory factor 2 was able to inhibit hepatocyte-stimulating factor in conditioned medium from human monocytes. Our data show that hepatocyte-stimulating factor and B-cell stimulatory factor 2 are functionally and immunologically related proteins.
 ...
PMID:Recombinant human B cell stimulatory factor 2 (BSF-2/IFN-beta 2) regulates beta-fibrinogen and albumin mRNA levels in Fao-9 cells. 330 75

The influence of recombinant human interleukin-6, the major mediator of the inflammatory response in liver, on the glucagon- and insulin-dependent induction of the phosphoenolpyruvate carboxykinase and glucokinase gene, respectively, was monitored on the level of gene transcription, mRNA abundance and enzyme activity in cultured rat hepatocytes. As control markers of the interleukin-6-induced acute-phase response the mRNA levels of the acute phase proteins alpha 2-macroglobulin and beta-fibrinogen were determined. In cultured rat hepatocytes, recombinant human interleukin-6, added simultaneously with glucagon and insulin, lowered the maximal increase in glucagon-induced phosphoenolpyruvate carboxykinase mRNA levels after 2 hr and the maximal increase in glucokinase mRNA levels after 3 hr to about 30%, respectively. It inhibited the glucagon-induced increase in phosphoenolpyruvate carboxykinase gene transcription and phosphoenolpyruvate carboxykinase enzyme activity, as well as the insulin-induced increases in glucokinase gene transcription and glucokinase enzyme activity. Recombinant human interleukin-6 increased the mRNA levels of the acute-phase proteins alpha 2-macroglobulin and beta-fibrinogen gradually over 4 to 6 hr. Recombinant human interleukin-6, added 2 hr after glucagon or 3 hr after insulin at the maximum of the hormone-induced enzyme mRNA levels, almost doubled the decay rate of phosphoenolpyruvate carboxykinase mRNA and glucokinase mRNA. The results show that interleukin-6 induced the expression of inflammatory proteins and simultaneously inhibited the hormone-induced expression of enzymes of intermediary metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Inhibition by recombinant human interleukin-6 of the glucagon-dependent induction of phosphoenolpyruvate carboxykinase and of the insulin-dependent induction of glucokinase gene expression in cultured rat hepatocytes: regulation of gene transcription and messenger RNA degradation. 752 6

The ability of p53 species (wild-type and mutant) to modulate the "differentiated" response of human hepatoma cell lines Hep3B and HepG2 to interleukin-6 (IL-6) was investigated. Transient transfection experiments were carried out in Hep3B and HepG2 cell cultures in which IL-6 was used to activate a beta-fibrinogen (beta Fib) enhancer/reporter construct containing two copies of the 36-base pair IL-6-response element (IL-6RE) (p beta FibCAT). Cotransfection with constitutive expression vectors for wild-type (wt) human or murine p53 inhibited the activation of the p beta FibCAT reporter by IL-6 in both Hep3B and HepG2 cells. Several mutant p53 species either did not inhibit the activation of p beta FibCAT or up-regulated the response. Hepatoma cell lines stably expressing the Val-135 temperature-sensitive mutant of murine p53 (wt-like at 32.5 degrees C and mutant-like at 37 degrees C) were derived from Hep3B cells and tested for the temperature-sensitive phenotype of their ability to synthesize and secrete fibrinogen and alpha 1-antichymotrypsin in response to IL-6. In an experimental protocol in which the parental Hep3B cells did not show a significant difference in plasma protein secretion at the two temperatures, hepatoma line 3 (p53Val-135+) had a greater response to IL-6 at 37 degrees C than parental Hep3B cells, while line 3 cells had a reduced response to IL-6 at 32.5 degrees C. Similarly, hepatoma lines 1 and 2 (both p53Val-135+) had reduced IL-6 responsiveness at 32.5 degrees C, whereas line 22 (transfected with pSVneo alone) and the parental Hep3B cells did not. These data indicate that mutations in p53 contained in tumor cells can modulate the "differentiated" response of these cells to cytokines.
 ...
PMID:Modulation of interleukin-6-induced plasma protein secretion in hepatoma cells by p53 species. 755 62

Interleukin-1 triggers the down-regulation of several hepatic cytochrome P450 gene products, but the cellular signaling pathways involved are not known. We have examined the role of sphingomyelin hydrolysis to ceramide in the suppression of CYP2C11, a major constitutive form of cytochrome P450, by interleukin-1. Treatment of rat hepatocytes cultured on matrigel with interleukin-1 beta caused a rapid turnover of sphingomyelin and an increase in cellular ceramide, with no change in cellular phosphatidylcholine. The ceramide was composed mainly of a D-erythro-sphingosine backbone, suggesting that it was derived from sphingolipid hydrolysis rather than from increased de novo synthesis. Treatment of the cells with either N-acetyl-D-erythro-sphingosine (C2-ceramide) or bacterial sphingomyelinase suppressed the expression of CYP2C11 and induced the expression of the interleukin-1-responsive alpha 1-acid glycoprotein mRNA. In contrast, the acute-phase gene beta-fibrinogen, which is induced by interleukin-6 but not by interleukin-1, did not respond to C2-ceramide. N-Acetyl-D-erythro-sphinganine mimicked the effect of C2-ceramide on CYP2C11, but not on alpha 1-acid glycoprotein expression. These results are consistent with a role for ceramide or a related sphingolipid in mediating the down-regulation of CYP2C11, the induction of alpha 1-acid glycoprotein, and perhaps other cellular effects of interleukin-1 in hepatocytes.
 ...
PMID:Regulation of cytochrome P450 2C11 (CYP2C11) gene expression by interleukin-1, sphingomyelin hydrolysis, and ceramides in rat hepatocytes. 755 61

Prospective epidemiological studies have shown that elevated levels of fibrinogen are associated with thrombosis and ischaemic heart disease. Several sequence changes in the promoter region of the beta-fibrinogen gene have been detected that are associated with slightly raised plasma fibrinogen levels in healthy, non-smoking carriers, but which have much larger genotype-associated effects in smokers. In in vitro assays, these sequence changes affect the binding of liver nuclear proteins and may alter the rate of transcription of the gene and thus the rate of fibrinogen production. One sequence change is close to the consensus sequence for the binding of a nuclear factor responsive to interleukin-6, one of the cytokines responsible for the acute-phase changes seen upon infection or injury. This provides a molecular explanation for the different effects on fibrinogen levels seen in smokers, who are experiencing a 'chronic' and low-grade response to injury. Thus, for elevated plasma fibrinogen, which is associated with a risk of thrombosis, a genetic variation has been detected that determines, in part, its plasma level; but the variability in an individual's response to environmental changes may also be determined in part by their genotype at this locus. In the future, such individual-specific genetic information may be of prognostic and therapeutic use.
 ...
PMID:Genetic regulation of fibrinogen. 779 24


1 2 Next >>