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

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.
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PMID:Interleukin-1 beta suppresses the induction of P4501A1 and P4501A2 mRNAs in isolated hepatocytes. 156 64

Intravenous treatment of male rats with recombinant human interleukin-6 (rhIL6) at 50, 100 and 200 micrograms/kg (corresponding to 4, 8 and 16 x 10(4) U/animal, respectively) reduced the activities of hepatic microsomal cytochrome P450-dependent monoxygenases to varying degrees. Ethylmorphine-N-demethylase activity fell to 53% of control values, an effect similar to that induced by 2.5 mg/kg Escherichia coli lipopolysaccharide (LPS). Ethoxycoumarin-O-deethylase activity was also sensitive to inhibition, whereas IL6 had little effect on the activities of other P450-dependent enzymes, including ethoxyresorufin-O-deethylase. Pentoxyresorufin dealkylase activity, which is representative of the cytochrome P450 IIB 1/2 subfamily, was unaffected by IL6 whereas LPS reduced it to 33.7% of control values. Another hepatocyte-related parameter, serum concentration of alpha 1-acid glycoprotein (AGP), was increased by up to 3.5-fold over baseline by IL6 and 10-fold by LPS. Recombinant human interleukin-1 beta (rhIL1 beta) (10 micrograms/kg, corresponding to 5 x 10(4) U/rat) and recombinant human tumor necrosis factor alpha (rhTNF) (150 micrograms/kg corresponding to 24 x 10(4) U/rat) were both as potent as LPS (2.5 mg/kg) in increasing serum AGP levels and reducing hepatic microsomal monoxygenase activities. IL6 did not potentiate the effects of rhIL1 beta. Hepatic microsomal glucuronyltransferase activities were little affected by LPS and unaffected by rhIL6. Finally, rhIL6 was more potent after i.p. injection than after i.v. or s.c. injection. These results suggest that the effects of LPS, TNF and IL1 on the mixed-function oxidase system in vivo may be due partly to an induction of IL6 in vivo. The different sensitivities of the enzymes to IL6 but not to IL1 or TNF may be due to the involvement of two distinct mechanisms.
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PMID:Effects of interleukin-6 on cytochrome P450-dependent mixed-function oxidases in the rat. 163 28

During the acute phase response to bacterial endotoxin in rats, hepatic levels of cytochrome P450IIC12 [AH, reduced flavoprotein:oxygen oxidoreductase (RH hydroxylating), EC 1.14.14.1] (P450IIC12) apoenzyme and mRNA are suppressed. We set out to determine the effects of potential humoral mediators of inflammation on the expression of P450IIC12 in female rats. A single injection of 12,000 or 60,000 units of interleukin-1 alpha had no effect on total cytochrome P450 content or P450IIC12 mRNA measured 12 hr later, although P450IIC12 apoenzyme was slightly but significantly increased by the higher dose. In the second experiment, animals were given dexamethasone (100 micrograms/kg at -30 min), interleukin-1 alpha (30,000 units/kg at 0, 2, and 4 hr), or both and were sacrificed at 12 hr. Treatment with interleukin-1 alpha alone significantly suppressed total cytochrome P450, P450IIC12 apoenzyme, and P450IIC12 mRNA to 77, 53, and 65% of control levels, respectively; beta-actin mRNA was significantly increased (206% of control levels). Treatment with dexamethasone alone suppressed total cytochrome P450 and P450IIC12 mRNA (73% of controls) but did not significantly affect P450IIC12 apoenzyme measured 12.5 hr later. Again, beta-actin mRNA was increased. When both interleukin-1 alpha and dexamethasone were given, total cytochrome P450 and P450IIC12 mRNA (43% of controls) were suppressed, and beta-actin mRNA was significantly increased. In the third experiment, animals were injected at 0 and 12 hr with dexamethasone (83 micrograms/kg), interleukin-6 (33 micrograms/kg), or both. Interleukin-6 alone did not significantly affect total cytochrome P450 or P450IIC12 apoenzyme or mRNA. Dexamethasone alone suppressed P450IIC12 apoenzyme and mRNA (to 52 and 41%, respectively, of controls). Treatment with both interleukin-6 and dexamethasone significantly suppressed total cytochrome P450 and P450IIC12 apoenzyme and mRNA; suppression of P450IIC12 mRNA (to 16% of controls) was greater than with dexamethasone alone. No change in the transcription rate of CYP2C12 was observed 24 hr after initiation of treatment with dexamethasone (83 micrograms/kg at 0 and 12 hr) or 12 hr after initiation of treatment with interleukin-1 alpha (30,000 units/kg at 0, 2, and 4 hr). We conclude that, in this model, interleukin-1 alpha and glucocorticoids are important mediators of the suppression of hepatic P450IIC12 expression during inflammation. Interleukin-6 was not as potent, but it did potentiate the effects of dexamethasone. Suppression of P450IIC12 expression by dexamethasone and interleukin-1 alpha appeared to be mediated at a pretranslational level, but the possibility of a transcriptional effect needs to be further investigated.
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PMID:Regulation of cytochrome P450IIC12 expression by interleukin-1 alpha, interleukin-6, and dexamethasone. 201 47

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.
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PMID:Regulation of cytochrome P450 2C11 (CYP2C11) gene expression by interleukin-1, sphingomyelin hydrolysis, and ceramides in rat hepatocytes. 755 61

Cultured rat hepatocytes have been used to compare the relative activities of cytokines to inhibit the phenobarbital (PB) or 3-methylcholanthrene (MC) induction of cytochrome P4502B1 and 2B2 (P4502B1/2) or P4501A1 and 1A2 (P4501A1/2), respectively. Recombinant cytokines tested were human interleukin-6 (IL-6), interleukin-1 alpha and -beta (IL-1 alpha and IL-1 beta, respectively), and rat gamma-interferon (INF gamma). Hepatocytes were cultured in the presence of 2 mM PB or 1 microgram MC/mL culture medium for 24 hr with or without the cytokines. Benzyloxyresorufin and ethoxyresorufin O-dealkylase (BROD and EROD, respectively) activities were determined as indices of P4502B1/2 and P4501A1/2, respectively. All cytokines produced a concentration-dependent inhibition of the PB induction of BROD activity. IL-1 beta and IL-6 were approximately equipotent with IC50 values of 1-2 U/mL, causing greater than 90% inhibition of PB induction of BROD activity at a concentration of 50 U/mL culture medium. IL-1 alpha tended to be less active. PB induction of BROD activity was also inhibited by INF gamma, but higher concentrations (62.5 to 500 U/mL culture medium) were required. All cytokines were less effective in inhibiting the MC induction of EROD activity than the PB induction of BROD activity. IL-1 beta and IL-6, at 50 U/mL culture medium, inhibited EROD induction by only 35% compared with the greater than 90% inhibitory effect on the PB induction of BROD activity. INF gamma was ineffective in inhibiting EROD activity at the concentrations studied. Western immunoblot analysis indicated that the cytokines prevented the ability of the inducers to increase the expression of P4502B1/2 and P4501A1/2 immunoreactive proteins, and this effect correlated with their inhibitory effect on induction of enzyme activity. The results suggest that inducible isoforms of cytochrome P450 differ in their susceptibility to regulation by the cytokines, and that cytokines possess differential activity to inhibit the induction of P450 isoforms, with IL-1 beta and IL-6 being the most effective.
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PMID:Differential effect of cytokines on the phenobarbital or 3-methylcholanthrene induction of P450 mediated monooxygenase activity in cultured rat hepatocytes. 784 Jul 89

Proinflammatory cytokines play an important role in the depression of cytochrome P450 (CYP450)-dependent drug metabolism in mammals during inflammation and infection. Although much has been learned concerning the effects and mechanisms of cytokine-mediated suppression of CYP450, there is limited knowledge about how cytokines affect UDP glucuronosyl transferases (UDPGT). The aim of the present study was to investigate the effects and dose dependency of recombinant human proinflammatory cytokines on both CYP450- and UDPGT-dependent enzyme activities in primary cultures of pig hepatocytes. A possible role of nitric oxide in cytokine-induced suppression of enzyme activities was studied by incubating hepatocytes in the presence of N G-nitro-L-arginine (L-NAME), a competitive inhibitor of nitric oxide (NO) biosynthesis. Incubation of hepatocytes with interleukin-1alpha (IL-1alpha), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) decreased both oxidation and glucuronidation activities dose dependently, in which the effects on glucuronidation activities were even more pronounced. IL-6 differed from IL-1alpha and TNF-alpha by inhibiting CYP450 and UDPFT more effectively after 24 hr of incubation, whereas the inhibition by IL-1alpha and TNF-alpha was more pronounced after 12 hr. Only at a concentration of 500 U/ml did interferon-gamma (IFN-ganna) inhibit CYP450 and UDPGT. The inhibition of CYP450 enzyme activities by cytokines was probably not due to the production of NO, because L-NAME totally blocked NO production but had no effect on the cytokine-induced suppression of CYP450 enzyme activities. However, there might be a role for NO in the decrease of glucuronidation by cytokines, as L-NAME slightly though significantly prevented the inhibition of glucuronidation.
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PMID:Suppression of cytochrome P450- and UDP glucuronosyl transferase-dependent enzyme activities by proinflammatory cytokines and possible role of nitric oxide in primary cultures of pig hepatocytes. 866 49

It is now established that inflammatory stimuli such as lipopolysaccharides (LPS) and polyinosinic acid:polycytidylic (polyIC) suppress hepatic expression of cytochrome P450 (P450) genes in rat liver. Previous studies have suggested that LPS- or polyIC-induced downregulation of P450 was due to endogenously released inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1, interleukin-6, and interferons (IFNs). To improve our understanding of the role of inflammatory cytokines in mediating P450 depression, we investigated the possibility of preventing P450 downregulation with pentoxifylline. Pentoxifylline has been shown to inhibit LPS-induced TNF-alpha production by suppression of TNF-alpha gene expression. The present study shows that in uninduced male rats pentoxifylline selectively prevents the downregulation of microsomal P4501A2 and P4502B caused by LPS. No protective effect of pentoxifylline on the downregulation of P4502E1 and P4503A1/2 was observed. PolyIC-induced downregulation of P4501A2, P4502B, P4502E1, and P4503A1/2 was not affected by pentoxifylline. These results suggest that the LPS-induced downregulation of P4501A2 and P4502B is mediated to a large extent by TNF-alpha. Other cytokines might be involved in the suppression of P4502E1 and P4503A1/2. The fact that polyIC-induced downregulation is not protected by pentoxifylline is further evidence that this agent acts via a selective induction of IFNs.
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PMID:Differential effect of pentoxifylline on lipopolysaccharide-induced downregulation of cytochrome P450. 893 26

1. The influence of interferon-alpha (IFN alpha) on the clearances of theophylline (TH), antipyrine (AP) and hexobarbitone (HB) was studied in seven cancer patients given IFN alpha as their only treatment. In addition, IFN alpha effects on drug clearance were correlated with changes in serum inflammatory cytokines and acute phase proteins. 2. A 'baseline' study was performed by administering an oral drug 'cocktail' of TH (150 mg), AP (250 mg) and HB (250 mg) with saline injected simultaneously and again 24 h later. One week later, an 'acute' study was performed at the initiation of IFN alpha therapy, 3 x 10(6) units injected with the drug cocktail and again 24 h later. After 2 weeks of IFN alpha treatment three times per week, a 'chronic' study was performed with IFN alpha injected the day prior to, simultaneously with, as well as 24 h after the drug cocktail. 3. Plasma samples were collected over 48 h and the clearances of TH, AP and HB were estimated. Serum samples were collected at various times for the measurement of tumor necrosis factor (TNF), interleukin-1 (IL-1), interleukin-6 (IL-6), C-reactive protein (C-RP) and alpha 1-acid glycoprotein (AGP). 4. IFN alpha caused a 33% decrease in the oral clearance of TH during the chronic study compared with baseline (P < or = 0.05). Although IFN alpha inhibited TH clearance by 16% during the acute study and AP clearance by 20-21% during both acute and chronic studies, these changes did not reach statistical significance. IFN alpha caused minimal changes in HB clearance. There were no chronic effects of IFN alpha on serum cytokines or acute phase proteins. 5. The findings confirm that the most commonly used dose of IFN alpha inhibits the hepatic clearance in humans of some but not all drugs and that this inhibition persists during IFN alpha therapy. Because inhibition was not associated with increases in serum cytokines or acute phase proteins, the mechanism by which IFN alpha inhibits cytochrome P450 activities in vivo does not appear to involve inflammatory mediators such as TNF. IL-1 or IL-6.
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PMID:Effects of interferon-alpha monotherapy on hepatic drug metabolism in cancer patients. 911 9

Advances in molecular biology and recombinant DNA technology have led to the development of cytokines as therapeutic agents for a variety of disease states. The pharmacokinetic analysis of cytokines involves the understanding of analytical methods capable of detecting these agents in biological fluids and recognition of several factors which may have an impact on the cytokine concentration-time curves. Enzyme-linked immunosorbent assays (ELISA) have become the most common method of detection and commercial kits are available for a wide variety of cytokines. Monoclonal antibody products are sensitive, have minimal cross-reactivity and are relatively inexpensive when compared with high performance liquid chromatography (HPLC). However, the primary limitation of these assays is their inability to measure biologically active protein. Conversely, bioassays do measure a biological event (i.e. proliferation or cytotoxicity) but are generally not used for cytokine analysis because of their high cost, long assay completion time, lack of specificity, poor sensitivity and influence of environmental conditions on the outcome. The pharmacokinetic profile of recombinant cytokines is influenced by a number of variables: endogenous production, circulating soluble receptors and cell-associated receptors, immunocompetence and antibody production against the cytokine all may influence the disposition of the agent. Thus, pharmacokinetic modelling of cytokines may involve complex models capable of characterising these nonlinear processes and resulting effects. The route of administration is an important variable since cytokines administered by subcutaneous injection may be partially metabolised by proteases present in the subcutaneous tissue. Other methods to simplify cytokine delivery are being actively investigated and include formulations for inhalation, topical and oral administration. A variety of cytokines (including interferon-alpha, interleukin-6 and tumour necrosis factor) are capable of inhibiting cytochrome P450 hepatic enzymes and, therefore, possess the potential to cause drug-cytokine interactions. Inhibition has been demonstrated in several in vitro systems and animal models, although clinical data are currently limited. An increased understanding of the many factors which can alter the analysis and pharmacokinetics of cytokines is essential to the design of optimal dosage regimens.
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PMID:Pharmacokinetic studies with recombinant cytokines. Scientific issues and practical considerations. 916 Jan 71

The primary culture of rat luteal cells and their long-term maintenance have been difficult. Low cellular yields have limited the possibility for the study of gene regulation in luteal cells. The goal of this study was to develop a cell line to serve as a model by which to study the expression and regulation of various genes specific to luteal cells. We attempted to develop a luteal cell line by transformation of large luteal cells through infection with a temperature-sensitive simian virus (SV-40 tsA209) mutant that has a temperature-sensitive mutation required for the maintenance of cell transformation. We report here the successful establishment of such a cell line, designated GG-CL cells. Large luteal cells were purified to homogeneity by flow cytometry from corpora lutea of day 14 pregnant rats, cultured for 24 h, and then infected with the SV-40 tsA209 mutant virus. Transformed cells were maintained at the permissive temperature (33 C) until colonies were identified. Several colonies of transformed cells were isolated and passaged. They multiplied at 33 C and formed multilayers. At the nonpermissive temperature (40 C), cells reverted to the normal differentiated phenotype similar to the primary luteal cells in culture. To determine whether GG-CL cells express the genes found in normal luteal cells, messenger RNA (mRNA) expression was examined by either Northern analysis or RT-PCR with primers specific to each mRNA. GG-CL cells were found to express receptors for interleukin-6 and glucocorticoid, as well as the newly discovered estrogen receptor-beta (ER-beta) and the orphan nuclear receptor nur 77. No receptors for ER-alpha, progesterone, LH, or PRL could be detected. This cell line also expressed 20alpha-hydroxysteroid dehydrogenase (20alpha-HSD), but not cholesterol side-chain cleavage cytochrome P450 (P450scc), 3beta-hydroxysteroid dehydrogenase, or aromatase cytochrome P450 (P450arom). Although the cells did not express the PRL receptor, they did express Janus kinase (JAK2) and signal transducers and activators of transcription (Stat5b), and, when transfected with the PRL receptor, they responded to PRL with a marked inhibition in 20alpha-HSD mRNA expression. In addition, estradiol enhanced ER-beta expression in a dose-dependent manner whereas cAMP stimulation caused a marked and rapid increase in the expression of the orphan receptor nur 77. In summary, a temperature-sensitive cell line was successfully established from the large luteal cells of rat corpora lutea. These cells express key genes encoding enzymes and receptors inherent to this defined luteal cell population and respond to stimulation by PRL, estradiol, and cAMP.
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PMID:Establishment and characterization of a simian virus 40-transformed temperature-sensitive rat luteal cell line. 952 80


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