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At least 109 records · Page 6Linked to original sources
PubMed1990

Dexamethasone-mediated potentiation of P450IA1 induction in H4IIEC3/T hepatoma cells is dependent on a time-consuming process and associated with induction of the Ah receptor.

The synergistic effect of dexamethasone (DEX) and polycyclic aromatic hydrocarbons on the induction of cytochrome P450IA1 (P450IA1) was examined in H4IIEC3/T Reuber hepatoma cells. P450IA1 activity was determined by the hydroxylation of benzo[a]pyrene (AHH) and deethylation of 7-ethoxyresorufin (EROD). The amount of Ah receptor, i.e. the specific cytosolic binding protein of 3-methylcholanthrene or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in H4IIEC3/T cells was characterized and quantitated by high performance gel filtration. Benz[a]anthracene and TCDD induced AHH and EROD activities, respectively, about 20-fold within 4 h. The increase was about 100-fold when cells were pretreated with DEX. The glucocorticoid alone induced P450IA1 activities 3-4 fold. DEX elicited half maximum AHH induction at a concentration of 20 nM in the presence or absence of benz[a]anthracene. Maximal potentiation of AHH induction required treatment with DEX for at least 32 h prior to the exposure to benz[a]anthracene. Treatment of H4IIEC3/T cells with DEX for 20 h caused a 2-3-fold increase in the amount of Ah receptor. The results suggest that the synergistic effect of DEX and polycyclic aromatic hydrocarbons on P450IA1 induction involves a time-consuming process which may consist of the synthesis or modification of a factor, possibly the Ah receptor.

Animals↗
PubMed1990

Phenobarbital induction of cytochromes P-450. High-level long-term responsiveness of primary rat hepatocyte cultures to drug induction, and glucocorticoid dependence of the phenobarbital response.

The induction of hepatic cytochromes P-450 by phenobarbital (PB) was studied in rat hepatocytes cultured for up to 5 weeks on Vitrogen-coated plates in serum-free modified Chee's medium then exposed to PB (0.75 mM) for an additional 4 days. Immunoblotting analysis indicated that P-450 forms PB4 (IIB1) and PB5 (IIB2) were induced dramatically (greater than 50-fold increase), up to levels nearly as high as those achieved in PB-induced rat liver in vivo. The newly synthesized cytochrome P-450 was enzymically active, as shown by the major induction of the P-450 PB4-dependent steroid 16 beta-hydroxylase and pentoxyresorufin O-dealkylase activities in the PB-induced hepatocyte microsomes (up to 90-fold increase). PB induction of these P-450s was markedly enhanced by the presence of dexamethasone (50 nM-1 microM), which alone was not an affective inducing agent, and was inhibited by greater than 90% by 10% fetal bovine serum. The PB response was also inhibited (greater than 85%) by growth hormone (250 ng/ml), indicating that this hormone probably acts directly on the hepatocyte when it antagonizes the induction of P-450 PB4 in intact rats. In untreated hepatocytes, P-450 RLM2 (IIA2), P-450 3 (IIA1) and NADPH P-450 reductase levels were substantially maintained in the cultures for 10-20 days. The latter two enzymes were also inducible by PB to an extent (3-4 fold elevation) that is comparable with that observed in the liver in vivo. Moreover, P-450c (IA1) and P-450 3 (IIA1) were highly inducible by 3-methylcholanthrene (5 microM; 48 h exposure) even after 3 weeks in culture. In contrast, the male-specific pituitary-regulated P-450 form 2c (IIC11) was rapidly lost upon culturing the hepatocytes, suggesting that supplementation of appropriate hormonal factors may be necessary for its expression. The present hepatocyte culture system exhibits a responsiveness to drug inducers that is qualitatively and quantitatively comparable with that observed in vivo, and should prove valuable for more detailed investigations of the molecular and mechanistic basis of the response to PB and its modulation by endogenous hormones.

Animals↗
PubMed1991

Induction of tubules in rat metanephrogenic mesenchyme in the absence of an inductive tissue.

Differentiation of metanephrogenic mesenchyme to renal tubular epithelium requires induction by the ureteric bud in vivo or any of several embryonic tissues in vitro. In an effort to eliminate the tissue requirement in embryonic induction, extracellular matrices and soluble factors were analyzed individually or in combination for their ability to stimulate tubulogenesis in uninduced metanephrogenic mesenchyme from 13-gestation-day rat embryos. These evaluations have established that pituitary extract and epidermal growth factor (EGF) in concert with a matrix can promote morphogenesis of mesenchymal rudiments in culture. While type I collagen, laminin, or fibronectin matrices all promoted tubulogenesis in the presence of pituitary extract and EGF, type IV collagen proved the most effective. Under these conditions, tubules were induced in 23/24 mesenchymal rudiments by 9 days in culture. Mesenchyme was not induced prior to explanation since it formed no tubules when cultured in a medium that allowed tubulogenesis in intact embryonic kidneys. Preliminary characterization of the undefined factor in pituitary extract was consistent with a protein of molecular weight greater than 100,000 but less than 300,000. When uninduced metanephrogenic mesenchyme from mouse was used instead of rat tissue, a similar pattern of morphogenesis was not observed, suggesting that the described medium is inappropriate for promoting differentiation in mouse or, less likely, that different mechanisms mediate differentiation in rat and mouse. These studies show that embryonic induction can occur in explanted rat renal mesenchyme in an appropriate environment and does not require the presence of an inductive tissue.

Animals↗
PubMed2002

Increase in urea in conjunction with L-arginine metabolism in the liver leads to induction of cytochrome P450 2E1 (CYP2E1): the role of urea in CYP2E1 induction by acute renal failure.

A number of xenobiotics and certain pathophysiological situations cause the induction of CYP2E1. The present study was designed to establish the role of plasma urea nitrogen and L-arginine on hepatic CYP2E1 expression in rats or rats with acute renal failure. Exposure of rats to a single intravenous dose of 5 mg/kg uranyl nitrate caused renal failure in 5 days (ARF), as evidenced by increases in plasma urea nitrogen level and kidney to body weight ratio. Northern and Western blot analyses revealed that hepatic CYP2E1 was 2- to 4-fold induced by ARF. Treatment of rats with either 10% glucose in drinking water for 5 days following a single injection of uranyl nitrate or two injections of recombinant growth hormone (5 units/kg, s.c., twice a day) on the 4th day after uranyl nitrate injection reduced both the rise in plasma urea nitrogen and the induction of CYP2E1. Exposure of rats to urea (approximately 225 mg/kg/day) in drinking water for 1 to 3 day(s) resulted in significant increases in CYP2E1 mRNA and protein. Furthermore, perfusion of the liver with 25 mM urea for 24 h resulted in CYP2E1 induction with an increase in the mRNA. The levels of CYP2E1 protein and mRNA were increased in rats perfused with 25 mM L-arginine for 24 h (i.e., a 4-fold increase). Hence, L-arginine, which is irreversibly hydrolyzed to urea and ornithine by arginase, also induced hepatic CYP2E1. The results of the present study provided evidence that increases in plasma urea in conjunction with L-arginine metabolism lead to the induction of CYP2E1 in the liver.

Acute Kidney Injury↗
PubMed1995

Induction of hepatic microsomal P450 by 4-phenylalkylpyridines in rat: chain length-dependent and sex-related differential induction of P450s.

The effects of 4-phenylalkylpyridines (chain length of 0-5, 7, 9 and 11 carbon atoms) on the induction of hepatic microsomal P450 and its multiple forms (1A1/2 (1A1, 1A2), 3A2, 2B1/2, 2C6 and 2E1) in the male and female rat have been investigated. P450 induction gradually declined with increasing chain length of the 4-phenylalkylpyridines. Immunoblot analysis revealed that three pyridine compounds having methylene units of 0, 1 and 2 only induced P4501A2, whereas those having 4, 5 or 7 methylene units only induced 1A1 in the male rat. In the female rat, however, we could not observe such a chain length-dependent differential induction of the P4501A subfamily. Induced levels of P4503A2 and 2E1 were dependent on total P450 specific content, but 2C6 was increased in a chain length-dependent manner in both sexes. These results provide new information on the differential effects of pyridine-containing compounds on P450 induction in the rat.

Aminopyrine N-Demethylase↗
PubMed2000

Redox regulation of glutathione S-transferase induction by benzyl isothiocyanate: correlation of enzyme induction with the formation of reactive oxygen intermediates.

Here we report the molecular mechanism underlying the induction of glutathione S-transferase (GST) in rat liver epithelial RL34 cells treated with a cancer chemopreventive isothiocyanate compound, benzylisothiocyanate (BITC). BITC was found to significantly induce GST activity in RL34 cells. Northern and Western blot analyses demonstrated that BITC specifically enhanced the production of the class pi GST isozyme (GSTP1). Our studies demonstrated for the first time that the addition of BITC to the cells resulted in an immediate increase in the reactive oxygen intermediates (ROIs) detected by a fluorescence probe, 2',7'-dichlorofluorescin diacetate. The level of the ROIs in the cells treated with BITC (10 microM) was approximately 50-fold higher than those in the control cells. Furthermore, glutathione depletion by diethyl maleate significantly enhanced BITC-induced ROI production and accelerated the BITC-induced elevation of the GST activity, whereas pretreatment of the cells with glutathione inhibited both the ROI production and GST induction. The structure-activity relationship of the isothiocyanates also indicated that the ROI-producing activities closely correlated with their GST-inducing potencies. Moreover, the GSTP1 enhancer I-containing region was found to be essential for induction of the GSTP1 gene by intracellular ROI inducers such as BITC and diethyl maleate. These data suggest the involvement of the redox regulation on the induction of GSTP1 by BITC.

Animals↗
PubMed2000

The glucocorticoid receptor is essential for induction of cytochrome P-4502B by steroids but not for drug or steroid induction of CYP3A or P-450 reductase in mouse liver.

Cytochrome P-4503A, CYP2B, and P-450 reductase are induced by glucocorticoids, antiglucocorticoids such as pregnenolone 16alpha-carbonitrile, and drugs such as rifampin and phenobarbital. Although the pregnane X receptor is reported to mediate steroid and drug activation of CYP3A via a conserved cis-element in CYP3A genes, discrepancies exist between the induction of the endogenous CYP3A genes and the activation of the pregnane X receptor. It is a formal possibility that the glucocorticoid receptor may account for some of these discrepancies. To determine the requirement in vivo of the glucocorticoid receptor in expression of CYP3A and CYP2B, we compared the induction of these proteins in the livers of normal mice and mice with a targeted mutation in the glucocorticoid receptor. Mice lacking the glucocorticoid receptor show no difference in constitutive hepatic expression of CYP3A but show a decrease in the level of CYP2B. Glucocorticoid receptor-deficient mice challenged with either dexamethasone or pregnenolone 16alpha-carbonitrile failed to induce CYP2B proteins, whereas CYP2B was readily induced in (+/+) mice. In contrast, CYP3A and P-450 reductase proteins were induced by either inducer in wild-type and glucocorticoid receptor-null mice. Similarly, rifampin induced CYP3A in either wild-type or glucocorticoid receptor-null mice. Despite reports that rifampin is a nonsteroidal ligand for the human glucocorticoid receptor, rifampin failed to induce tyrosine aminotransferase in mice regardless of glucocorticoid receptor genotype, and rifampin did not compete for ligand binding to either mouse or human glucocorticoid receptor. Phenobarbital induced CYP3A, CYP2B, and P-450 reductase in all mice, but the amplitude of induction was diminished 37% in glucocorticoid receptor-null mice. Thus, there are distinctly different essential requirements of CYP3A, CYP2B, and P-450 reductase genes for the glucocorticoid receptor in their induction by steroids and drugs.

Aldosterone↗
PubMed1997

Recurrent molar pregnancy after ovulation induction and repeat ovulation induction. A case report.

BACKGROUND: Although hydatidiform mole is not commonly encountered following ovulation induction, patients who have already had molar pregnancies are at increased risk of developing further molar diseases with worsening histologic characteristics. That fact underlies the ethical dilemma of repeat ovulation induction. CASE: A 38-year-old woman, gravida 3, para 0, had three consecutive episodes of hydatidiform subsequent to clomiphene citrate and gonadotropin ovulation induction. She seems to be the first in the literature to develop three consecutive molar pregnancies without a normal intrauterine pregnancy. CONCLUSION: Although ovulation induction commenced again in this patient after she gave informed consent, the risks underlying the ethical dilemma persist.

Adult↗
PubMed1995

Human gamma delta T cells are resistant to induction of anergy but not to induction of cell death in vitro.

A condition of hyporesponsiveness can be induced in certain mature human alpha beta (TCR2) cells relatively easily by their stimulation in the absence of costimulatory signals (signal 1 alone). This state of "anergy" has been implicated in tolerance to self and transplanted organs as well as tumors and may represent an important regulatory component of immune responsiveness. Little is known about whether the same condition applies to gamma delta (TCR1) cells. We therefore undertook to investigate anergy induction in TCR1 cell clones using several approaches known to induce this state in TCR2 cells. First, TCR1 clones were found not to be anergized by culture on immobilized CD3 monoclonal antibody (mAb), while the majority of TCR2 clones were anergized. Second, blocking of autocrine proliferation (stimulated in TCR1 or TCR2 clones by mitogen in the presence of accessory cells) using CTLA-4-lg, a soluble B7 family counterreceptor resulted in anergy induction in TCR2 cells but not TCR1 cells, although experiments with CHO cells transfected with B7-1 (CD80) genes confirmed that these TCR1 clones were responsive to costimulation with B7. Third, blocking mitogen-induced proliferation with anti-IL 2 receptor antibodies and anti-IL 2 antisera resulted in anergy induction in TCR2 but not TCR1 cells. Fourth, stimulation with the calcium ionophore ionomycin also anergized TCR2 but not TCR1 cells. In all four systems, but especially in the latter, stimulation by signal 1 alone resulted in high levels of cell death (> 50%) which was similar for both TCR1 and TCR2 cells. Therefore, these data may reflect a high level of resistance to tolerance induction (manifested as proliferative anergy) but not to clonal deletion (manifested as stimulation-dependent cell death) on the part of TCR1 cells.

Abatacept↗
PubMed1993

Induction of an immune network cascade in cancer patients treated with monoclonal antibodies (ab1). I. May induction of ab1-reactive T cells and anti-anti-idiotypic antibodies (ab3) lead to tumor regression after mAb therapy?

The antitumor effector functions of unconjugated monoclonal antibodies in cancer therapy are complex. Direct cytotoxic mechanisms such as antibody-dependent cellular cytotoxicity, complement-dependent cytolysis and apoptosis have been suggested. Induction of anti-idiotypic (ab2) and anti-anti-idiotypic (ab3) antibodies as well as T cell (T2 and T3 respectively) responses have also been proposed to be of clinical importance. In this study induction of an immune network cascade in patients with colorectal carcinoma, treated with mAb 17-1A (ab1) was assessed. All patients developed anti-idiotypic antibodies (ab2) of the IgG class after treatment with ab1 and four of nine patients showed induction of mouse Ig reactive T cells [a proliferative response to F(ab')2 fragments of ab1]. Patients with such a T cell response developed anti-anti-idiotypic antibodies (ab3), while those lacking the T cell reactivity failed to mount an ab3 response. Three of four patients with a T cell response achieved a tumor response to mAb therapy. Thus, all responding patients belonged to the group of individuals developing ab3. Induction of mAb(ab1)-reactive T cells as well as an immune network cascade might be important antitumor effector functions of mAb and should be considered in the future design of mAb-based therapy protocols in cancer patients.

Adult↗
PubMed1990

Synergistic and additive induction of metallothionein in Chang liver cells. A possible mechanism of marked induction of metallothionein by stress.

We have studied metallothionein (MT) induction by three primary inducers; a heavy metal, a glucocorticoid and a cytokine, and by the combinations of these inducers in the cultured cells. MT-protein was synergistically induced by either a cytokine or a heavy metal with a glucocorticoid hormone and was additively induced by the combination of a cytokine and a heavy metal, but MT-mRNA levels were not completely correlated with MT-protein levels. These results suggest that posttranscriptional regulation may be involved in the synergistic induction of MT-protein. We propose a possible mechanism in which marked MT induction by stress in vivo is dependent on the combined effect of two or more inducers, because marked MT induction is not seen by an injection of a plausible dose of either a glucocorticoid hormone or a cytokine in vivo.

Blotting, Northern↗
PubMed1984

Induction of plasminogen activator in a human diploid fibroblast cell line (MRC-5) by conditions which cause induction of interferon: the role of calcium ions.

The human diploid fibroblast cell line, MRC-5, derived from embryo lung tissue produced only small quantities of plasminogen activator (PA) when harvested using a standard nutrient medium (Eagle's Minimal Essential Medium, MEM). Use of a schedule designed to induce high concentrations of fibroblast interferon in these cells also resulted in production of considerably enhanced levels of PA. The kinetics of PA production differed from those of interferon production; specifically, PA was produced for at least 6 days following induction despite the toxicity of the inducers whereas interferon synthesis continued for only 1 day. Further investigation of the induction conditions for PA revealed that double-stranded RNA which was absolutely required for interferon production was not required for induction of PA. Indeed, the stimulus for enhancement of PA production appeared to be solely an elevated concentration of calcium ions in the extracellular medium. The possible physiological relevance of this induction of PA by elevated concentrations of calcium ions is discussed.

Calcium↗
PubMed2005

Heat shock protein induction in the freshwater prawn Macrobrachium malcolmsonii: acclimation-influenced variations in the induction temperatures for Hsp70.

The intracellular build-up of thermally damaged proteins following exposure to heat stress results in the synthesis of heat shock proteins (Hsps). In the present study, the upper thermal tolerance and expression of heat shock protein 70 (Hsp70) were examined in juveniles of the freshwater prawn Macrobrachium malcolmsonii that had been acclimated at two different temperatures, i.e. 20 degrees C (group A) and 30 degrees C (group B), in the laboratory for 30 days. Upper thermal tolerance was determined by a standard method. For heat-shock experiments, prawns in groups A and B were exposed to various elevated temperatures for 3 h each, followed by 1 h recovery at the acclimation temperature. Endogenous levels of Hsp70 were determined in the gill, heart, hepatopancreas and skeletal muscle tissues by Western blotting analysis of one dimensional sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE). The critical thermal maximum (CT max) for prawns in groups A and B was 37.7+/-0.27 degrees C and 41.41+/-0.16 degrees C, respectively. In general, Western blotting analysis for Hsp70 revealed one band at the 70 kDa region, containing both constitutive (Hsc70) and inducible (Hsp70) isoforms, in the gill and heart tissues; these were not detected in the hepatopancreas and skeletal muscle tissues. The onset temperature for Hsp70 induction in both gill and heart tissues was 30 degrees C for prawns in group A and 34 degrees C for those in group B. The optimum induction temperatures (at which Hsp70 induction was maximum) were found to be 34 degrees C and 32 degrees C, respectively, in the gill and heart tissues of group A prawns, and 38 degrees C and 36 degrees C, respectively, for group B prawns. These results suggest that the temperature at which acclimation occurs influences both upper thermal tolerance and Hsp70 induction in M. malcolmsonii.

Acclimatization↗
PubMed1989

Induction of tolerance across major barriers using a two-step method with genetic analysis of tolerance induction.

Using a murine skin allograft tolerance induction system that consists of intravenous injection of 1 x 10(8) allogeneic spleen cells followed by intraperitoneal (i.p.) injection of 200 mg/kg cyclophosphamide (CP) 2 days later, sensitivity to tolerance induction was examined across various histocompatibility (H) barriers. Although each group of class I, class II or multiminor H antigens was not by itself a prohibitively strong barrier, resistance to tolerance induction increased when the three types of barriers were combined in various ways. When the donor-recipient combinations were disparate at the entire spectrum of both H-2 plus non H-2 antigens (fully allogeneic), profound tolerance to skin allografts was not induced by this method in any of the combinations examined. Based on these results, induction of tolerance across fully allogeneic barriers was attempted in C57BL/10SnJ (B10; H-2b) mice against C3H/HeSnJ (C3H; H-2k) strain by addressing the 11 barriers as two separate challenges. B10 mice were first given B10.BR/SgSnJ (B10.BR; H-2k) spleen cells plus CP to make them tolerant to the H-2k component represented among C3H antigens, and then later were given C3H spleen cells plus CP to establish a tolerant state to the remainder of the disparate antigens of the C3H donors. After these two separate manipulations, C3H skin was accepted in the B10 mice, and normal hair growth was observed in the grafted C3H skin. By contrast, B10 mice given C3H spleen cells plus CP and then again another injection of C3H spleen cells plus CP were not rendered tolerant to C3H skin. In B10 mice, tolerance to C3H induced with B10.BR spleen cells plus CP and then C3H spleen cells plus CP was specific to C3H, and the tolerant B10 mice rejected third-party skin from DBA/2J (DBA; H-2d) strain in a normal fashion. In transfer experiments, the mechanism of tolerance was found to be based largely on reduction of the effector cells rather than on a mechanism involving active suppression. Assays for chimerism revealed that maintaining the tolerant state required persistence of cells of donor origin. These data indicate that in a primary immune response to a certain dose of allogeneic cells (tolerogen), the existence of a relatively large proportion of potentially reactive clones in the host may trigger proliferation of only a part of the population and some of the potentially reactive cells may differentiate rapidly without a prolonged period of proliferation.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

Dose-dependent acinar induction of cytochromes P450 in rat liver. Evidence for a differential mechanism of induction of P450IA1 by beta-naphthoflavone and dioxin.

Rats received various doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), Aroclor 1254 (ARO), beta-naphthoflavone (BNF) or phenobarbital (PB), and the hepatic expression of cytochromes P450IA1 and/or P450IIB1/IIB2 was analysed by immunohistochemistry and Western blotting. A clear heterogeneous acinar induction of IA1 was detected when a low dose of TCDD, ARO or BNF was administered. When a low dose of TCDD or ARO was administered, IA1 was found to be induced primarily in hepatocytes located in acinus zone 3, whereas when a low dose of BNF was administered, IA1 was found to be preferentially induced in hepatocytes located in acinus zone 1. A clear zonal induction of IIB1/IIB2 was also observed when a low dose of PB or ARO was administered. Both compounds induced IIB1/IIB2 preferentially in hepatocytes located in acinus zone 3. When rats were administered high doses of TCDD, ARO, BNF or PB there was no zonal pattern of induction of IA1 or IIB1/IIB2; instead, a pan-acinar induction of these enzymes was observed. These results indicate that the overall hepatic concentration of IA1 or IIB1/IIB2 is merely dependent on the proportion of 'induced hepatocytes' within the acinus, which in turn depends on the dose of the inducer.

Animals↗
PubMed1998

A comparison of midazolam co-induction with propofol predosing for induction of anaesthesia.

In a double-blind, placebo-controlled study of 90 ASA 1 and 2 patients scheduled for elective surgery we compared the effect of pre-administering midazolam 2 mg or propofol 30 mg on the dose of propofol subsequently required to induce anaesthesia. Using loss of response to verbal command and tolerance to placement of a facemask as end-points, the dose of propofol required to induce anaesthesia was significantly smaller in the patients given propofol (1.87 mg.kg-1) or midazolam (1.71 mg.kg-1) when compared to the control group (2.38 mg.kg-1). Although the decrease in blood pressure following induction was no difference between the two study groups and the decrease was felt not to be of clinical significance in this group of patients. As propofol is presented ' ... for use in a single patient only' and the technique of predosing with propofol allowed induction of all patients with less than 200 mg (a single ampoule), we question on a cost basis whether midazolam co-induction is necessary to reduce propofol induction doses.

Adjuvants, Anesthesia↗
PubMed1992

Differential induction of transcription factors that regulate the interleukin 2 gene during anergy induction and restimulation.

T cell activation requires two distinct signals. The first is delivered through the antigen-specific T cell receptor (TCR), and the second is provided by costimulatory molecule(s) present on the surface of the antigen-presenting cell (APC). Stimulation of T helper type 1 T cell clones through the TCR in the absence of the costimulatory activity results in a lack of interleukin 2 (IL-2) secretion and proliferation, and the induction of a long-lived state of nonresponsiveness, termed anergy. In this study, we have examined the transcription factors involved in IL-2 gene expression that are expressed after stimulation of normal T cell clones through the TCR with and without engagement of the necessary costimulatory molecule(s). Antigen-specific activation of the clones results in the induction of a similar pattern of transcription factors that have been previously shown to regulate IL-2 expression. In contrast, antigen presentation by chemically fixed APC, a condition that results in T cell anergy, induces neither NF-AT nor one of the two NF-kappa B binding factors. Thus, the failure to express IL-2 during the induction of T cell anergy may be attributed to the absence of these two transcription factors. When anergized T cells are restimulated with antigen and conventional APC, they induce the transcription factors associated with IL-2 expression, but they fail to synthesize measurable IL-2. Taken together, these data indicate that the control of IL-2 gene expression during anergy induction and during normal stimulation of anergized cells are distinct, and suggest the presence of additional regulatory elements in the IL-2 gene.

Animals↗
PubMed1984

Interferon induction by viruses. XI. Early events in the induction process.

The mechanism by which NDV, Sindbis virus, and VSV enter "aged" primary chick embryo cells to initiate IFN induction was studied by using NH4Cl, a lysosomotropic weak base that compromises low pH-dependent membrane fusion. NH4Cl was used to perturb the early steps in virus entry into the cytosol thought to result ultimately in presentation of dsRNA to the cell's first-stage recognition system for IFN induction. Three parameters were monitored: (i) the nature of the dose (multiplicity)-response (IFN yield) curve, (ii) the activity of IFN-inducing particles (IFP), and (iii) the quantum yield of IFN. In all tests, the qualitative nature of the dose-response curve was not altered by NH4Cl treatment. NH4Cl had no effect on infectivity of IFN induction by NDV in keeping with a mode of entry involving acidic-independent fusion through the plasma membrane. Sindbis virus infectivity and IFN-inducing particle activity were inhibited similarly in an NH4Cl concentration-dependent manner. While the infectivity of VSV was very sensitive to the action of NH4Cl, virtually all IFN-inducing particles were functional; however, the quantum yield of IFN they induced was reduced in an NH4Cl concentration-dependent manner. Only 1 of 6 VSV [+/-]DI-011 particles registered in NH4Cl-treated cells; however, they induced more than one-half the normal quantum yield of IFN. The mechanism of entry of Sindbis virus (acidic-fusion) and VSV (acidic-endocytosis) was distinguished by the action of cytochalasin B. Infectivity and IFN induction by Sindbis virus and VSV share a common, limiting step in NH4Cl treated cells: transfer of viral RNA from basic vacuoles into the cell cytosol. The similar sensitivity of Sindbis IFP and PFP to NH4Cl suggests that both activities respond the same to increased intravacuolar pH; neither can be expressed. VSV-IFP, requiring only partial genomic expression (or none in the case of DI-011) can register in NH4Cl-treated cells to varying degrees under conditions that prevent expression of the full genome.

Ammonium Chloride↗