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PubMed2000

Role of cAMP-dependent protein kinase (PKA) in opioid agonist-induced mu-opioid receptor downregulation and tolerance in mice.

Studies suggest that acute and chronic opioids can regulate the cAMP-dependent protein kinase (PKA) signaling pathway and that changes in this pathway may be involved in opioid tolerance. In the present study, we examined the role of cAMP-PKA on mu-opioid receptor downregulation and tolerance in mice. Mice were injected intracerebroventricular (i.c.v.) and intrathecal (i.t.) once a day with an antisense oligodeoxynucleotide directed at the mRNA for the alpha catalytic subunit of mouse PKA. Controls were treated with saline or a mismatch oligodeoxynucleotide. On day 2 of treatment, mice were implanted s.c. with a 25-mg morphine pellet and an osmotic minipump infusing morphine (40 mg/kg/day) for 3 days. Other mice were implanted with an osmotic minipump infusing etorphine (125, 250 microg/kg/day) for 2 days. Control mice were implanted s.c. with inert placebo pellets. At the end of treatment, pumps and pellets were removed and mice tested for morphine or etorphine analgesia. Other mice were sacrificed and mu-opioid receptor binding assays conducted in whole brain. Both infusion doses of etorphine produced significant tolerance (ED(50) shift = 3.6 and 6.3-fold). The higher etorphine infusion produced downregulation of mu-receptor density ( approximately 30%) while the lower infusion dose of etorphine did not. Morphine treatment also produced significant tolerance in mice (ED(50) shift = 4.5-fold), but no receptor downregulation. Antisense to PKA partially blocked tolerance induced by the higher dose of etorphine, but had no effect on receptor downregulation. On the other hand, antisense to PKA completely blocked tolerance induced by morphine and the lower infusion dose of etorphine. The mismatch oligodeoxynucleotide had no effect on any measure. These results suggest that PKA has a limited role in opioid agonist-induced receptor downregulation. However, the partial block of tolerance for the high infusion dose of etorphine and the complete block of tolerance for morphine and the low infusion dose of etorphine suggests that PKA may play a critical role in tolerance that is "receptor-regulation-independent."

Analgesics, Opioid↗

PubMed2001

TGF-beta1 and donor dendritic cells are common key components in donor-specific blood transfusion and anti-class II heart graft enhancement, whereas tolerance induction also required inflammatory cytokines down-regulation.

Heart allograft tolerance in adult recipients can be induced in the LEW.1W to LEW.1A congeneic strain combination by pre-graft donor-specific blood transfusion (DST). Long-term survivors accept LEW.1W graft but reject third party skin grafts. As tolerant recipients of heart allografts showed an increase in anti-donor class II antibodies, we hypothesize that these antibodies could be instrumental in tolerance induction. However, anti-donor MHC class II alone prolonged graft survival but did not induce heart allograft tolerance in this combination. We analyzed the immune response patterns in heart allograft recipients following the injection of anti-donor class II antibodies (prolongation) or DST priming (tolerance). As suggested by the different phenomena, several immunological patterns were strikingly different between the two models. In strong contrast to DST-tolerant recipients, at 5 days after transplantation, neither Th1/Th2 nor inflammatory cytokines were inhibited in recipients treated with anti-donor class II antibodies, in which only prolongation of graft survival was induced. Nevertheless, in both models, depletion of resident dendritic cells (DC) from donor hearts inhibited tolerance induction (DST) or shortened allograft survival (anti-donor class II antibodies). Moreover, TGF-beta1 was not down-regulated and administration of neutralizing anti-TGF-beta1 antibody, which inhibited tolerance induction (DST), also shortened allograft survival (anti-donor class II antibodies). These results suggest that, in these two MHC class II-restricted models, both TGF-beta1 and donor DC have a pivotal role in prolonging graft survival. However, in the days following transplantation, further inhibition of inflammatory cytokine production, particularly Th1 and macrophage-derived cytokines is required for tolerance induction.

Animals↗

PubMed2001

Induction of oral tolerance to cellular immune responses in the absence of Peyer's patches.

Systemic hyporesponsiveness occurs following oral administration of antigen (oral tolerance) and involves the uptake and processing of antigen by the gut-associated lymphoid tissue (GALT), which includes Peyer's patches (PP) lamina propria lymphocytes and mesenteric lymph nodes (MLN). Animals with targeted mutations of genes in the tumor necrosis factor (TNF) family have differential defects in the development of peripheral lymphoid organs including PP and MLN, and provide a unique opportunity to investigate the role of GALT structures in the induction of oral tolerance. Oral tolerance could not be induced in TNF/lymphotoxin (LT) alpha-/- mice, which are devoid of both PP and MLN, although these animals could be tolerized by intraperitoneal administration of antigen, demonstrating the requirement for GALT for oral tolerance induction. LTbeta-/- mice and LTalpha/LTbeta+/- animals do not have PP but could be orally tolerized, as measured by IFN-gamma production and delayed-type hypersensitivity responses by administration of both low or high doses of ovalbumin. To further investigate the requirement for PP, we tested the progeny of LTbeta-receptor-IgG-fusion-protein (LTbetaRigG)-treated mice, which do not form PP but have an otherwise intact immune system. Although these animals had decreased fecal IgA production, they could be orally tolerized. Our results demonstrate that PP are not an absolute requirement for the induction of either high- or low-dose oral tolerance, although oral tolerance could not be induced in animals devoid of both PP and MLN.

Administration, Oral↗

PubMed1976

Effect of anti-carrier antibody on carrier-determined tolerance.

These experiments were originally designed to determine whether an anti-carrier antibody, e.g., anti-allotype could break hapten-specific tolerance in vivo. Tolerance to 2,4-dinitrophenyl (DNP) was induced in C57BL/6J mice using DNP-BALB/c IgG2a conjugate. When anti-allotype serum was injected in C57BL/6J mice one day after a single injection of DNP-IgG2a the mice were not tolerant. In contrast, when tolerance was induced by four weekly injections of tolerogen, the anti-allotype serum had no effect on the tolerant state. This effect was specific for tolerance-inducing carrier. Anti-carrier antibody injected in C57BL/6J mice one day after DNP-IgG2a produced a small but significant anti-DNP response without administration of the immunogen, whereas the tolerogen (DNP-IgG2a) by itself was not immunogenic. Similarly, despite multiple injections of DNP-IgG2a bearing the foreign allotype, only one out of 7 C57BL/6J mice showed a weak anti-carrier response. In contrast, a marked anti-carrier (IgG2a) response was obtained when the anti-allotype antibody was passively administered in C57BL/6J mice. In conclusion, these experiments suggest that tolerance to an antigenic determinant may be broken by an antibody directed not to this determinant, but to another on the same molecule. The significance of this finding in relationship to the mechanism of the carrier-determined tolerance and the breakdown of self-tolerance is discussed.

Animals↗

PubMed2005

A key role for autoreactive B cells in the breakdown of T-cell tolerance to pyruvate dehydrogenase complex in the mouse.

The key immunological event in the pathogenesis of the autoimmune liver disease primary biliary cirrhosis is breakdown of T-cell self-tolerance to pyruvate dehydrogenase complex (PDC). The mechanism resulting in this breakdown of tolerance remains unclear. Mice exposed to self-PDC mount no immune response; however, animals coexposed to self-PDC and PDC of foreign origin (which in isolation induces a cross-reactive antibody but not an autoreactive T-cell response) show breakdown of T-cell as well as B-cell tolerance. This observation raises the possibility that a cross-reactive antibody response to self-PDC can promote breakdown of T-cell tolerance. The aim of this study was to address the hypothesis that breakdown of T-cell tolerance to PDC can be driven by the presence of B cells and/or antibodies cross-reactive with this self-antigen. Naive female SJL/J mice were exposed to self-PDC alone and in the presence of purified splenic B cells from animals primed with foreign PDC (or controls) or purified immunoglobulin (Ig) G from the same animals. Breakdown of T-cell tolerance was assessed by splenic T-cell proliferative response to antigen at 5 weeks. CD4(+) T-cell proliferative responses indicative of breakdown of T-cell tolerance to self-PDC were seen in the majority (7 of 9, 78%) of animals receiving self-PDC together with purified PDC-reactive B cells. Tolerance breakdown was not seen in animals receiving self-PDC with purified anti-PDC IgG or with B cells from animals sensitized with an irrelevant antigen. In conclusion, breakdown of T-cell tolerance to the highly conserved self-antigen PDC may be mediated by high-level presentation of self-derived epitopes by activated cross-reactive B cells.

Animals↗

PubMed1996

Production of high levels of Th1 and Th2 cytokines in mice with acquired transplantation tolerance.

Specific transplantation tolerance was induced in newborn mice by the intravenous injection of hematopoietic cells from semiallogeneic donors. Success of tolerance induction was tested by skin allografts. Spleen cells from mice bearing tolerated allografts for more than 60 days after transplantation spontaneously produced high levels of various cytokines. Production of both Th1 (IL-2, IFN-gamma) and Th2 (IL-4, IL-10) cytokines, as well as of IL-3, was significantly increased in tolerant animals. The elevated production of Th1 cytokines was associated with the high secretory activity of CD4+ cells, while the production of Th2 cytokines was high in both CD4+ and CD8+ cell populations. The hyperproduction of cytokines was an intrinsic property of the T cells from tolerant animals and was not caused by a larger size of major T-cell subsets. The production of high levels of cytokines was a consequence of neonatal induction of tolerance and persisted for a long time after skin grafting of neonatally tolerized animals. These results show that neonatal induction of transplantation tolerance results in the production of enhanced levels of Th1 and Th2 cytokines which could be involved in the establishment and maintenance of immunological tolerance.

Animals↗

PubMed2000

Induction of oral tolerance in the primed immune system: influence of antigen persistence and adjuvant form.

Oral tolerance is being promoted as a therapy for autoimmune diseases and therefore will need to be functional in a primed immune system. In previous studies, we found that although primed mice could be tolerized by feeding ovalbumin (OVA), the degree of the tolerance and its effects on individual components of the systemic immune response were more limited than that found in naive animals. Here we increased the dose and frequency of antigen feeding in an attempt to extend the effects of oral tolerance in primed mice and to understand why its effects are limited under these conditions. Increasing the amounts of OVA fed, up to a single dose of 400 mg, or using multiple feeds of 5 x 5 or 5 x 25 mg OVA, did not radically alter the extent of tolerance, with DTH responses, antigen-specific proliferation, and IL5 and IFN-gamma production still being tolerized, but antibody responses remaining generally resistant. The deficient tolerance in primed mice could not be overcome by waiting for maximum clonal expansion to wane and was not influenced by persistent release of antigen from a depot adjuvant. We conclude that the resistance of primed mice to oral tolerance may be due to the fact that antigen-experienced T cells may be inherently resistant to induction of tolerance, or that the microenvironment of the primed immune system inhibits the delivery of tolerogenic signals to antigen-specific T cells.

Administration, Oral↗

PubMed1997

Tolerance to putrescine toxicity in Chinese hamster ovary cells is associated with altered uptake and export.

When Chinese hamster ovary (CHO) cells were cultured with low concentrations of putrescine (< 5 mM) their cell cycle time increased significantly and a fraction of the cells died. A cell line tolerant to the cytotoxic and growth inhibitory effects of millimolar concentrations of putrescine was developed by growing CHO cells over many months in increasing concentrations of the polyamine. A putrescine-tolerant cell line was obtained which was capable of growing in concentrations up to 25 mM putrescine and displayed growth and cell division rates similar to the original untreated/parental CHO cells. The tolerant cells grown in putrescine displayed relatively high intracellular putrescine yet the cell-associated putrescine concentration was estimated to be 10-fold less than the culture medium level. This high concentration of cellular putrescine diminished within 60 min when the cells were changed to non-putrescine-containing media. The putrescine-tolerant phenotype was further characterized in regards to the mechanisms involved in putrescine uptake, efflux, and biosynthesis. The parental and tolerant cell lines had similar or identical levels of cellular spermidine and spermine and no differences in the acetylated polyamine pools or diamine oxidase activity. The activity of ornithine decarboxylase was also similar in the two cell lines in both the presence and the absence of ornithine. The tolerant cells, however, had a decreased uptake rate for putrescine. The tolerant cell line also showed a greatly enhanced ability to export putrescine, especially when treated with ornithine, suggesting that an upregulated polyamine export system may be present in the tolerant cells which could be responsible for the increased cell survival in high putrescine concentrations. The data are discussed in regard to the potential for identifying the transport protein(s) responsible for the maintenance of nontoxic intracellular concentrations of putrescine in a tolerant cell line grown in putrescine.

Amine Oxidase (Copper-Containing)↗

PubMed1984

The natural history of impaired glucose tolerance in the Micronesian population of Nauru: a six-year follow-up study.

A longitudinal study of 266 randomly selected non-diabetic Nauruans (215 normal subjects, 51 with impaired glucose tolerance) has permitted the natural history of impaired glucose tolerance to be studied in this Micronesian population. Nauruans are known to suffer from a very high prevalence of abnormal glucose tolerance. The subjects were first examined in 1975-1976, and a follow-up examination was performed in 1982. Of the subjects with impaired glucose tolerance, 26% developed diabetes during the study period (4% per annum) compared with 7% of normal subjects (1% per annum). After controlling for the effects of both age and obesity, the risk of subsequent diabetes for subjects with impaired glucose tolerance remained significantly higher than for normal subjects (odds ratio 3.6, 95% confidence interval 1.4-9.1). Of those with impaired glucose tolerance on initial examination, 39% were normoglycaemic at follow-up. In subjects with impaired glucose tolerance, of nine factors examined only plasma glucose concentration at the time of the initial examination was consistent in predicting progression to diabetes, when the data were examined by both univariate and multivariate methods. Both 2-h and fasting plasma glucose values were useful predictors. Thus, Nauruans with impaired glucose tolerance have a higher risk of subsequent diabetes than their normoglycaemic counterparts, after controlling for age and obesity. Nevertheless, the prognosis of impaired glucose tolerance is unpredictable as a substantial proportion of such subjects return to normality.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1985

Features of environment-dependent tolerance to ethanol.

Mice given multiple injections of ethanol in a standardized environment develop environment-dependent tolerance to the hypnotic and hypothermic effects of ethanol. These animals also demonstrate environment-dependent cross-tolerance to the hypnotic and hypothermic effects of pentobarbital. Examination of the levels of ethanol in the brain and blood at various times after injection of a test dose of ethanol, as well as the examination of the rate of disappearance of ethanol from the blood, indicated that environment-dependent tolerance could be explained by dispositional factors. On the other hand, mice rendered tolerant to ethanol by a liquid diet technique demonstrate tolerance that is not environment-dependent, and there is no alteration in ethanol levels in different environments for animals fed the liquid diet. When the animals in either paradigm are tested by injecting ethanol directly into the brain, tolerance is observed that is not dependent on the environment. Tolerance produced by these two different paradigms is apparently due to different adaptive strategies used by the animal. Environment-dependent tolerance is partially related to the ability of the animal to change the disposition of ethanol, while environment-independent tolerance may be entirely due to other factors, such as changes in neuronal sensitivity to ethanol.

Analysis of Variance↗

PubMed1991

Predictive value of intravenous glucose tolerance test insulin secretion less than or greater than the first percentile in islet cell antibody positive relatives of type 1 (insulin-dependent) diabetic patients.

We have followed-up 35 islet cell antibody-positive first degree relatives of patients with Type 1 (insulin-dependent) diabetes mellitus for an average of 1,300 days with sequential intravenous glucose tolerance tests. At the time of analysis and manuscript submission approximately half (18 of 35) had developed diabetes during follow-up. At initial intravenous glucose tolerance test, 11 had a 1 + 3 min insulin secretion below the first percentile of insulin secretion compared to 225 similarly studied normal control subjects. Six islet cell antibody positive relatives on follow-up developed an intravenous glucose tolerance test less than the first percentile. Fifteen out of 17 (88%) of these islet cell antibody positive relatives with secretion ever found to be below the first percentile are now overtly diabetic (positive predictive value = 88%) and insulin-treated, while only 3 of 18 (17%) without an intravenous glucose tolerance test demonstrating loss of first phase insulin secretion have progressed to diabetes (with approximately 1,300 days of follow-up for both groups relative risk or odds ratio with intravenous glucose tolerance test ever below vs never below the first percentile = 38, p less than 0.001). Intravenous glucose tolerance test response below the first percentile preceded diabetes by an average of 656 days. Even when first phase insulin secretion is below the first percentile, the absolute value of 1 + 3 min insulin above basal insulin correlates with the time to development of diabetes (r = 0.586, p less than 0.001). With our current duration of follow-up, the negative predictive value (intravenous glucose tolerance test never below the first percentile) is 83%, and overall accuracy 86%. Incidence rates of diabetes development amongst our islet cell antibody positive relatives with follow-up while intravenous glucose tolerance test is below the first percentile is 0.48 per year (15 conversions to diabetes amongst 17 relatives in 30.8 patient years of follow-up) vs 0.05 per year (three diabetic patients in 55.5 patient years) with intravenous glucose tolerance test greater than the first percentile.

Administration, Oral↗

PubMed1995

Acute tolerance to nicotine in smokers: lack of dissipation within 2 hours.

Greater understanding of development and dissipation of acute tolerance to nicotine may help explain temporal patterns of nicotine self-administration in smokers. The time course of dissipation of acute tolerance to nicotine was examined in 16 smokers (8M, 8F) participating in four sessions differing on pretreatment exposure or time interval prior to nicotine (20 micrograms/kg) challenge: placebo 30 min before, or nicotine (20 micrograms/kg) 30, 60, or 120 min before challenge. Nicotine and placebo were administered by measured-dose nasal spray. The measurement battery consisted of subjective, cardiovascular, thermal pain detection, and behavioral performance measures. Results demonstrated significant acute tolerance (i.e. smaller responses to nicotine challenge following nicotine versus placebo pretreatment) for most subjective measures and for heart rate. Acute tolerance dissipated with lengthening inter-dose interval for two subjective measures, dose strength and arousal, but there was no tolerance dissipation for other measures. In contrast, nicotine pretreatment resulted in acute sensitization of finger temperature (vasoconstriction) response, which dissipated with lengthening interval. No acute tolerance was observed for thermal pain detection or performance measures. These findings demonstrate that acute tolerance develops quickly to some subjective and cardiovascular effects of nicotine. However, acute tolerance to most effects did not dissipate over 2 h, suggesting that, following acute tolerance development during initial exposure, most smokers generally obtain similar magnitude of effects from each subsequent nicotine exposure (i.e. cigarettes smoked later in the day).

Adult↗

PubMed1995

A pharmacokinetic-pharmacodynamic model of tolerance to morphine analgesia during infusion in rats.

A pharmacokinetic-pharmacodynamic (PK-PD) model was constructed to describe the kinetics of tolerance development to morphine-induced antinociception. Tail-flick latencies in response to hot water (50 degrees C) were assessed in male Sprague-Dawley rats exposed to a 12-hr iv infusion of either morphine (1.4 to 3.0 mg/kg per hr) or saline. Morphine-induced antinociception, expressed as the percentage of maximum possible response (% MPR), peaked after 120 min of infusion and decreased thereafter despite sustained systemic morphine concentrations. Both the rate and extent of tolerance development increased with increasing concentrations; an overall residual effect of approximately 24% MPR was observed at the end of the infusion regardless of the steady-state morphine concentration. The kinetics of tolerance offset were examined in a separate experiment by assessing tail-flick latency 15 min after morphine iv bolus (2 mg/kg) in tolerant and control rats. Recovery of response neared completion 18.5 days after a 12-hr exposure to morphine (2.0 mg/kg per hr). A PK-PD model was constructed to account for the delay in onset of antinociceptive effect and tolerance development relative to the blood concentration-time profile. According to this model, both the extent and the rate of tolerance development were modulated by the kinetics of the drug in the central compartment. Accumulation of a hypothetical "inhibitor" acting either as a reverse agonist, a competitive or noncompetitive antagonist, or a partial agonist could potentially account for the loss of pharmacologic effect in the presence of an agonist. The rate of tolerance development predicted from the PK-PD model varied widely (28-fold) depending on the type of pharmacologic interaction selected to account for the loss of effect. Using the rate of tolerance offset to discriminate between the different models (t1/2 offset 5.4 days), onset and offset of tolerance was described accurately by postulating that the inhibitor behaves as a partial agonist with low intrinsic activity (5.5% MPR) and high binding affinity for the receptor (IC50 15.0 ng/ml).

Analgesia↗

PubMed2002

Comparative study of the endotoxemia and endotoxin tolerance on the production of Th cytokines and macrophage interleukin-6: differential regulation of indomethacin.

Endotoxin tolerance reduces the capacity of monocytes to produce proinflammatory cytokines, results in cellular immune paralysis, and down-regulates the production of helper T (Th)1 type cytokines with a shift toward a Th2 cytokine response. Prostaglandin (PG)E2 in the immune system also results in macrophage inactivation and the suppression of Th1 activation and the enhancement of Th2 activation. However, the inhibitory effects of PGE2 on the altered polarization of the Th cell and macrophage interleukin (IL)-6 production characterized in part by cellular immune paralysis in a state of endotoxin tolerance is unclear. This study was undertaken, using indomethacin, to investigate the role of endogenous PGE2 on the Th cytokines and macrophage IL-6 production in a state of endotoxin tolerance compared to those with endotoxemia mice, wherein, in this latter case, the increased production of proinflammatory cytokines and PGE2 is exhibited. Endotoxemia was induced by injection of lipopolysaccharide (LPS; 10 mg/kg in saline) ip. once in BALB/c mice, and endotoxin tolerance was induced by pretreatment with LPS (1 mg/kg in saline) injected i.p. daily for two consecutive days and then with LPS 10 mg/kg on day 4. Splenocytes or macrophages were obtained from endotoxemia and endotoxin tolerance models pretreated with indomethacin, and then cytokine production was induced by Con A-stimulated splenocytes for the Th cytokine assays and LPS-stimulated macrophages for the IL-6 assay. Our results showed that endotoxemia led to significantly reduced IL-2 and IL-4 production, to significantly increased IL-6 production, whereas interferon (IFN)-gamma production was not affected. Indomethacin in the case of endotoxemia markedly attenuated IFN-gamma and IL-6 production and didnt reverse IL-2 and IL-4 production. Endotoxin tolerance resulted in the significantly reduced production of IL-2 and IFN-gamma and the significantly increased production of IL-4 and IL-6. Indomethacin in endotoxin tolerance greatly augmented IL-2 production, significantly decreased IL-4 production, and slightly attenuated IL-6 production. These findings indicate that endogenous PGE2 may mediate the suppressed Th1 type immune response, with a shift toward a Th2 cytokine response in a state of endotoxin tolerance, whereas endotoxemia may be regulated differentially. Also, endogenous PGE2 may mediate macrophage IL-6 production in the case of endotoxemia to a greater extent than in the case of endotoxin tolerance.

Animals↗

PubMed2001

Alprazolam withdrawal and tolerance measured in the social conflict test in mice.

RATIONALE: It is difficult to assess withdrawal from benzodiazepines, and preclinical assessment of behaviour during social conflict offers the opportunity to quantify tolerance and withdrawal by measuring aggressive, defensive and social behaviour. The relationship between benzodiazepine withdrawal symptoms and the development of tolerance is not well understood. Are withdrawal symptoms dependent on the development of tolerance? OBJECTIVE: The aim of the present study was to compare the development of tolerance to alprazolam effects on the behavioural repertoire during the social conflict test in mice, and to determine whether or not behavioural changes during alprazolam withdrawal are correlated with the development of tolerance. METHODS: An experimental model consisting of interactions of pairs of singly housed male mice with non-aggressive group-housed male mice was used. Alprazolam (1 mg/kg) was given orally once or repeatedly (twice daily) for 8 or 21 days. Behaviour was measured, based on videoanalysis, in aggressive mice before treatment, 30 min or 3 days after the last dose, respectively. RESULTS: A single administration of alprazolam significantly reduced aggressive activities and increased social investigation without changing locomotion or other behaviour. Tolerance developed to the inhibitory effects of alprazolam on aggressive behaviour but not to the effects of alprazolam to increase social investigation. When withdrawn from alprazolam, mice exhibited less social investigation and locomotion while aggression tended to be increased. CONCLUSIONS: Tolerance to the alprazolam effects on aggressive and social behaviour developed at different rates suggesting that they are differentially regulated. Furthermore, the evidence of withdrawal responses appearing in a behaviour to which tolerance had not developed does suggest that tolerance and withdrawal phenomena are dissociated in benzodiazepines.

Alprazolam↗

PubMed2025

Effect of transgene on salt tolerance of tobacco.

To explore the effects of salt-tolerance gene accumulation on salt tolerance in transgenic plant, we used four types of plant expression vector (N27, N28, N29, and N30) carrying mtlD, mtlD + gutD, mtlD + gutD + BADH, mtlD + gutD + BADH + sacB genes respectively, to transform tobacco through Agrobacterium-mediated method. Transgenic lines were identified through polymerase chain reaction (PCR) detection. Transgenic lines and non-transgenic plant (CK) were subjected to 6‰ sodium chloride solution stress; then, fluorescence quantitative PCR (FQ-PCR) and salt tolerance indexes were used to assess characteristics. PCR showed the exogenous genes had been integrated into the tobacco genome. FQ-PCR showed under clean water treatment the target genes were expressed in all transgenic plants at the transcriptional level. The transcript abundances of target genes changed with the number of genes increased, and improved following salt stress. Comparative analyses of salt tolerance indexes showed height growth, biomass (except for N29), chlorophyll content, net photosynthetic rate, Fv/Fm, and PI of all transgenic plants and CK were lower under salt stress than under clean water treatment, to varying degrees. However, the descent ratio was smaller in transgenic plants. A comprehensive evaluation of multiple salt-tolerance indicators performed using the membership function method showed the average salt tolerance of each vector transgenic line was higher than that of CK, and salt tolerance was greater in transgenic polyvalent gene lines than in transgenic monovalent gene lines. The average salt tolerance was N29 > N28 > N30 > N27 > CK. This study provides a theoretical and practical reference for salt tolerance breeding in other plants.

Plants, Genetically Modified↗

PubMed1989

Arachidonic acid turnover in peritoneal macrophages is altered in endotoxin-tolerant rats.

Peritoneal macrophages from endotoxin-tolerant rats have been found to exhibit depressed metabolism of arachidonic acid (AA) to prostaglandins and thromboxane in response to endotoxin. The effect of endotoxin tolerance on AA turnover in peritoneal macrophages was investigated by measuring [14C]AA incorporation and release from membrane phospholipids. Endotoxin tolerance did not affect the amount of [14C]AA incorporated into macrophages (30 min-24 h). However, the temporal incorporation of [14C]AA into individual phospholipid pools (15 min-24 h) was altered. In endotoxin-tolerant macrophages, [14C]AA incorporation into phosphatidylcholine (PC) (2, 4, 24 h) and phosphatidylethanolamine (PE) (8 h) was increased, while the incorporation into phosphatidylserine (PS) (2-24 h) was reduced (P less than 0.005) compared to control macrophages. There was no change in [14C]AA incorporation into phosphatidylinositol (PI). Following 2 or 24 h of incorporation of [14C]AA, macrophages were incubated (3 h) with endotoxin (50 micrograms/ml) or A23187 (1 microM), and [14C]AA release was measured. Endotoxin-tolerant macrophages released decreased (P less than 0.05) amounts of [14C]AA in response to both endotoxin and the calcium ionophore A23187 compared to controls. Control macrophages in response to endotoxin released [14C]AA from PC, PI and PE. In contrast, tolerant cells released [14C]AA only from PC (P less than 0.05). A23187 released [14C]AA from all four pools in the control cells, but only from PC and PE in the tolerant cells. These data demonstrate that endotoxin tolerance alters the uptake and release of AA from specific macrophage phospholipid pools. These results suggest that changes in AA turnover and/or storage are associated with endotoxin tolerance.

Animals↗

PubMed1996

Nitrate tolerance impairs nitric oxide-mediated vasodilation in vivo.

OBJECTIVES: Nitroglycerin (NTG) is metabolized to nitric oxide (NO) in vascular smooth muscle cells. It is currently not clear whether prolonged exposure to NTG and tolerance development directly affects endogenous NO-mediated vasodilation in vivo. This study investigates NO-mediated vasodilation in conscious chronically catheterized rats before and after development of nitrate tolerance. The effect of the thiol compound N-acetylcysteine (NAC), which may affect NTG responsiveness, was also studied. METHODS: Nitrate tolerance was induced by a 72-h intravenous infusion of NTG and confirmed by a 65-68% reduction in the hypotensive response to NTG (P < 0.05). The hypotensive effects of acetylcholine (ACh) and sodium nitroprusside, (SNP) and possible NAC-mediated changes in the responses to these compounds were examined in nontolerant and nitrate-tolerant rats. Furthermore, the hypertensive response to the NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) was measured. RESULTS: Nitrate tolerance was associated with a significantly attenuated hypotensive response to ACh (before 24 +/- 1 mmHg; after 17 +/- 2 mmHg, n = 7, P < 0.05). Similarly, the response to SNP was reduced from 32 +/- 1 mmHg to 26 +/- 3 mmHg (n = 7, P < 0.05). NTG-vehicle (placebo) did not affect the response to ACh and SNP (P > 0.05). NAC augmented the effect of NTG, ACh and SNP in both nontolerant and nitrate-tolerant animals (P < 0.05). The hypertensive response to L-NAME (n = 8), was reduced by 67% (from 34 +/- 6 mmHg to 11 +/- 1 mmHg, P < 0.05) after induction of nitrate tolerance. CONCLUSIONS: The results suggest (1) that nitrate tolerance in vivo is associated with cross tolerance to NO-mediated vasodilation produced by both exogenous and endogenous nitrovasodilators and (2) that also responses to nitrovasodilator agents other than NTG are improved by the addition of NAC.

Acetylcholine↗