Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In vitro studies were performed to determine the role of metabolic bioactivation in mediating immunosuppression by CCl4. Direct addition of CCl4 to naive spleen cell cultures sensitized with either sheep erythrocytes, DNP-Ficoll or lipopolysaccharide (LPS) resulted in a marked inhibition of the antibody forming cell (AFC) response to all three of the selected antigens at 3.0 mM concentration in culture. However, this inhibition was primarily due to the direct cytotoxic effects of CCl4 on spleen cells following 3-5 days of culture in the presence of the chemical as evidenced by a decrease in cell number and viability and by the absence of selective effects on T-cell dependent humoral responses which is contradictory to the effects observed in vivo. Co-incubation of splenocytes for 1 h with primary hepatocytes, but not with subcellular metabolic activation systems, such as S9 or microsomes, enhanced the immunotoxic effects of CCl4 in vitro. Interestingly, a 3-h co-incubation of spleen cells with metabolically active hepatocytes in primary culture resulted in an even greater potentiation of the immunotoxic effects of CCl4 as determined by the T-cell dependent IgM AFC response. Conversely, under identical conditions, CCl4 did not suppress humoral responses to the polyclonal B-cell activator LPS which is in agreement with the effects produced by in vivo exposure to CCl4. It is important to emphasize that for the metabolic activation studies (i.e. co-incubation with either S9, microsomes or hepatocytes), spleen cells were washed free of CCl4 immediately following the co-incubation period. Control splenocyte cultures (i.e. no metabolic activation system) incubated in the presence of CCl4 alone at 3.0 mM over a 3-h time-period, had no effect on spleen cell function, number or viability. In agreement with our previous findings which indicate that pretreatment of mice with inducers and inhibitors of the mixed function oxygenase system prior to CCl4 administration modulated the immunotoxic effects of CCl4 in vivo, these results lead us to conclude that immunotoxicity by CCl4 requires metabolic activation.
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PMID:The role of metabolism in carbon tetrachloride-mediated immunosuppression. In vitro studies. 146 54

The cytotoxicity, immunotoxicity and immunomodulatory potential of four dithiocarbamate derivatives were assessed and compared with the effects of Immuthiol (diethyl dithiocarbamate, DE-DTC) in mice. Cellular stimulation and cell viability were examined after in vitro exposure of spleen lymphocytes to selected DTC analogues: N-methyl-D-glucamine dithiocarbamate (NMG-DTC), dimethyl dithiocarbamate (DM-DTC), dibuthyl dithiocarbamate (DB-DTC) and diisobuthyl dithiocarbamate (DIB-DTC). Lymphocyte activation by plant and bacterial mitogens: concanavalin A (Con A), phytohaemagglutinin (PHA), lipopolysaccharide (LPS) and allogeneic stimulation of cells in mixed lymphocyte reaction (MLR) were examined in vitro in the presence of 10(-4)-10(-9) g/ml DE-DTC and other selected DTC derivatives. No direct in vitro lymphoproliferative activity of DTC derivatives was observed, although a relatively stronger cytotoxicity with DE-DTC and DM-DTC was noted. In addition, the in vivo effects of DTC derivatives were examined by cytofluorometric profile of splenic and bone marrow cells as well as in mitogenic and allogenic responses, after i.v. exposures of animals to two subsequent (25 mg/kg b.w.) doses of the chemical. Less cytotoxic DIB-DTC, NMG-DTC and DB-DTC expressed weak in vivo immunostimulatory potential when compared with the effect of DE-DTC, whereas the effects of DM-DTC on alloantigenic and mitogenic lymphocyte stimulation were comparable with the known effects of DE-DTC. Cytofluorometric studies showed that the number of cytotoxic/suppressor T-cells (Ts) and helper T-cells (Th) in the cell was increased by DE-DTC and NMG-DTC only. In addition, DM-DTC appeared to affect the Ts/Th ratio. DE-DTC did not affect the B-cell subpopulation, whereas other derivatives induced marked modifications of the pre-B-cell subpopulations in bone marrow. Our data suggest that in vivo the immunostimulatory effect of DM-DTC could be accompanied with major changes in bone marrow B-cell frequency and alteration of spleen Ts/Th ratio.
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PMID:Evaluation of the immunomodulatory potential of diethyl dithiocarbamate derivatives. 166 50

In these studies, the mitogen responsiveness of lymphocytes obtained from local gut-associated lymphoid tissues (GALT) and the spleen were evaluated following a 5-day exposure to 7,12-dimethylbenz(a)anthracene (DMBA) at doses of 50 or 150 mg/kg. Phytohemagglutinin and lipopolysaccharide (LPS) responses were suppressed in all lymphoid tissues studied. However, the LPS response in mesenteric lymph nodes and Peyer's Patches seemed to be the most sensitive indicator of immunotoxicity, indicating that B cells appear to be particularly sensitive to DMBA toxicity in the GALT. These studies demonstrate that both splenic tissues and GALT are important targets of immunotoxicity following oral administration of DMBA. Based upon these and past studies we conclude that the total administered dose of DMBA is a more important determinant of immunotoxicity than the length of exposure.
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PMID:Suppression of local gut-associated and splenic mitogen responsiveness of lymphoid cells following oral exposure of B6C3F1 mice to 7,12-dimethylbenz[a]anthracene. 176 29

Monocrotaline (MCT) is a member of a class of naturally occurring phytotoxins known as pyrrolizidine alkaloids, and is a toxicological concern to both man and his livestock. The purpose of these studies was to evaluate the effect of a 14-day oral MCT (0-100 mg/kg per day) exposure on the functional integrity of various immunocyte effector systems in C57BL/6 mice, as well as to investigate potential mechanisms for its immunotoxicity. Decreases in lymphoid organ weights and cellularity, and resident peritoneal exudate cell (PEC) number were only observed after exposure to the highest dose of 100 mg/kg MCT. This dose also inhibited NK cell cytotoxicity, while the total number of NK lytic units per spleen was decreased (-53%) after exposure to 50 mg/kg MCT. Following i.p. injection of SRBC, the percentage of PEC macrophages containing engulfed SRBC was significantly increased in MCT-exposed mice, while the percentage of large vacuolated (activated) macrophages was decreased in a dose-dependent manner. Exposure to MCT significantly decreased the total number of Ig+ cells without altering the number of CD4+ and CD8+ cells. The antibody responses (PFC/10(6) spleen cells) to two T cell-independent antigens, TNP-LPS and DNP-Ficoll, were significantly decreased at all MCT doses, and the degree of suppression of both responses was identical at coincident doses. MCT exposure (25 mg/kg) significantly suppressed the blastogenic response to the T cell mitogen concanavalin A (-38%), and to the B cell mitogen lipopolysaccharide (-58%). These results indicate that exposure to MCT can alter the functional integrity of various immune effector responses in a dose-dependent manner, and suggest that the B cell may be a relatively more sensitive target of MCT immunotoxicity compared to T cells, macrophages and NK cells.
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PMID:Tier-2 studies on monocrotaline immunotoxicity in C57BL/6 mice. 177 39

We previously demonstrated that the glycol ether 2-methoxyethanol (ME) is immunotoxic in the rat. In this study, the immunotoxicity of 2-methoxyacetic acid (MAA), the principal metabolite of ME, was evaluated in adult male Fischer 344 rats. Rats were dosed by gavage with MAA on 10 consecutive days at dosages ranging from 50 to 200 mg/kg/day. Thymic involution, in the absence of body weight loss, was observed at 100 and 200 mg/kg/day MAA. Lymphoproliferative responses to the mitogens concanavalin A, phytohemagglutinin, and pokeweed mitogen were also reduced at these dosages. The in vitro generated cytotoxic T lymphocyte response was reduced at 200 mg/kg/day MAA. The mixed lymphocyte reaction and natural killer cell activity were unaffected by exposure to MAA. Enumeration of splenic lymphocyte populations revealed a reduction in the percentage of W3/25-positive cells at 100 and 150 mg/kg/day and an increase in the percentage of OX39-positive cells at 200 mg/kg/day; however, no changes in the absolute number of either of these subsets were observed. The plaque forming cell (PFC) response to trinitrophenyl-lipopolysaccharide (TNP-LPS) was suppressed at 50-200 mg/kg/day MAA, while the PFC response to sheep red blood cells (SRBC) was elevated at 50 mg/kg/day. Immunization of rats with TNP-LPS or SRBC followed by oral exposure to MAA at 4 and 28 hr postimmunization resulted in the suppression of the PFC response to TNP-LPS and SRBC at dosages of 100 and 200 mg/kg and 200 and 400 mg/kg, respectively. Equal suppression of the PFC response to TNP-LPS was achieved at equimolar concentrations of ME and MAA. The effects of MAA on the immune system of the rat presented here are very similar to results reported from this lab for ME-induced immune alterations. These results, along with results of experiments in which ME-induced suppression of the PFC response to TNP-LPS was reversed by 4-methylpyrazole, an inhibitor of the oxidation of ME to MAA by alcohol dehydrogenase, indicate that MAA is the proximate immunotoxicant following exposure to the glycol ether 2-methoxyethanol.
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PMID:Evaluation of the immunotoxicity of orally administered 2-methoxyacetic acid in Fischer 344 rats. 177 63

The immunotoxicity of the glycol ether 2-methoxyethanol (ME) was evaluated in adult Fischer 344 rats using a variety of in vitro and in vivo immune function assays. In the first phase of this study, male rats were dosed by oral gavage with ME in water, at dosages ranging from 50 to 200 mg/kg/day, for 10 consecutive days. Decreases in thymus weights were observed at dosages of 50-200 mg/kg/day in the absence of decreased body weights. Lymphoproliferative (LP) responses to concanavalin A and phytohemagglutinin were reduced at 50-200 mg/kg/day while pokeweed mitogen and Salmonella typhimurium mitogen responses were reduced at 200 mg/kg/day. No alterations were observed in natural killer cell activity, mixed lymphocyte reaction, or cytotoxic T lymphocyte responses. The frequency of W3/25-positive splenocytes was reduced in rats dosed at 200 mg/kg/day. Interleukin-2 production was reduced in splenocytes from rats exposed to all dosages of ME. The plaque-forming cell (PFC) response to sheep red blood cells was enhanced in rats dosed at 50 mg/kg/day. However, the PFC response to trinitrophenyl-lipopolysaccharide (TNP-LPS) was suppressed at all dosages. Similarly, the PFC response to TNP-LPS was suppressed in adult female rats dosed with ME. A reduction in the expulsion of adult worms was observed in rats dosed at 200 mg/kg/day that were infected with Trichinella spiralis. A number of male reproductive parameters were also evaluated in rats dosed with ME over 10 days. A significant reduction in testicular weight was observed in rats dosed at 200 mg/kg/day. In the second phase of this study, the PFC response to TNP-LPS was employed to assess the role that metabolism of ME to 2-methoxyacetic acid (MAA) plays in the immunotoxicity of this glycol ether. Ten-day oral dosing with MAA resulted in the inhibition of the PFC response to TNP-LPS at dosages of 50-200 mg/kg/day. Concomitant exposure of rats to ME and the alcohol dehydrogenase inhibitor 4-methylpyrazole blocked ME-induced suppression of this PFC response. Attempts to ameliorate ME-induced suppression of the PFC response with serine, which has been shown to reverse ME-induced developmental and reproductive toxicity, were unsuccessful. These results suggest that the immune system may be more sensitive than the reproductive system to the toxic effects of ME. Furthermore, it appears that MAA is the proximate toxicant for ME-induced alterations in the immune system, as has been demonstrated for ME-induced reproductive and developmental toxicity.
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PMID:Immunotoxicity of 2-methoxyethanol following oral administration in Fischer 344 rats. 185 47

There are conflicting reports in the literature regarding the role of the Ah locus in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) immunotoxicity. The present studies have utilized two congenic strains of C57Bl/6 mice that differ only at this locus to assess its influence on TCDD-induced suppression of antibody responses. Mice were given a single oral dose of TCDD 2 days prior to challenge with sheep red blood cells (SRBC) or trinitrophenyl-lipopolysaccharide (TNP-LPS). The subsequent dose-dependent effects of TCDD on the amount of antibody produced by splenic plasma cells were measured using the hemolytic antibody isotope release assay. In addition, the relative importance of the Ah genotype of lymphoid versus nonlymphoid tissue was examined in adoptive transfer experiments. Aryl hydrocarbon hydroxylase (AHH) activity was significantly induced in Ahbb mice by a dose of 0.5 micrograms/kg TCDD and maximally induced by a dose of 2 micrograms/kg. Ahdd mice required 10-fold higher doses of TCDD to induce comparable levels of AHH. The degree of thymic involution and liver hypertrophy induced by TCDD was also influenced by the Ah genotype of the animals. Both Ahbb and Ahdd mice exhibited dose-dependent suppression of the anti-TNP response following TCDD exposure. The ID50 was 7.0 micrograms/kg in Ahbb mice and 30.8 micrograms/kg in Ahdd mice. Suppression of the antibody response to SRBC was also dependent on the Ah locus. The ID50 in Ahbb mice was 0.6 micrograms/kg TCDD. However, an apparent biphasic dose response for suppression of the anti-SRBC response in Ahdd mice suggested the involvement of an Ah-independent component of suppression as well. In adoptive transfer studies, lymphocytes were identified as an Ah-dependent component of the response. The Ah-independent component of the response was not identified, and could be either lymphoid or nonlymphoid in nature. The possibility that T helper cells represent the Ah-independent component is discussed.
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PMID:Influence of the Ah locus on the humoral immunotoxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin: evidence for Ah-receptor-dependent and Ah-receptor-independent mechanisms of immunosuppression. 216

Macrocyclic trichothecenes are a class of mycotoxins, some of which exhibit substantial antileukemic properties. These compounds vary in their toxicity by approximately 100 fold and are suspected immunotoxins. We studied 11 of these mycotoxins: roritoxin B, myrotoxin B, roridin A, verrucarin A, 16-hydroxyverrucarin A, verrucarin J, baccharinoid B12, roridin D, roridin E, baccharinoid B4 and baccharinoid B5 for their immunotoxicity in CD-1 mice. An equitoxic dose was prepared in 1% DMSO in saline and administered i.p. at half the LD50. Organ weights, WBC, RBC, differentials of blood cell counts, blastogenesis of splenic lymphocytes in response to concanavalin A (Con A), lipopolysaccharide (LPS), phytohemagglutinin (PHA) and pokeweed mitogen (PWM), and mixed lymphocyte reaction (MLR) were studied on day 4 after administration of each mycotoxin. Organ weights showed significant differences between the controls and the baccharinoids with a decrease in spleen weight in baccharinoid B12 and an increased liver weight in B4 and B5 treated animals. Administration of myrotoxin B, roridin A, verrucarin J and roridin E had total WBC counts statistically different from controls, while mice administered myrotoxin B shoed a decrease in numbers of RBC. Differentials of WBC were unremarkable regardless of the mycotoxin. Roritoxin B and baccharinoid B5 increased Con A stimulation of splenic lymphocytes. Roridin A and baccharinoid B12 increased LPS stimulation of splenic lymphocytes while baccharinoid B5 decreased the LPS response. Stimulation of splenic lymphocytes with PHA was significantly increased by roridin A and baccharinoid B5. Stimulation of splenic lymphocytes with PWM was not altered significantly by any mycotoxin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of macrocyclic trichothecene mycotoxins on the murine immune system. 278 85

Recent reports suggest that the immunotoxicity of certain polycyclic aromatic hydrocarbons is associated with the Ah locus in mice. To test whether immunosuppression mediated by 7,12-dimethylbenz[a]anthracene (DMBA) is regulated by the Ah locus, several endpoints of immune function were measured in Ah-responsive B6C3F1 and Ah-nonresponsive DBA/2N and in Ah-congenic C57BL/6J (responsive B6-AhbAhd and nonresponsive B6-AhdAhd) mice dosed sc with up to 100 micrograms/g DMBA in corn oil. Some groups of B6C3F1 and DBA/2N mice were exposed to 100 micrograms/g benzo[a]pyrene (B(a)P) or 1 nmol 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) for determination of hepatic microsomal monooxygenase activity. The body weights of all mice were unaffected by DMBA exposure, but thymus weights and spleen cellularity were decreased. Antibody plaque-forming cells (PFC) measured 4 days after iv sheep erythrocyte (SRBC) immunization were suppressed 99% in B6C3F1 and 96% in DBA/2 mice. Antibody PFC after in vitro immunization to SRBC were similarly suppressed 98% in both B6-AhbAhd and B6-AhdAhd Ah-congenic mice exposed to 100 micrograms/g DMBA. Responses to the T-cell mitogens concanavalin A and phytohemagglutinin were significantly suppressed in both B6C3F1 and DBA/2N strains, as was mitogenesis to bacterial lipopolysaccharide. The unidirectional mixed lymphocyte responses of the congenic strains were suppressed 76% in B6-AhbAhd and 85% in B6-AhdAhd, cytotoxic lymphocyte generation was suppressed 68% in B6-AhbAhd and 78% in B6-AhdAhd. The overall differences between immunosuppressive responses in splenocytes from B6-AhbAhd and B6-AhdAhd congenics were not significant. Induction of cytochrome P1-450, a marker of Ah responsiveness, was determined by 7-ethoxycoumarin O-deethylase monooxygenase activity in hepatic microsomes or splenocytes. This monooxygenase activity was not significantly increased in either B6C3F1 or DBA/2 mice exposed to DMBA, whereas B(a)P and TCDD exposure significantly induced enzyme activity in B6C3F1 hepatocytes. These data suggest that DMBA has an immunosuppressive action on murine splenocytes which is independent of the Ah locus and associated induction of cytochrome P1-450 xenobiotic-metabolizing enzymes.
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PMID:Immunosuppression following exposure to 7,12-dimethylbenz[a]anthracene (DMBA) in Ah-responsive and Ah-nonresponsive mice. 312 68

Female B6C3F1 mice were exposed to graded doses of nickel sulfate to determine a threshold response for myelotoxicity and immunotoxicity, and to identify which of the populations of lymphoreticular cells were most sensitive to the toxic effects of nickel. Animals were given free access to the chemical in the drinking water at 0, 1, 5, or 10 g/l for 180 d. Water consumption, blood and tissue nickel concentrations, body and organ weights, histopathology, immune responses, bone marrow cellularity and proliferation, and cellular enzyme activities were evaluated. There was no mortality. Mice in the 5-g/l and 10-g/l dose groups drank less water than controls; the responses measured in the 10-g/l group may have been due to a combination of dehydration and chemical toxicity. Decreases in body and organ weights were confined to mice in the 10-g/l dose group, except for the dose-related reductions in thymus weights. Blood nickel was measured at 4, 8, 16, and 23 wk of exposure. The mean blood nickel values showed increases between 4 and 8 wk that were proportional to time and dose; thereafter there was no substantial increase in blood nickel in any of the dose groups, except for an increase in the mean blood concentration in the 10-g/l group at 23 wk. The kidney was the major organ of nickel accumulation. The primary toxic effects of nickel sulfate were expressed in the myeloid system. There were dose-related decreases in bone marrow cellularity, and in granulocyte-macrophage and pluripotent stem-cell proliferative responses. In unfractionated bone marrow cells glucose-6-phosphate dehydrogenase enzyme activity from the hexose monophosphate shunt was more sensitive to nickel sulfate than were representative glycolytic or Krebs cycle enzymes, with 25-35% maximum inhibition at 5 g/l and 10 g/l. Aliquots of bone marrow cells were separated into enriched bands of lymphocytes, granulocyte-macrophages, and erythrocytes; enzyme inhibition that occurred in unfractionated bone marrow cell aliquots was only expressed after cell separation in the enriched granulocyte-macrophage cell population, suggesting that these committed stem cells were a primary target of nickel sulfate toxicity. There was one example of systemic immunotoxicity, reduction in the lymphoproliferative response to lipopolysaccharide, and it was regarded as secondary to the primary effect of nickel sulfate on the myeloid system, since this was the only significant change among a panel of seven immune parameters that were evaluated.
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PMID:Evaluation of tissue disposition, myelopoietic, and immunologic responses in mice after long-term exposure to nickel sulfate in the drinking water. 339 77


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