The Experts below are selected from a list of 189 Experts worldwide ranked by ideXlab platform
James J Pestka - One of the best experts on this subject based on the ideXlab platform.
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murine anorectic response to deoxynivalenol Vomitoxin is sex dependent
Toxins, 2015Co-Authors: Erica S Clark, Brenna M Flannery, James J PestkaAbstract:Deoxynivalenol (DON, Vomitoxin), a common trichothecene mycotoxin found in cereal foods, dysregulates immune function and maintenance of energy balance. The purpose of this study was to determine if sex differences are similarly evident in DON’s anorectic responses in mice. A bioassay for feed refusal, previously developed by our lab, was used to compare acute i.p. exposures of 1 and 5 mg/kg bw DON in C57BL6 mice. Greater anorectic responses were seen in male than female mice. Male mice had higher organ and plasma concentrations of DON upon acute exposure than their female counterparts. A significant increase in IL-6 plasma levels was also observed in males while cholecystokinin response was higher in females. When effects of sex on food intake and body weight changes were compared after subchronic dietary exposure to 1, 2.5, and 10 ppm DON, males were found again to be more sensitive. Demonstration of male predilection to DON-induced changes in food intake and weight gain might an important consideration in future risk assessment of DON and other trichothecenes.
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peptide yy3 36 and 5 hydroxytryptamine mediate emesis induction by trichothecene deoxynivalenol Vomitoxin
Toxicological Sciences, 2013Co-Authors: Wenda Wu, Brenna M Flannery, Hui Ren Zhou, Melissa A Bates, Steven J Bursian, Jane E Link, Haibin Zhang, James J PestkaAbstract:Deoxynivalenol (DON, Vomitoxin), a trichothecene mycotoxin produced by Fusarium sp. that frequently occurs in cereal grains, has been associated with human and animal food poisoning. Although a common hallmark of DON-induced toxicity is the rapid onset of emesis, the mechanisms for this adverse effect are not fully understood. Recently, our laboratory has demonstrated that the mink (Neovison vison) is a suitable small animal model for investigating trichothecene-induced emesis. The goal of this study was to use this model to determine the roles of two gut satiety hormones, peptide YY3–36 (PYY3–36) and cholecystokinin (CCK), and the neurotransmitter 5-hydroxytryptamine (5-HT) in DON-induced emesis. Following ip exposure to DON at 0.1 and 0.25mg/kg bw, emesis induction ensued within 15–30min and then persisted up to 120min. Plasma DON measurement revealed that this emesis period correlated with the rapid distribution and clearance of the toxin. Significant elevations in both plasma PYY3–36 (30–60min) and 5-HT (60min) but not CCK were observed during emesis. Pretreatment with the neuropeptide Y2 receptor antagonist JNJ-31020028 attenuated DON- and PYY-induced emesis, whereas the CCK1 receptor antagonist devezapide did not alter DON’s emetic effects. The 5-HT3 receptor antagonist granisetron completely suppressed induction of vomiting by DON and the 5-HT inducer cisplatin. Granisetron pretreatment also partially blocked PYY3–36-induced emesis, suggesting a potential upstream role for this gut satiety hormone in 5-HT release. Taken together, the results suggest that both PYY3–36 and 5-HT play contributory roles in DON-induced emesis.
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effects of Vomitoxin deoxynivalenol on the binding of transcription factors ap 1 nf κb and nf il6 in raw 264 7 macrophage cells
Journal of Toxicology and Environmental Health, 2002Co-Authors: Shu Shyan Wong, Hui Ren Zhou, James J PestkaAbstract:The effects of Vomitoxin (VT) on the binding activity of three transcription factors critical to pro-inflammatory cytokine regulation were assessed in the RAW 264.7 murine macrophage model by electrophoretic mobility shift assay (EMSA). When cells were treated with 100 to 250 ng/ml of VT, activator protein-1 (AP-1 binding) was increased after 2 and 8 h. This effect was potentiated when cells were coincubated with lipopolysaccharide (LPS) (synchronous model) but not when preincubated with LPS (delayed synchronous model). Supershift EMSA revealed that VT preferentially induced JunB, JunD, phosphorylated c-Jun, c-Fos, and Fra-2 binding activities of the AP-1 family. Nuclear factor s B (NF- s B) binding was increased at 2 and 8 h in cells subjected to synchronous and delayed synchronous VT exposure in the presence of LPS. Supershift EMSA indicated that the p-50 and c-Rel subunits of NF- s B/ Rel were specifically affected. Nuclear factor-IL6 (NF-IL6) binding was increased at 2 and 8 h with or without LPS in s...
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differential upregulation of tnf α il 6 and il 8 production by deoxynivalenol Vomitoxin and other 8 ketotrichothecenes in a human macrophage model
Journal of Toxicology and Environmental Health, 2001Co-Authors: Yoshiko Sugitakonishi, James J PestkaAbstract:The effects of deoxynivalenol (DON or Vomitoxin) and four closely related 8-ketotrichothecenes on proinflammatory cytokine and chemokine production were evaluated in a clonal human macrophage model. U-937 cells, which represent a human monocytelike histocytic lymphoma, were differentiated into macrophages by preincubation with phorbol 12-myristate 13-acetate (PMA). Differentiated macrophages were incubated with DON in the absence or presence of lipopolysaccharide (LPS), and supernatant was analyzed by enzyme-linked immunosorbent assay (ELISA) for the proinflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor- f (TNF- f ), and for the chemokine interleukin-8 (IL-8). In the absence of LPS, DON at 500 or 1000 ng/ml upregulated TNF- f production as early as 3 h and up to 6 h, whereas 100 to 1000 ng/ml of DON significantly increased production of IL-6 from 3 to 24 h and IL-8 from 6 to 48 h. In cells costimulated with 0.2 µg/ml LPS, DON at 500 or 1000 ng/ml markedly superinduced TNF- f and IL-8 pr...
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Down-regulation of the endoplasmic reticulum chaperone GRP78/BiP by Vomitoxin (deoxynivalenol).
Toxicology and Applied Pharmacology, 2000Co-Authors: Gi Hyeok Yang, Shiguang Li, James J PestkaAbstract:Abstract The mechanisms by which trichothecene mycotoxins cause immunological effects in leukocytes such as cytokine up-regulation, aberrant IgA production, or apoptotic cell death are not fully understood. In the present study, mRNA differential display analysis was used to evaluate changes in gene expression induced by the trichothecene Vomitoxin (VT or deoxynivalenol) in a T-cell model, the murine EL-4 thymoma, that was stimulated with phorbol 12–myristate 13–acetate (PMA) and ionomycin (ION). Ten differentially expressed fragments of cDNA were isolated and sequenced and three of these were identified as the known genes GRP78/BiP, P58 IPK , and RAD17. Most notably, expression of GRP78/BiP (a 78-kDa glucose-regulated protein), a stress-response gene induced by agents or conditions that adversely affect endoplasmic reticulum (ER) function, was found to decrease in VT-exposed cells. Competitive RT-PCR analysis revealed that 250 ng/ml VT decreased GRP78/BiP mRNA expression in both unstimulated and PMA/ION-stimulated EL-4 cells at 6 and 24 h after VT treatment. Western blotting confirmed that VT (50 to 1000 ng/ml) also significantly diminished GRP/BiP protein levels in a dose-response manner in PMA/ION-stimulated cells. GRP78/BiP has been shown to play a role in regulation of protein folding and secretion, and to protect cells from apoptosis. When PMA/ION-stimulated cells were incubated with 50 to 1000 ng/ml VT for 24 h, 200-bp DNA laddering, a hallmark of apoptosis, increased in a dose-dependent manner. In addition to GRP78, mRNA expression of the cochaperone P58 IPK , which is the 58-kDa cellular inhibitor of the double-stranded RNA-regulated protein kinase (PKR), was also shown to be suppressed by VT-treatment. GRP78 and P58 IPK are critical for maintenance of cell homeostasis and prevention of apoptosis. The down-regulation of these molecular chaperones by VT represent a novel observation and has the potential to impact immune function at multiple levels.
L Rasooly - One of the best experts on this subject based on the ideXlab platform.
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polyclonal autoreactive iga increase and mesangial deposition during Vomitoxin induced iga nephropathy in the balb c mouse
Food and Chemical Toxicology, 1994Co-Authors: L Rasooly, James J PestkaAbstract:Abstract To establish the relationship between autoreactive antibodies and Vomitoxin-induced immunoglobulin A (IgA) nephropathy, the effects of dietary Vomitoxin exposure on the antigen specificity of serum IgA. IgA-producing cells and accumulated mesangial IgA in BALB/c mice were assessed. Exposure to dietary Vomitoxin for 8 wk caused a significant increase in total serum IgA. There was a concurrent significant increase in serum IgA specific for trinitrophenol (TNP), phosphorylcholine, cardiolipin and sphingomyelin compared with controls, suggesting an elevation of autoreactive IgA. Casein, a protein found in the AIN-76A diet, could inhibit binding of serum IgA to sphingomyelin and cardiolipin, indicating that these antibodies may be polyspecific. When enzyme-linked immunospot assay was used to monitor autoreactive IgA production, trends were observed towards increased IgA-secreting cells specific for TNP, cardiolipin and sphingomyelin in Peyer's patches from Vomitoxin-fed mice compared with control mice. IgA-producing cells reactive with TNP were increased in the spleen of Vomitoxin-fed mice whereas effects on IgA-secreting cells for the other antigens were marginal. Marked deposition of mesangial IgA was also observed in Vomitoxin-fed mice compared with controls. When IgA was eluted from the kidney sections of treated mice and tested by enzyme-linked immunosorbent assay, it exhibited a strong binding to the above antigen panel as well as inulin, DNA and casein. These data suggest that dietary Vomitoxin induced the polyclonal activation of IgA-producing cells and that resultant autoreactive IgA was subsequently deposited in the kidney mesangium.
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Polyclonal autoreactive IgA increase and mesangial deposition during Vomitoxin-induced IgA nephropathy in the BALB/c mouse
Food and Chemical Toxicology, 1994Co-Authors: L Rasooly, James J PestkaAbstract:Abstract To establish the relationship between autoreactive antibodies and Vomitoxin-induced immunoglobulin A (IgA) nephropathy, the effects of dietary Vomitoxin exposure on the antigen specificity of serum IgA. IgA-producing cells and accumulated mesangial IgA in BALB/c mice were assessed. Exposure to dietary Vomitoxin for 8 wk caused a significant increase in total serum IgA. There was a concurrent significant increase in serum IgA specific for trinitrophenol (TNP), phosphorylcholine, cardiolipin and sphingomyelin compared with controls, suggesting an elevation of autoreactive IgA. Casein, a protein found in the AIN-76A diet, could inhibit binding of serum IgA to sphingomyelin and cardiolipin, indicating that these antibodies may be polyspecific. When enzyme-linked immunospot assay was used to monitor autoreactive IgA production, trends were observed towards increased IgA-secreting cells specific for TNP, cardiolipin and sphingomyelin in Peyer's patches from Vomitoxin-fed mice compared with control mice. IgA-producing cells reactive with TNP were increased in the spleen of Vomitoxin-fed mice whereas effects on IgA-secreting cells for the other antigens were marginal. Marked deposition of mesangial IgA was also observed in Vomitoxin-fed mice compared with controls. When IgA was eluted from the kidney sections of treated mice and tested by enzyme-linked immunosorbent assay, it exhibited a strong binding to the above antigen panel as well as inulin, DNA and casein. These data suggest that dietary Vomitoxin induced the polyclonal activation of IgA-producing cells and that resultant autoreactive IgA was subsequently deposited in the kidney mesangium.
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polyspecific and autoreactive iga secreted by hybridomas derived from peyer s patches of Vomitoxin fed mice characterization and possible pathogenic role in iga nephropathy
Food and Chemical Toxicology, 1994Co-Authors: L Rasooly, Kathryn H Brooks, Mohamed M Abouzied, James J PestkaAbstract:Abstract A total of 122 immunoglobulin (Ig)A-producing hybridoma clones were isolated from the Peyer's patches of Vomitoxin-fed BALB/c mice and the resultant antibodies were characterized for their antigenic specificity and pathogenic potential. When reactivity was tested against a panel consisting of DNA, sphingomyelin, thyroglobulin, collagen, casein, cardiolipin and bovine serum albumin conjugates of phosphorylcholine, inulin and trinitrophenol that were representative of self and non-self antigens, approximately 95% of the monoclonal IgAs bound to at least one of the panel antigens and 80% bound to more than one antigen. The polyspecificity of some of the monoclonal IgAs was further suggested by demonstrating the capacity of one antigen to inhibit binding of monoclonal IgA to another antigen. Protein staining and Western blotting of gradient native polyacrylamide gels, indicated that trimeric IgA predominated in the isolated monoclonal IgAs. Repeated injections of mice with representative monoclonal IgAs induced microhaematuria in three of four of the clones tested but not IgA deposition in the kidney glomerulus. In addition, three of the four monoclonal IgAs caused IgG and C3 deposition in the kidney mesangium. These and previous results suggest that dietary Vomitoxin promotes the polyclonal activation and expansion of IgA-secreting B cells at the Peyer's patch level and that resultant polyspecific, autoreactive IgA may contribute to kidney pathogenesis.
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Vomitoxin induced dysregulation of serum iga igm and igg reactive with gut bacterial and self antigens
Food and Chemical Toxicology, 1992Co-Authors: L Rasooly, James J PestkaAbstract:Abstract The effect of dietary Vomitoxin exposure on immunoglobulins that react with naturally occurring gut bacterial and self antigens was assessed in the B6C3F1 mouse. Ingestion of 25 ppm Vomitoxin for 4 and 8 wk resulted in significantly elevated total IgA but depressed total IgG and IgM in serum when compared with control mice fed semi-purified diet only. IgA specific for phosphorylcholine (PC) and inulin (haptens associated with intestinal bacteria) increased significantly in mice fed Vomitoxin whereas IgM with the identical specificity decreased. When sera were assessed for autoantibodies recognizing DNA and bromelated mouse red blood cells (MRBC), Vomitoxin-exposed mice exhibited elevated specific IgA as compared with controls. This occurred together with decreases in DNA-specific IgG and IgM, and decreases in MRBC-specific IgM. Additionally, Vomitoxin exposure did not enhance the specific serum IgA response to orally administered trinitrophenylated sheep red blood cells (TNP-SRBC), but significantly depressed TNP-specific serum IgG. The results suggest that hyperelevation of total and specific serum IgA for oral and self antigens occurs during Vomitoxin feeding and that may be coupled with down-regulation of total and specific IgM or IgG. These effects could be contributory to the capacity of Vomitoxin to induce IgA immune complex glomerulonephritis.
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elevated membrane iga and cd4 t helper populations in murine peyer s patch and splenic lymphocytes during dietary administration of the trichothecene Vomitoxin deoxynivalenol
Food and Chemical Toxicology, 1990Co-Authors: James J Pestka, R L Warner, Wumin Dong, L Rasooly, G S Bondy, Kathryn H BrooksAbstract:Abstract Recent investigations indicate that dietary exposure to the trichothecene Vomitoxin increases total and antigen-specific serum immunoglobulin A (IgA) and glomerular IgA accumulation in mice. In this study, the effects of 25 ppm dietary Vomitoxin on the histological and lymphocytic profile of component immune organs in the mucosal lymphocyte migratory pathway were evaluated in the B6C3F 1 mouse. Vomitoxin administration resulted in marked stimulation of the size and frequency of germinal centres in Peyer's patches, mesenteric lymph nodes and the spleen. A slight increase in the percentage of B cells in the Peyer's patch was observed, although Vomitoxin treatment had no effect on the percentage of B cells in the spleen. The percentage of IgA + cells in Peyer's patches and spleen were approximately twice that of controls at 4, 8 and 12 wk of Vomitoxin exposure whereas the percentage of IgG + cells decreased in these two organs. Exposure to Vomitoxin increased the percentage of T cells in Peyer's patches and the spleen. The percentage of CD4 + cells (T helper subset) increased slightly in Peyer's patches and more markedly (30–50%) in the spleen following Vomitoxin treatment. Contrastingly, there was only a slight increase in the percentage of CD8 + cells (T cytotoxic/suppressor subset) in the spleens of Vomitoxin-treated mice in comparison with controls, and no effect in Peyer's patches. The relative effects of Vomitoxin on these two T cell populations was also reflected in increased CD4 + :CD8 + ratios in Peyer's patches and spleen. These results are consistent with the hypothesis that dietary Vomitoxin modulates normal regulation of the IgA response at the Peyer's patch level and that this is manifested in an altered lymphocyte distribution pattern in both the mucosal and systemic compartment. Notably increased levels of IgA + and CD4 + cells are indicative of IgA-producing progenitors and T helper subsets, respectively, that in tandem could favour IgA hyperproduction and elevated IgA in serum.
Wumin Dong - One of the best experts on this subject based on the ideXlab platform.
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superinduction of il 2 gene expression by Vomitoxin deoxynivalenol involves increased mrna stability
Toxicology and Applied Pharmacology, 1997Co-Authors: Shiguang Li, Wumin Dong, Yan L Ouyang, James J PestkaAbstract:Abstract To better understand molecular mechanisms by which the trichothecene Vomitoxin (VT) superinduces cytokine gene expression, we studied the posttranscriptional effects of this mycotoxin on interleukin-2 (IL-2) gene expression in murine EL-4 thymoma cells stimulated with phorbol 12-myristate 13-acetate and ionomycin (PMA + ION). Northern analysis revealed that doses of 50 to 500 ng/ml VT superinduced IL-2 mRNA expression in a dose- and time-dependent manner in a synchronous model where VT was added at onset of PMA + ION stimulation. In accordance with the mRNA levels, IL-2 production was significantly elevated in the presence of 50 to 250 ng/ml VT. Superinduction of IL-2 mRNA was also observed in a delayed synchronous model (VT added 20 hr after PMA + ION stimulation) and an asynchronous model (VT added 20 hr after PMA + ION stimulation and removal). To assess the effects of VT (500 ng/ml) on IL-2 mRNA half-life, three transcriptional inhibitors were used in the delayed synchronous model. Actinomycin D (ActD) had a pronounced stabilizing effect on IL-2 mRNA but not on mRNA for the housekeeping gene GAPDH. VT did not affect IL-2 mRNA levels in ActD-treated cells. Although 5,6-dichloro-β- d -ribofuranosyl-benzimidazole (DRB) also had a stabilizing effect on IL-2 mRNA, IL-2 mRNA half-life t 1/2 in VT-treated cells was three times that of control. In contrast, inclusion of cyclosporin A (CsA) into the cultures specifically arrested IL-2 transcription in EL-4 cells without any stabilizing effect. VT exposure in the presence of CsA markedly prolonged the half-life of IL-2 mRNA in a dose-dependent manner. The t 1/2 for IL-2 mRNA in the control culture was 2.1 hr, whereas t 1/2 was 3.1, 3.4, 4.2, and 10.5 hr in cultures containing 50, 100, 250, and 500 ng/ml VT, respectively. These results suggest that VT can superinduce IL-2 at both the mRNA and the protein level and that this superinduction can be explained, in part, by posttranscriptional mechanisms such as enhanced mRNA stability.
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Progressive Serum IgE Elevation in the B6C3F1 Mouse Following Withdrawal of Dietary Vomitoxin (Deoxynivalenol)
Toxicological Sciences, 1994Co-Authors: James J Pestka, Wumin DongAbstract:Abstract Progressive Serum IgE Elevation in the B6C3F1 Mouse Following Withdrawal of Dietary Vomitoxin (Deoxynivalenol). Pestka, J. J., and Dong, W. (1994). Fundam. Appl. Toxicol. 22, 314-346. Vomitoxin (deoxynivalenol) is a fungal toxin that induces serum IgA hyperelevation, IgA autoantibodies, mesangial IgA deposition in mice upon dietary exposure. The capacity of dietary Vomitoxin to similarly alter serum IgE was assessed in female B6C3F1 mice. Ingestion of 25 ppm Vomitoxin in AIN-76A semipurified diet resulted in 2.7-, 4-, 5-, and 2.3-fold increases in serum IgE relative to controls after 12, 16, 20, and 24 weeks of toxin feeding, respectively. When mice were fed 25 ppm Vomitoxin for 8 weeks and continued on toxin-free diet, serum IgE levels were 2.4, 4, 4.9, and 2-fold that of controls at 12, 16, 20, and 24 weeks, respectively. IgE levels were not significantly different between treatment and withdrawal groups at Weeks 12-24. These results differed from those of serum IgA, which increased much earlier and only during toxin administration, and those of IgG, which was largely unaffected compared to controls. The results indicate that a defined period of Vomitoxin ingestion can subsequently induce progressive dysregulation of IgE production in addition to previously described IgA-related pathologic effects.
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in vitro Vomitoxin exposure alters iga and igm secretion by ch12lx b cells relationship to proliferation and macromolecular synthesis
Mycopathologia, 1993Co-Authors: Fiorenza Minervini, Wumin Dong, James J PestkaAbstract:The CH12LX cell line was used as a clonal model to assess the direct effects of Vomitoxin on IgM and IgA secretion in B cells. When Vomitoxin was included in LPS-driven CH12LX B cell cultures, it had multiple effects on Ig secretion. Whereas Vomitoxin doses of 115 and 120 ng/ml caused 50% inhibition(ID50) of IgA and IgM production, respectively, toxin concentrations in the 5 to 50 ng/ml range slightly stimulated IgA production. However, low Vomitoxin doses did not induce switching of membrane IgM+ CH12LX B cells to membrane IgA+. Total cell number was unaffected at Vomitoxin concentrations up to 100 ng/ml but dropped markedly at 200 ng/ml (ID50=170 ng/ml). Using the MTT reduction assay as another measure of viability and cell function, Vomitoxin was also inhibitory (ID50=130 ng/ml). Both thymidine incorporation and leucine incorporation were also inhibited by the toxin with estimated ID50s being 120 and 110 ng/ml, respectively. The results indicate that although at high doses, Vomitoxin inhibits proliferation, Ig secretion and DNA/protein synthesis in the clonal B cell model, the toxin marginally stimulated IgA secretion at lower doses.
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persistent dysregulation of iga production and iga nephropathy in the b6c3f1 mouse following withdrawal of dietary Vomitoxin deoxynivalenol
Toxicological Sciences, 1993Co-Authors: Wumin Dong, James J PestkaAbstract:Abstract Persistent Dysregulation of IgA Production and IgA Nephropathy in the B6C3FI Mouse Following Withdrawal of Dietary Vomitoxin (Deoxynivalenol). Dong. W., and Pestka, J. J. (1993). Fundam. Appl. Toxicol. 20, 38-47. To assess whether Vomitoxin-induced dysregulation of IgA production and IgA nephropathy are reversible, relevant immunologic parameters were compared among experimental groups of B6C3F1 mice that were fed: (1) 25 ppm Vomitoxin in AIN-76A semipurified diet for 24 weeks (treatment group), (2) 25 ppm Vomitoxin for 8 weeks and then control diet for 16 weeks (withdrawal group), and (3) control diet for 24 weeks (control group). Levels of serum IgA and microhematuria index in the treatment group were elevated after 4 to 8 weeks and continued to increase with further Vomitoxin exposure. IgA immune complexes and mesangial IgA deposition, as quantitated by interactive laser cytometer image analysis, were also increased with toxin exposure at Weeks 8, 16, and 24, whereas IgM, IgG, and complement component C3 deposition were unaffected or depressed. Serum IgA, microhematuria index, and mesangial IgA deposition in withdrawal mice remained elevated over those of the controls at Weeks 16 and 24 but were less than those of the treatment group. Cell recovery from Peyer's patches (PP) as well as the percentages of IgA + and CD4 + cells in PP and spleen at Weeks 16 and 24 were greater in treatment mice than in controls, but only the percentage of IgA + cells in PP was elevated in the withdrawal nice at these the same time points. When IgA secretion by unstimulated and LPS-stimuluted splenic lymphocytes was used as the measure of systemic production, it was elevated in both treatment and withdrawal mice at Weeks 16 and 24. The results indicated that experimental dysregulation of IgA production and IgA nephropathy persisted up to 4 months after a discrete period of dietary Vomitoxin exposure, but that the severity of these effects did not increase in a progressive fashion.
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quantitative assessment of mesangial immunoglobulin a iga accumulation elevated circulating iga immune complexes and hematuria during Vomitoxin induced iga nephropathy
Toxicological Sciences, 1991Co-Authors: Wumin Dong, John E Sell, James J PestkaAbstract:Abstract Extended dietary exposure to the trichothecene Vomitoxin (deoxynivalenol), a naturally occurring fungal contaminant of cereal grains, induces elevated serum IgA and mesangial IgA accumulation in a manner similar to the human glomerulonephritis, IgA nephropathy. A 12-week feeding study was conducted in the B6C3F1 mouse to evaluate the effects of exposure to 25 ppm dietary Vomitoxin over time on formation of IgA immune complexes (IgA-IC), hematuria, and mesangial deposition of IgA, IgG, IgM, and complement component C3. Both serum IgA and IgA-IC were significantly elevated in Vomitoxin-exposed treatment groups compared to controls at weeks 4, 8, and 12, whereas serum IgG was unaffected. The incidence of hematuria was also significant in Vomitoxin-exposed mice at weeks 4, 8, and 12. Quantitative immunofluorescence intensity measurements using interactive laser cytometer image analysis revealed significantly greater mesangial IgA accumulation in Vomitoxin-fed mice compared to controls at weeks 4, 8, and 12. Although glomerular IgG and IgM deposition was present in both controls and treated mice, it was significantly lower in treated mice as compared to controls at week 12. Mesangial C3 deposition was not induced by Vomitoxin feeding. Elevated IgA-IC, hematuria, and IgA mesangial accumulation occurring during exposure to Vomitoxin mimicked human IgA nephropathy, whereas the absence of mesangial C3 represented a major difference between this toxin-induced immune dysregulation and the human disease.
R L Warner - One of the best experts on this subject based on the ideXlab platform.
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in vitro effects of Vomitoxin deoxynivalenol on t cell interleukin production and iga secretion
Food and Chemical Toxicology, 1994Co-Authors: R L Warner, K Brooks, James J PestkaAbstract:Abstract The exposure of lymphocyte cultures to Vomitoxin was used to determine possible mechanisms by which this naturally occurring toxin induces serum immunoglobulin A (IgA) elevation and IgA nephropathy in the mouse. Vomitoxin exposure within the range of 10 to 1000 ng/ml inhibited DNA synthesis, protein synthesis as well as IgA, IgG and IgM production in lymphocyte cultures prepared from the Peyer's patch (PP) and spleen. When purified B cells were cultured in the presence of Vomitoxin, inhibition of IgA, IgG and IgM production was similarly observed. However, on 24-hr pulsed co-exposure to Vomitoxin and the mitogen concanavalin A (ConA), CD4 + /CD8 + cells were capable of inducing a three- to five-fold increase in production of IgA, but not IgG and IgM by cocultured B cells when compared with B cells cocultured with control T cells exposed to the mitogen only. When pulsed for 48 hr with ConA and toxin, CD4 + cells were similarly capable of causing a significant increase in IgA production by B cells. 48-hr pulsed exposure of CD4 + cells to ConA and Vomitoxin resulted in significantly increased production of the T helper cytokines IL-4, IL-5 and IL-6 after 5 additional days of culture, compared with ConA-stimulated CD4 + cells alone. These results suggest that Vomitoxin was capable of enhancing CD4 + -mediated help for IgA production by B cells and that this could possibly be mediated by way of increased cytokine production.
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Immunoglobulin a Nephropathy as a Manifestation of Vomitoxin (Deoxynivalenol) Immunotoxicity
Microbial Toxins in Foods and Feeds, 1990Co-Authors: James J Pestka, R L Warner, Mark A. Moorman, M.f. Witt, James H. ForsellAbstract:The trichothecenes, mycotoxins produced by members of the genus Fusarium, are of immense concern because of their frequent presence in agricultural staples such as wheat, corn, barley and oats.19,30,42 These compounds are sesquiterpenoids that are characterized by a trichothecane nucleus and that include some of the most potent inhibitors of protein synthesis known.27,45 Acute exposure to trichothecenes results in severe damage to actively dividing cells in tissues such as bone marrow, lymph nodes, spleen, thymus and intestinal mucosa. Trichothecenes have been implicated as causative agents in numerous episodes of fatal human and animal toxicoses.5,20,44.
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altered serum immunoglobulin response to model intestinal antigens during dietary exposure to Vomitoxin deoxynivalenol
Toxicology Letters, 1990Co-Authors: James J Pestka, M A Moorman, R L WarnerAbstract:The effect of dietary Vomitoxin on the serum IgA and IgG responses to two model intestinal antigens, casein and cholera toxin (CT), were assessed in 4 experimental groups: (1) mice fed casein-based diet, (2) mice fed casein-based diet containing 25 ppm Vomitoxin, (3) mice fed casein-based diet and immunized with CT, and (4) mice fed casein-based diet containing 25 ppm Vomitoxin and immunized with CT. Unimmunized and CT-immunized mice that were fed Vomitoxin exhibited increased levels of total serum IgA relative to matched control animals fed the standard diet. Relative concentrations of casein-specific IgA were greater in both unimmunized mice and CT-immunized mice fed standard diet with Vomitoxin than in matched controls fed standard diet only. CT-specific serum IgA in CT-immunized mice was not affected by Vomitoxin feeding, but relative levels of CT-specific IgA were higher in unimmunized mice fed Vomitoxin than in unimmunized mice fed standard diet. Both casein- and CT-specific serum IgG were depressed in mice fed Vomitoxin. Significant differences in total, casein-specific and CT-specific IgA within the intestinal contents were not observed between CT-immunized mice fed Vomitoxin and those fed the control diet. The results suggest that Vomitoxin altered regulation of the normal immunoglobulin response to intestinal antigens and that this was manifested in the systemic compartment.
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elevated membrane iga and cd4 t helper populations in murine peyer s patch and splenic lymphocytes during dietary administration of the trichothecene Vomitoxin deoxynivalenol
Food and Chemical Toxicology, 1990Co-Authors: James J Pestka, R L Warner, Wumin Dong, L Rasooly, G S Bondy, Kathryn H BrooksAbstract:Abstract Recent investigations indicate that dietary exposure to the trichothecene Vomitoxin increases total and antigen-specific serum immunoglobulin A (IgA) and glomerular IgA accumulation in mice. In this study, the effects of 25 ppm dietary Vomitoxin on the histological and lymphocytic profile of component immune organs in the mucosal lymphocyte migratory pathway were evaluated in the B6C3F 1 mouse. Vomitoxin administration resulted in marked stimulation of the size and frequency of germinal centres in Peyer's patches, mesenteric lymph nodes and the spleen. A slight increase in the percentage of B cells in the Peyer's patch was observed, although Vomitoxin treatment had no effect on the percentage of B cells in the spleen. The percentage of IgA + cells in Peyer's patches and spleen were approximately twice that of controls at 4, 8 and 12 wk of Vomitoxin exposure whereas the percentage of IgG + cells decreased in these two organs. Exposure to Vomitoxin increased the percentage of T cells in Peyer's patches and the spleen. The percentage of CD4 + cells (T helper subset) increased slightly in Peyer's patches and more markedly (30–50%) in the spleen following Vomitoxin treatment. Contrastingly, there was only a slight increase in the percentage of CD8 + cells (T cytotoxic/suppressor subset) in the spleens of Vomitoxin-treated mice in comparison with controls, and no effect in Peyer's patches. The relative effects of Vomitoxin on these two T cell populations was also reflected in increased CD4 + :CD8 + ratios in Peyer's patches and spleen. These results are consistent with the hypothesis that dietary Vomitoxin modulates normal regulation of the IgA response at the Peyer's patch level and that this is manifested in an altered lymphocyte distribution pattern in both the mucosal and systemic compartment. Notably increased levels of IgA + and CD4 + cells are indicative of IgA-producing progenitors and T helper subsets, respectively, that in tandem could favour IgA hyperproduction and elevated IgA in serum.
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effect of dietary administration of the trichothecene Vomitoxin deoxynivalenol on iga and igg secretion by peyer s patch and splenic lymphocytes
Food and Chemical Toxicology, 1990Co-Authors: James J Pestka, R L Warner, L Rasooly, W Dong, G S BondyAbstract:Abstract Prolonged dietary exposure of mice to the trichothecene Vomitoxin induces abnormally high levels of serum IgA and kidney mesangial IgA accumulation in a manner that is highly analogous to the human glomerulonephritis IgA nephropathy. In this study, the capacity of Peyer's patch and splenic lymphocytes to produce IgA and IgG were compared in B6C3F 1 mice that were fed diets with and without 25 ppm Vomitoxin for up to 12 wk. Serum IgA increased 2-,4- and 8-fold after 4, 8 and 12 wk, respectively, of Vomitoxin exposure and it became the primary serum isotype, whereas serum IgG was unaffected. On termination of the experiment there were increased numbers of IgA-secreting cells in Peyer's patches after 8 wk of toxin exposure and in the spleen after 4, 8 and 12 wk of toxin exposure. There were also increased numbers of IgG-secreting cells in Peyer's patches on termination of the experiment at 4, 8 and 12 wk but no effect was observed in the spleen. Supernatant IgA and IgA-secreting cell numbers were also markedly elevated in lymphocyte cultures obtained from Peyer's patches and, to a lesser extent, from spleens of treated mice compared with controls. Based on output of treated mice relative to corresponding controls, IgA secretion was greatest in concanavalin-A-stimulated and unstimulated Peyer's patch cultures. Enhanced IgG secretion and IgG-secreting cells were also observed in mitogen-stimulated and unstimulated Peyer's patch lymphocyte cultures of treated relative to control mice, but differences in splenocyte cultures were negligible. Based on total Ig output, IgA production was 8- to 20-fold greater than IgG production in both control and treatment Peyer's patch cultures. In contrast, Vomitoxin treatment caused a shift from primarily IgG production in lipopolysaccharide-stimulated spleen cultures to equivalent IgA production. These data provide in vitro evidence that ingestion of Vomitoxin promotes terminal differentiation of IgA-secreting progenitors in the Peyer's patch and, to a lesser extent, in the spleen. These functional changes are consistent with the shift from IgG to IgA as the primary serum isotype.
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down regulation of the endoplasmic reticulum chaperone grp78 bip by Vomitoxin deoxynivalenol
Toxicology and Applied Pharmacology, 2000Co-Authors: Gi Hyeok Yang, Shiguang Li, James J PestkaAbstract:Abstract The mechanisms by which trichothecene mycotoxins cause immunological effects in leukocytes such as cytokine up-regulation, aberrant IgA production, or apoptotic cell death are not fully understood. In the present study, mRNA differential display analysis was used to evaluate changes in gene expression induced by the trichothecene Vomitoxin (VT or deoxynivalenol) in a T-cell model, the murine EL-4 thymoma, that was stimulated with phorbol 12–myristate 13–acetate (PMA) and ionomycin (ION). Ten differentially expressed fragments of cDNA were isolated and sequenced and three of these were identified as the known genes GRP78/BiP, P58 IPK , and RAD17. Most notably, expression of GRP78/BiP (a 78-kDa glucose-regulated protein), a stress-response gene induced by agents or conditions that adversely affect endoplasmic reticulum (ER) function, was found to decrease in VT-exposed cells. Competitive RT-PCR analysis revealed that 250 ng/ml VT decreased GRP78/BiP mRNA expression in both unstimulated and PMA/ION-stimulated EL-4 cells at 6 and 24 h after VT treatment. Western blotting confirmed that VT (50 to 1000 ng/ml) also significantly diminished GRP/BiP protein levels in a dose-response manner in PMA/ION-stimulated cells. GRP78/BiP has been shown to play a role in regulation of protein folding and secretion, and to protect cells from apoptosis. When PMA/ION-stimulated cells were incubated with 50 to 1000 ng/ml VT for 24 h, 200-bp DNA laddering, a hallmark of apoptosis, increased in a dose-dependent manner. In addition to GRP78, mRNA expression of the cochaperone P58 IPK , which is the 58-kDa cellular inhibitor of the double-stranded RNA-regulated protein kinase (PKR), was also shown to be suppressed by VT-treatment. GRP78 and P58 IPK are critical for maintenance of cell homeostasis and prevention of apoptosis. The down-regulation of these molecular chaperones by VT represent a novel observation and has the potential to impact immune function at multiple levels.
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Down-regulation of the endoplasmic reticulum chaperone GRP78/BiP by Vomitoxin (deoxynivalenol).
Toxicology and Applied Pharmacology, 2000Co-Authors: Gi Hyeok Yang, Shiguang Li, James J PestkaAbstract:Abstract The mechanisms by which trichothecene mycotoxins cause immunological effects in leukocytes such as cytokine up-regulation, aberrant IgA production, or apoptotic cell death are not fully understood. In the present study, mRNA differential display analysis was used to evaluate changes in gene expression induced by the trichothecene Vomitoxin (VT or deoxynivalenol) in a T-cell model, the murine EL-4 thymoma, that was stimulated with phorbol 12–myristate 13–acetate (PMA) and ionomycin (ION). Ten differentially expressed fragments of cDNA were isolated and sequenced and three of these were identified as the known genes GRP78/BiP, P58 IPK , and RAD17. Most notably, expression of GRP78/BiP (a 78-kDa glucose-regulated protein), a stress-response gene induced by agents or conditions that adversely affect endoplasmic reticulum (ER) function, was found to decrease in VT-exposed cells. Competitive RT-PCR analysis revealed that 250 ng/ml VT decreased GRP78/BiP mRNA expression in both unstimulated and PMA/ION-stimulated EL-4 cells at 6 and 24 h after VT treatment. Western blotting confirmed that VT (50 to 1000 ng/ml) also significantly diminished GRP/BiP protein levels in a dose-response manner in PMA/ION-stimulated cells. GRP78/BiP has been shown to play a role in regulation of protein folding and secretion, and to protect cells from apoptosis. When PMA/ION-stimulated cells were incubated with 50 to 1000 ng/ml VT for 24 h, 200-bp DNA laddering, a hallmark of apoptosis, increased in a dose-dependent manner. In addition to GRP78, mRNA expression of the cochaperone P58 IPK , which is the 58-kDa cellular inhibitor of the double-stranded RNA-regulated protein kinase (PKR), was also shown to be suppressed by VT-treatment. GRP78 and P58 IPK are critical for maintenance of cell homeostasis and prevention of apoptosis. The down-regulation of these molecular chaperones by VT represent a novel observation and has the potential to impact immune function at multiple levels.
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superinduction of il 2 gene expression by Vomitoxin deoxynivalenol involves increased mrna stability
Toxicology and Applied Pharmacology, 1997Co-Authors: Shiguang Li, Wumin Dong, Yan L Ouyang, James J PestkaAbstract:Abstract To better understand molecular mechanisms by which the trichothecene Vomitoxin (VT) superinduces cytokine gene expression, we studied the posttranscriptional effects of this mycotoxin on interleukin-2 (IL-2) gene expression in murine EL-4 thymoma cells stimulated with phorbol 12-myristate 13-acetate and ionomycin (PMA + ION). Northern analysis revealed that doses of 50 to 500 ng/ml VT superinduced IL-2 mRNA expression in a dose- and time-dependent manner in a synchronous model where VT was added at onset of PMA + ION stimulation. In accordance with the mRNA levels, IL-2 production was significantly elevated in the presence of 50 to 250 ng/ml VT. Superinduction of IL-2 mRNA was also observed in a delayed synchronous model (VT added 20 hr after PMA + ION stimulation) and an asynchronous model (VT added 20 hr after PMA + ION stimulation and removal). To assess the effects of VT (500 ng/ml) on IL-2 mRNA half-life, three transcriptional inhibitors were used in the delayed synchronous model. Actinomycin D (ActD) had a pronounced stabilizing effect on IL-2 mRNA but not on mRNA for the housekeeping gene GAPDH. VT did not affect IL-2 mRNA levels in ActD-treated cells. Although 5,6-dichloro-β- d -ribofuranosyl-benzimidazole (DRB) also had a stabilizing effect on IL-2 mRNA, IL-2 mRNA half-life t 1/2 in VT-treated cells was three times that of control. In contrast, inclusion of cyclosporin A (CsA) into the cultures specifically arrested IL-2 transcription in EL-4 cells without any stabilizing effect. VT exposure in the presence of CsA markedly prolonged the half-life of IL-2 mRNA in a dose-dependent manner. The t 1/2 for IL-2 mRNA in the control culture was 2.1 hr, whereas t 1/2 was 3.1, 3.4, 4.2, and 10.5 hr in cultures containing 50, 100, 250, and 500 ng/ml VT, respectively. These results suggest that VT can superinduce IL-2 at both the mRNA and the protein level and that this superinduction can be explained, in part, by posttranscriptional mechanisms such as enhanced mRNA stability.
