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

The immunotoxicity of chemical combinations commonly encountered by the lake trout (Salvelinus namaycush) immune system was the focus of this study. It was hypothesised that combinations of an environmental contaminant (mercuric chloride or Aroclor 1254) and an immunomodulatory agent (bacterial endotoxin or cortisol) might interact to produce a greater toxicity than that of the environmental contaminant alone at concentrations typically encountered in piscine blood and other tissues. Thus lake trout thymocytes were isolated and treated with mercuric chloride or Aroclor 1254 in the presence and absence of cortisol or lipopolysaccharide. Incubations were performed for 6 or 20 h at 4 degrees C or 10 degrees C. Lipopolysaccharide did not affect the toxicity of either contaminant. In contrast, cortisol enhanced the toxicity of both environmental contaminants. Hence, stressors that lead to increased cortisol production, but not lipopolysaccharide directly, may increase the toxicity of mercury and Aroclor 1254 to lake trout thymocytes.
 ...
PMID:In vitro toxicity and interactions of environmental contaminants (Arochlor 1254 and mercury) and immunomodulatory agents (lipopolysaccharide and cortisol) on thymocytes from lake trout (Salvelinus namaycush). 1220 50

Immunotoxicology is a relatively new field in toxicology, and is one of emerging importance, because immunotoxicity appears to contribute to the development of cancer, autoimmune disorders, allergies and other diseases. At present, there is a lack of human cell-based immunotoxicity assays for predicting the toxicity of xenobiotics toward the immune system in a simple, fast, economical and reliable way. Existing immunotoxicity tests are mainly performed in animals, although species differences favour human-based testing. Whole-blood cytokine release models have attracted increasing interest, and are broadly used for pharmacological in vitro and ex vivo studies, as well as for pyrogenicity testing. We have adapted those methods for immunotoxicity testing, to permit the potency testing of immunostimulants and immunosuppressants. Following stimulation with a lipopolysaccharide or staphylococcal enterotoxin B, monocytes and lymphocytes release interleukin-1beta and interleukin-4, respectively. Thirty-one pharmaceutical compounds, with known effects on the immune system, were used to optimise and standardise the method, by analysing their effects on cytokine release. The in vitro results were expressed as IC50 values for immunosuppression, and SC(4) (fourfold increase) values for immunostimulation, and compared with therapeutic serum concentrations of the compounds in patients, and in vivo LD50 values from animal studies. The in vitro results correlated well with the in vivo data, so the test appears to reflect immunomodulation. Results were reproducible (CV = 20 +/- 5%), and the method could be transferred to another laboratory (r(2) = 0.99). We therefore propose this method for further validation and for use in immunotoxicity testing strategies.
 ...
PMID:Evaluation and prevalidation of an immunotoxicity test based on human whole-blood cytokine release. 1251 84

Tricyclic antidepressants (TCAs) of which imipramine is one, are commonly used in the treatment of depressive disorders and other forms of psychiatric illness. There have been many reports regarding the suppressive effects of TCAs on immune function. However, information is still limited regarding the effects of TCAs on the immune system, as many of the studies conducted to date have concentrated on in vitro exposure to such drugs, or ex vivo measures of immunity following drug administration. Thus in the present investigation, an in vivo challenge with bacterial lipopolysaccharide (LPS) (100 microg/kg; i.p.) was used to assess immunocompetence following administration of a single high dose of the TCA, imipramine (100 mg/kg, p.o.). The results demonstrated that imipramine pretreatment inhibits LPS-induced increases in serum concentrations of the proinflammatory cytokine, tumor necrosis factor (TNF)-alpha both 3 and 6 h, following administration. However, LPS-induced interleukin (IL)-1beta secretion was not significantly altered following imipramine treatment at either of the timepoints examined. In addition, serum concentrations of corticosterone and the antiinflammatory cytokine IL-10 were measured, and imipramine treatment failed to alter either basal, or LPS-induced increases in these immunosuppressive agents. In conclusion, although IL-1beta and TNF-alpha are both macrophage-derived proinflammatory cytokines, the present study demonstrates a differential sensitivity of these cytokines to the suppressive effects of the TCA imipramine. Furthermore, the suppressive effects of imipramine on LPS-induced TNF-alpha secretion could not be attributed to either increased glucocorticoid levels, or increased secretion of the antiinflammatory cytokine IL-10. The relevance of these findings to antidepressant-induced immunotoxicity are discussed.
 ...
PMID:Differential effect of a single high dose of the tricyclic antidepressant imipramine on interleukin-1beta and tumor necrosis factor-alpha secretion following an in vivo lipopolysaccharide challenge in rats. 1260 61

Interleukin-6 (IL-6) is a central mediator of immunotoxicity that is associated with exposure to the trichothecene vomitoxin (VT). The purpose of this investigation was to test the hypothesis that the inducible cyclooxygenase-2 (COX-2) and its metabolites contribute to VT-induced IL-6 upregulation. VT at 100 to 250 ng/ml readily induced COX-2 protein expression in the RAW 264.7 murine macrophage cell line. Superinduction of lipopolysaccharide (LPS)-mediated IL-6 production by VT in these cells was significantly reduced by the COX inhibitors indomethacin and NS-398, whereas the inhibitors did not affect direct induction of IL-6 by LPS alone. Mice that had been gavaged orally with 5 and 25 mg/kg VT exhibited elevated COX-2 mRNA expression in Peyer's patches and spleen with peak induction occurring 2 h after VT exposure. IL-6 mRNA was also induced by VT in vivo, however, peak expression occurred from 2 to 4 h after toxin exposure, suggesting that maximal COX-2 gene upregulation preceded or was concurrent with that for IL-6. Also consistent with a putative contributory role for COX-2 was the finding that both induction of splenic IL-6 mRNA and serum IL-6 by VT were significantly reduced by pretreating mice with the COX inhibitors indomethacin or NS-398. Finally, COX-2 knockout mice showed significantly reduced splenic IL-6 mRNA and serum IL-6 responses to oral VT exposure compared to their parental wild type. Taken together, these in vitro and in vivo data suggest that VT-induced COX-2 gene expression and resultant COX-2 metabolites contributed, in part, to subsequent upregulation of IL-6 gene expression, which has been previously shown to be a hallmark of VT-mediated immunotoxicity.
 ...
PMID:Cyclooxygenase-2 mediates interleukin-6 upregulation by vomitoxin (deoxynivalenol) in vitro and in vivo. 1264 40

Microcystis aeruginosa is a common cyanobacterium in water blooms that appear world widely in eutrophic freshwaters, and its toxic blooms have caused many death and illness cases. This paper presents the first data on the immunotoxicity of a microcystin (MC) extract of cyanobacteria bloom collected from Taihu Lake, China to BALB/c mice. The cyanobacteria bloom extract (CBE) containing MCs was administered by i.p. injection for 14 days at three sublethal doses of 16, 32, 64 mg lyophilized algae cells/kg body weight. Exposure to CBE decreased body weights dose-dependently. Meanwhile, liver body weight ratios were markedly increased. The significant differences were also observed in spleen and thymus body ratios upon the elevation of treatment dose comparing to control. CBE was also found to reduce the phagocytosis evaluated using phagocytic index of peritoneal phagocyte; this suppression was not evident in percentage phagocytosis. Treatment of CBE produced the inhibition of lipopolysaccharide-induced lymphoproliferation and the dose-dependent decrease of the numbers of antibody-forming cells in mice that were immunized by using T-dependent antigen sheep red blood cells. However, CBE did not affect concanavalin A-induced T cell proliferation. Our results demonstrate that exposure to CBE resulted in immunosuppression in mice.
 ...
PMID:Effects of cyanobacteria bloom extract on some parameters of immune function in mice. 1269 77

Polychlorinated biphenyls (PCBs) are persistent environmental contaminants, and their ubiquitous nature has prompted studies of their potential health hazards. As a result of their lipophilic nature, PCBs accumulate in breast milk and subsequently affect the health of offspring of exposed individuals. Biological effects of PCBs in animals have mostly been attributed to coplanar congeners, although effects of ortho congeners also have been demonstrated. To investigate the relationship of immunotoxicity and chlorine substitution pattern, the effects of PCB congeners and mixtures of ortho and non-ortho-substituted constituents of Aroclor 1242 on splenocytes from C57B1/6 mice were examined. The immunotoxic endpoints investigated included splenocyte viability, lipopolysaccharide (LPS)-induced splenocyte proliferation, and LPS-induced antibody secretion. Congeners with multiple ortho chlorines preferentially inhibited splenocyte proliferation as compared with non- or mono-ortho-substituted congeners. However, mixtures of non- and mono-ortho-substituted congeners and multi-ortho-substituted congeners inhibited LPS-induced splenocyte proliferation and antibody secretion at similar concentrations. Exposure of splenocytes to these mixtures did not activate the aryl hydrocarbon receptor (AhR) signal transduction pathway. These results suggest individual multi-ortho-substituted congeners preferentially inhibit LPS-induced splenocyte proliferation, while congeners not exhibiting an effect individually may have additive effects in a mixture to produce an immunotoxic response through an AhR-independent pathway.
 ...
PMID:Inhibition of LPS-induced splenocyte proliferation by ortho-substituted polychlorinated biphenyl congeners. 1276 1

The aim of the present study was to investigate dose- and time-dependent effects of NiCl2 on T-lymphocyte and macrophage-derived cytokine production in rats. Moreover we have determined the concentrations of nickel in the plasma that are required to elicit alterations in T-lymphocyte and macrophage function. NiCl2 suppressed T-lymphocyte proliferation and Th1 (IFN-gamma) and Th2 (IL-10) cytokine production in a dose- and time-dependent fashion. In addition, NiCl2 inhibited production of the pro-inflammatory cytokine TNF-alpha and increased production of the anti-inflammatory cytokine IL-10 from lipopolysaccharide (LPS) stimulated cultures. We have determined that the minimal plasma concentrations of nickel required to provoke immunosuppression are in the range 209-585 ng/mL. In the time-course study NiCl2 (3.3 mg/kg) provoked immunological changes that were maximal 1 h following administration, and some of these changes persisted for up to 24 h post administration. Overall these data clearly demonstrate that NiCl2 suppresses T-cell function and promotes an immunosuppressive macrophage phenotype in rats. This study also indicates that measuring T-cell proliferation is as sensitive a marker of NiCl2-induced immunotoxicity as measuring T-cell or macrophage cytokine production. Co-measurement of circulating nickel concentrations and immune parameters yields valuable information with regard to the potency of nickel to alter immune function in vivo. These data also suggest that quite a large quantity of nickel needs to reach the systemic circulation before any adverse effects on immune function are observed.
 ...
PMID:A toxicokinetic study of nickel-induced immunosuppression in rats. 1468 5

Immunological effects of polychlorinated biphenyls (PCBs) have been demonstrated in our laboratories with the peferential inhibition of lipopolysaccharide (LPS)-induced splenocyte proliferation by ortho-substituted PCB congeners. An investigation of the mechanism behind this immunotoxicity revealed an interruption in the progression of murine lymphocytes from G0/G1 into S phase by Aroclor 1242 and the di-ortho-substituted congener, 2,2'-chlorobiphenyl (CB), whereas, a non-ortho-substituted congener, 4,4'-CB, did not affect cell cycle progression. This interruption of cell cycle progression by 2,2'-CB and Aroclor 1242 was associated with a decreased expression of the cell cycle regulatory protein, cyclin D2, while expression was not affected by exposure to the non-ortho-substituted 4,4'-CB. These results suggest the preferential inhibition of LPS-induced splenocyte proliferation by ortho-substituted congeners is a result of a decreased expression of cyclin D2, which leads to an interruption in cell cycle progression. In addition, PCB mixtures with an increased percentage of chlorines in the ortho position following an environmentally occurring degradation process inhibited LPS-induced proliferation, interrupted cell cycle progression, and decreased cyclin D2 expression. This study provides evidence for a mechanism of action of the immunological effects of ortho-substituted individual congeners as well as environmentally relevant mixtures enriched in congeners with this substitution pattern.
 ...
PMID:The inhibition of LPS-induced splenocyte proliferation by ortho-substituted and microbially dechlorinated polychlorinated biphenyls is associated with a decreased expression of cyclin D2. 1536 49

The presence of cyanobacterial toxins in drinking and recreational waters represent a potential health hazard to the public. Microcystin-LR (MC-LR) is the most commonly encountered toxin and is a potent cyclic heptapeptide hepatotoxin produced by cyanobacteria. In this study, the immunomodulation by MC-LR of BALB/c mice peritoneal macrophages was investigated in vitro on mRNA levels of induced nitric oxide synthase and multiple cytokines by reverse-transcription polymerase chain reaction (RT-PCR). Lavaged peritoneal macrophages were incubated for 6 h with lipopolysaccharide (LPS) at a concentration of 100 microg/L and MC-LR at doses of 1, 10, 100, and 1000 nmol/L. Total RNA was extracted from the incubated macrophages, and then the levels of mRNA for induced nitric oxide synthase (iNOS), IL-1beta, TNF-alpha, GM-CSF, and IFN-gamma were detected. The results showed that expression of mRNA for iNOS, IL-1beta, TNF-alpha, GM-CSF, and IFN-gamma decreased significantly compared to the positive control (LPS only). These results have led us to propose the need for the establishment of a survey of the immunotoxicity of microcystins.
 ...
PMID:Effects of microcystin-LR on patterns of iNOS and cytokine mRNA expression in macrophages in vitro. 1571 26

Beta-chlorolactic acid is a major intermediate of 3-monochloro-1,2-propanediol (MCPD) in mammalian species, which a well-known by-product of acid-hydrolyzed soy sauce during its manufacturing process. beta-Chlorolactic acid has not been studied on immunotoxicity. To evaluate the immunomodulatory effect of beta-chlorolactic acid on murine splenocyte and macrophage in vitro, we investigated splenocyte blastogenesis by concanavalin A (Con A), anti-CD3 and lipopolysaccharide (LPS), the production of cytokines from splenocyte, and the activity of mouse peritoneal macrophages. beta-Chlorolactic acid suppressed significantly splenic blastogenesis to Con A or anti-CD3 from 8.5 to 54.7% at doses comprised between 200 and 800 microM. beta-Chlorolactic acid also suppressed significantly splenic blastogeneis to LPS from 8.5 to 71.5% at doses comprised between 200 and 800 microM. The production level of interferon (IFN)-g on splenocyte culture with Con A was significantly reduced from 21.5 to 51.4% at the higher concentration than 100 microM of beta-chlorolactic acid. The levels of interleukin (IL)-2 and IL-4 were also decreased 22.6-58.4 and 10.2-36.6%, respectively, at high concentrations of beta-chlorolactic acid. There was a significant decrease from 6.1 to 40.8% in the production of nitric oxide (NO) by peritoneal macrophages treated with 400-1000 microuM beta-chlorolactic acid. These results indicate that beta-chlorolactic acid might be able to induce immunotoxic effect on immune response of lymphocytes and peritoneal macrophages in vitro.
 ...
PMID:Immunotoxic effect of beta-chlorolactic acid on murine splenocyte and peritoneal macrophage function in vitro. 1584 Apr 31


<< Previous 1 2 3 4 5 6 7 8 Next >>