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)

Cells that produce interleukin-6 (IL-6) require the presence of signaling molecules since this cytokine is not normally constitutively expressed. It is now established that astrocytes produce IL-6; however, the precise inducing molecules and the kinetics of their action have not yet been clearly identified. In the current study, we show that either interleukin-1 beta (IL-1 beta) or tumor necrosis factor-alpha (TNF-alpha) exert a strong inducing signal for IL-6 in primary rat astrocytes. When the two cytokines are added together the response is synergistic, suggesting that each cytokine may induce IL-6 gene expression by different pathways. Interferon-gamma (IFN-gamma) does not affect IL-6 expression although if it is added in conjunction with IL-1 beta, an augmented induction of IL-6 occurs. In addition to the cytokines, bacterial lipopolysaccharide (LPS) and the calcium ionophore, A23187, induce IL-6 expression. IL-6 expression can be blocked by the glucocorticoid analogue, dexamethasone. IL-6 induction by LPS/Ca2+ ionophore is more sensitive to the suppressive effects of dexamethasone than is IL-6 induction by TNF-alpha/IL-1 beta. Cycloheximide (CHX), an inhibitor of protein synthesis, markedly increased levels of IL-6 mRNA in both unstimulated and stimulated astrocytes, indicating that ongoing protein synthesis is not required for astrocyte IL-6 gene expression. We propose that astrocyte-produced IL-6 may have a role in augmenting intracerebral immune responses in neurological diseases such as multiple sclerosis (MS), AIDS dementia complex (ADC), and viral infections. These diseases are characterized by infiltration of lymphoid and mononuclear cells into the central nervous system (CNS), and intrathecal production of immunoglobulins. IL-6 may act to promote terminal differentiation of B cells in the CNS, leading to immunoglobulin synthesis.
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PMID:Induction and regulation of interleukin-6 gene expression in rat astrocytes. 212

The hypothesis that 7,12-dimethyl-benz[a]anthracene (DMBA) suppresses immune function in mice via an inhibition of lymphocyte activation was examined in these studies. Daily exposure of B6C3F1 mice to DMBA (cumulative doses of 1.4 to 140 mg/kg) via the oral route for 14 days was found to inhibit phytohemagglutinin (PHA) and lipopolysaccharide mitogen responses in lymphoid cells obtained from the spleen. Peyer's Patches, and mesenteric lymph nodes. The 14 mg/kg cumulative dose of DMBA produced no significant decrease in the number of recovered viable cells, yet mitogen responses were suppressed by approximately 50% in the spleen and mesenteric lymph nodes, and by greater than 70% in the Peyer's Patches. DMBA inhibited PHA-induced Ca+2 mobilization measured by flow cytometry in each of these three lymphoid tissues. There was no change in the percentage of T cells recovered from the spleen, mesenteric lymph nodes, or Peyer's Patches. Peyer's Patch lymphocytes obtained from the GI tract appeared to be slightly more sensitive to inhibition of mitogen responsiveness and perhaps Ca+2 mobilization, potentially due to the oral route of exposure to DMBA. These studies provide evidence that DMBA inhibits early events associated with lymphocyte activation in mice.
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PMID:Inhibition of lymphocyte activation in splenic and gut-associated lymphoid tissues following oral exposure of mice to 7,12-dimethylbenz[a]anthracene. 212 50

We have produced hematopoietic chimeric mice from an embryonic stem (ES) cell line carring Ly-1 cDNA under the control of IgH promoter and enhancer. Various amounts of serum IgM (5-86% of total IgM) in chimeric mice were of ES origin and 30-60% of IgM-positive B cells from the chimeric mice analyzed were reconstituted from ES cells. Using these chimeric mice, the expression of the Ly-1 transgene on lymphoid tissues was examined by polymerase chain reaction assay with primers specific for the transgene, and by cell sorter analysis. Transcription of the Ly-1 transgene was detected in spleen cells, thymocytes and lymph node cells; however, the expression of the Ly-1 molecule was observed only on lipopolysaccharide (LPS)-stimulated splenic IgM-positive B cells but not on resting splenic B cells. There was no significantly increased expression of Ly-1 on splenic T cells and thymocytes. Thus, our findings demonstrate that conventional splenic B cells could express the Ly-1 transgene on their surface in vivo after LPS stimulation. Also discussed is the ES-derived chimeric hematopoietic system.
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PMID:Expression of IgH promoter/enhancer Ly-1 transgene in hematopoietic chimeric mice generated by embryonic stem cell line. 212 65

In double-transgenic mice expressing a gene construct encoding hen egg lysozyme as well as rearranged anti-lysozyme antibody genes, large numbers of anti-lysozyme B cells are present in peripheral lymphoid tissues but are profoundly tolerant. The cellular basis for this form of non-deletional self-tolerance was explored. The tolerant anti-lysozyme B cells from double-transgenic mice were found to produce much less antibody than nontransgenic controls in T-cell-dependent antigen-specific responses, in adoptive transfer in vivo, and in hanging-drop cultures in vitro, as well as in response to stimulation with the nonspecific mitogen lipopolysaccharide. The diminished responsiveness of the tolerant B cells was not due to a reduction in the number of responding B-cell precursors per se nor were suppressor cells detected in titration, depletion, or mixing experiments. Nondeletional tolerance in this model, therefore, appears to result from an intrinsic functional change in the self-reactive B cells themselves.
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PMID:Intrinsic B-cell hyporesponsiveness accounts for self-tolerance in lysozyme/anti-lysozyme double-transgenic mice. 214 20

We have isolated cDNA clones complementary to a truncated immunoglobulin heavy-chain C epsilon RNA transcript previously found to be induced in B lymphoid cells by treatment with lipopolysaccharide (LPS) combined with interleukin-4 (IL-4). We demonstrate that this transcript initiates from a promoter upstream of the germ line epsilon class-switch recombination region (S epsilon region). The major germ line C epsilon transcript contains a small 5' exon contributed by sequences upstream of the S epsilon region spliced to the normal C epsilon exons. Treatment of splenic B lymphoid cells with LPS plus IL-4 induces the expression of transcripts from the germ line epsilon transcription unit followed by expression of normal immunoglobulin epsilon heavy-chain mRNA. Furthermore, we demonstrate that similar treatment of transformed precursor B cell lines induces the expression of germ line epsilon transcripts followed by class switching to epsilon expression in these lines. This is the first demonstration of switching to epsilon in cells of the pre-B stage. The general structure of the germ line epsilon transcript and transcription unit is similar to that previously characterized for germ line gamma 2b transcripts. However, expression of these two germ line transcription units in B-lineage cells is inversely regulated by IL-4 (plus LPS) treatment, correlating with the effects of these treatments on switching to these loci.
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PMID:Structure and expression of germ line immunoglobulin heavy-chain epsilon transcripts: interleukin-4 plus lipopolysaccharide-directed switching to C epsilon. 215 39

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

We characterized the basis for the follicular lymphoproliferation in transgenic mice bearing a Bcl-2-immunoglobulin (Bcl-2-Ig) minigene representing the t(14;18) of human follicular lymphoma. Discriminatory S1 nuclease protection assays revealed that the Bcl-2-Ig transgene was overexpressed relative to endogenous mouse Bcl-2 in spleen and thymus. Western (immunoblot) analysis demonstrated the overproduction of the human 25-kilodalton Bcl-2 protein, which arose from the transgene, in spleen, thymus, and the expanded B-cell subset. Despite the generalized lymphoid pattern of deregulation, two-color flow cytometry and density gradient centrifugation indicated that the expanded lymphocytes were predominantly small, resting B cells coexpressing B220, immunoglobulin M (IgM), IgD, Ia, and kappa. Cell cycle analysis confirmed that about 97% of these expanded B cells reside in G0/G1. An extensive characterization of transgenic lines revealed a fourfold excess of IgM-IgD-expressing B cells in spleen and dramatically increased numbers in bone marrow. While resting, these cells proliferated in response to lipopolysaccharide and anti-IgM and demonstrated normal B-cell colony formation in soft agar. Moreover, these B cells, which demonstrated an extended survival in vitro even in the absence of stroma, were also resting in G0, yet were capable of proliferative responses. These findings provide consistent evidence that the accumulation of B cells after Bcl-2 overproduction is secondary to prolonged cell survival and not increased cell cycling. This suggests a unique role for Bcl-2 as a proto-oncogene that enhances cell survival independent of promoting cell division.
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PMID:Deregulated Bcl-2-immunoglobulin transgene expands a resting but responsive immunoglobulin M and D-expressing B-cell population. 218 11

Studies with FLV infected mice, a model for retrovirus induced acquired immunodeficiency, showed that intact lipopolysaccharide rich extract from Serratia marcescens as well as the nontoxic polysaccharide derivative free of lipid A were equally adjuvantic in enhancing antibody formation to sheep erythrocytes, both in vivo and in vitro. The PS-rich endotoxin derivative had little or no toxic activity in leukemic animals as occurred with intact endotoxin. The adjuvanticity of both the nontoxic polysaccharide derivative as well as the intact endotoxin in enhancing antibody formation in FLV infected mice was evident also in vitro when spleen cells from infected animals were immunized with sheep erythrocytes simultaneously with the polysaccharide in comparison with the LPS. Supernatants from normal spleen cells treated in vitro either with the polysaccharide or the intact endotoxin showed immunoenhancing helper activity for both normal and FLV infected spleen cells and this enhancing activity was due to IL-1 induced by either bacterial product. Thus the immunoenhancing soluble mediator, i.e., IL-1, is induced equally by PS or LPS and has immunorestorative activity for FLV infected animals. The potential value of the nontoxic PS as an immunoadjuvant in retrovirus immunosuppressed lymphoid cells is evident. The results of these studies suggest that further investigations concerning the nature and mechanism involved in such adjuvancticity is warranted.
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PMID:Immunoadjuvanticity of endotoxins and nontoxic derivatives for normal and leukemic immunocytes. 218 63

A hypothesis has been proposed by this laboratory that endogenous gut-derived lipopolysaccharide is responsible for systemic endotoxemia in animals with acute liver injury particularly after partial (67%) hepatectomy. Systemic lipopolysaccharide and possibly fibrin aggregates or tissue debris then elicit release of cytokines from phagocytizing macrophages and/or monocytes that may be essential for normal liver regeneration. To test this hypothesis liver regeneration was assessed in germ-free euthymic mice that lack the gram-negative bacterial source of lipopolysaccharide, as well as being deficient in lymphoid tissue and relatively resistant to endotoxin. To complement the germ-free animals, conventional athymic nude BALB/c mice and conventional lipopolysaccharide-resistant C3H/HeJ mice were also examined. Liver regeneration, quantified by [3H] thymidine incorporation into hepatic DNA after partial hepatectomy was performed on mice anesthetized with ether, was significantly depressed in germ-free euthymic and conventional athymic BALB/c mice and delayed in conventional lipopolysaccharide-resistant C3H/HeJ mice, as compared with conventional control BALB/c and C3H/HeN animals. Pretreatment of conventional euthymic control mice with lipopolysaccharide 24 hr before surgery significantly stimulated hepatic DNA synthesis after 67% liver resection. Germ-free euthymic, conventional athymic, and conventional lipopolysaccharide-resistant mice pretreated with endotoxin did not manifest significant stimulation of liver regeneration. Evidence is reviewed that cytokine release in response to endotoxin was depressed in germ-free euthymic, conventional athymic, and conventional lipopolysaccharide-resistant mice as compared with conventional euthymic controls.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Depressed liver regeneration after partial hepatectomy of germ-free, athymic and lipopolysaccharide-resistant mice. 219 22

Here we report a survey of c-rel proto-oncogene transcription in murine tissues, cell lines and lymphoid cells. In addition to the previously described 7.5-kb mRNA, we have identified a mRNA of 2.5-kb. As DNA hybridization indicates that there is only one gene with significant homology to c-rel in the mouse genome, it appears that multiple mRNAs are transcribed from c-rel. The nucleotide sequence of a cDNA clone derived from the 2.5-kb c-rel mRNA demonstrates that the 7.5- and 2.5-kb mRNAs encode identical proteins. The different size of the two mRNAs is due to variation in the length of the 3' untranslated region, which arises from the use of alternate polyadenylation signals. These mRNAs are present at low levels in organs tested, and in cell lines representing a wide variety of lineages. Fibroblasts are the only cells in which expression was not detectable. In B-cell lines representing different stages of differentiation, the highest levels of mRNA are seen in B-lymphomas, and this level drops markedly in plasmacytomas. There is a transient increase of 10- to 20-fold in the level of c-rel mRNAs in T-cells treated with concanavalin A, while lipopolysaccharide-stimulated B-cells exhibit a transient 5-fold elevation of c-rel expression. This study indicates that the control of c-rel expression can vary between and within different cell lineages, and the widespread expression of this gene points to a fundamental cellular function, rather than one restricted to hematopoietic cells as previously suggested.
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PMID:The murine c-rel proto-oncogene encodes two mRNAs the expression of which is modulated by lymphoid stimuli. 220 17


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