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)

Interleukin 12 (IL-12) has a key role during the initial phase of the immune response, favouring development of T helper class 1 (Th1) cells. IL-12 is composed of two subunits, p35 and p40, which are both needed for bioactivity. The level of p35 expression determines the level of bioactive IL-12 (p70), while the p40 subunit is produced in excess. In the present study we examined the sensitivity of bioactive IL-12 production by human monocytes to a corticosteroid, budesonide. We also compared the corticosteroid sensitivity of IL-12 and two other cytokines, interleukin 1beta and granulocyte-macrophage colony-stimulating factor (GM-CSF). Monocytes obtained from peripheral blood of healthy donors (n=12) were stimulated with lipopolysaccharide (LPS; 10 microg/ml; 20 h) in the presence or absence of budesonide (10(-11)-10(-7) M). The supernatants were assayed for IL-12 (p70), IL-1beta and GM-CSF concentrations using specific immunoassays. Budesonide potently inhibited the production of bioactive IL-12. A significant suppression was obtained by treatment with even very low budesonide concentrations; even 10(-11) M budesonide significantly inhibited IL-12 to 81.6+/-7.6% of the control level (P<0.05). The maximal inhibitory effect of budesonide was seen at 10(-8) M. The inhibition of IL-12 production was significantly higher than the inhibition of GM-CSF (P<0.01) or IL-1beta (P<0.001). Whereas IL-12 production was totally inhibited, GM-CSF production was inhibited to 16.4+/-3.7 and IL-1beta production to 43.1+/-7.3% of control, respectively. The dramatic capacity of corticosteroids to modulate production of IL-12 as well as other cytokines may be a major mechanism underlying the effectiveness of these drugs in a broad spectrum of inflammatory diseases.
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PMID:Effects of a corticosteroid, budesonide, on production of bioactive IL-12 by human monocytes. 981 32

Prostaglandin E series (PGEs) are known to protect against lipopolysaccharide (LPS)-induced liver injury by down-regulating the production of inflammatory cytokines. We show here a novel mechanism whereby prostaglandin E(1) protects mice against liver injury after Escherichia coli infection. Prostaglandin E(1) administration suppressed circulating interleukin 12 (IL-12) levels but increased the IL-10 production after E. coli challenge. Furthermore, prostaglandin E(1)-alpha-cyclodextrin (PGE(1)) shifted the Th1/Th2 balance of CD3(intermediate) IL-2Rbeta(+) T cells in the liver to a dominant Th2-like response. Neutralization of endogenous IL-4 by administration of anti-IL-4 monoclonal antibody (mAb) diminished the inhibitory effect of prostaglandin E(1) on liver injury after E. coli challenge. These results suggested that the Th2-like response of liver T cells may be at least partly involved in the mechanism whereby prostaglandin E(1) protects against E. coli-induced liver injury.
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PMID:Prostaglandin E(1) protects against liver injury induced by Escherichia coli infection via a dominant Th2-like response of liver T cells in mice. 1057 26

Mice given lipopolysaccharide (LPS) intravenously developed lung edema, which was maximum after 6 h. Tumor necrosis factor, interleukin 12 (IL-12), IL-6, and interferon-gamma (IFN-gamma) appeared in the serum, and levels of nitrogen oxide (NO) derivatives were increased in serum and bronchoalveolar fluid. Mice pretreated with neutralizing anti-IFN-gamma antibodies had lower serum levels of IFN-gamma, and fewer died. However, levels of other cytokines and NO derivatives as well as lung edema were unchanged. If IFN-gamma and LPS were given together, pulmonary edema was less, but levels of cytokines and NO derivatives in serum were raised, and the mortality was greater. IFN-gamma receptor knockout mice had more edema after LPS, but were less sensitive to the lethal effects. Treatment with anti-IL-12 antibody inhibited IFN-gamma induction and reduced mortality, but had no effect on the lung edema; exogenous IL-12 also failed to affect edema, but boosted serum cytokine levels and increased the mortality. Aminoguanidine, an inhibitor of NO synthase, protected against pulmonary edema, but did not modify the lethal effects of LPS. Clearly, in this model, early pulmonary edema and lethality are not directly related, and induced IFN-gamma has no role in causing early lung edema, but augments other events that result in death.
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PMID:Role of interferon-gamma and nitric oxide in pulmonary edema and death induced by lipopolysaccharide. 1061 6

Interferon gamma (IFN-gamma) priming is considered to be critical for interleukin 12 (IL-12) production of murine macrophages and human monocytes by lipopolysaccharide (LPS) stimulation. In our present experiments, freshly prepared spleen cells (f-spleen cells) were confirmed not to produce detectable level of IL-12 by LPS stimulation, although they produced significant amount of IL-12 by the stimulation with LPS plus IFN-gamma. However, the stimulation only with LPS induced IL-12 production of spleen cells preincubated in the absence of IFN-gamma. Findings on IL-12 p40 mRNA accumulation were consistent with their IL-12 production. Essentially the same results were obtained using spleen cells from IFN-gamma deficient mice. In the presence of anti-IL-10, f-spleen cells produced IL-12 upon LPS stimulation, indicating that the failure of f-spleen cells in IL-12 production is caused by IL-10 produced by themselves upon LPS stimulation. In addition, f-spleen cells produced IL-12 upon CD40 ligand stimulation, and the production was hardly affected by the presence of IFN-gamma or preincubation. These results indicate that IFN-gamma priming is not critical for IL-12 production of spleen cells stimulated with LPS or CD40 ligand, although IFN-gamma enhances the production, especially, in response to LPS stimulation.
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PMID:Interferon gamma priming is not critical for IL-12 production of murine spleen cells. 1062 37

Cervine interferon gamma (IFN-gamma) was cloned and expressed using an Escherichia coli expression system pET-32. The expressed protein contained a 6 histidine purification tag and an 11 kDa thioredoxin fusion partner 5' to the IFN-gamma molecule. The ability of IFN-gamma to inhibit the killing of Madin-Darby bovine kidney cells by Semliki forest virus was used as a measure of the bioactivity of the recombinant cervine IFN-gamma (rIFN-gamma). It was shown that the presence of the thioredoxin fusion partner 5' to the IFN-gamma molecule did not affect its biological activity. As in the mouse model, it was shown that cervine rIFN-gamma was able to down-regulate the transcription of interleukin 10 mRNA while up-regulating the transcription of interleukin 12 mRNA in lipopolysaccharide-sensitized, peripheral blood mononuclear cells. A prototype ELISA was tested for its ability to detect both recombinant and native IFN-gamma. The ELISA was able to detect rIFN-gamma at concentrations greater than 100 pg/ml. It was also used to detect native IFN-gamma produced by peripheral blood lymphocytes from Mycobacterium bovis infected or vaccinated deer after in vitro restimulation with antigen. The rIFN-gamma and the cervine IFN-gamma specific ELISA provide valuable tools with which to study important zoonotic infections in farmed and wild deer.
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PMID:The production and biological assessment of cervine interferon gamma. 1093 Feb 98

To prime immune responses, dendritic cells (DCs) need to be activated to acquire T cell stimulatory capacity. Although some stimuli trigger interleukin 12 (IL-12) production that leads to T helper cell type I (TH1) polarization, others fail to do so and favor TH2 polarization. We show that after activation by lipopolysaccharide, DCs produced IL-12 only transiently and became refractory to further stimulation. The exhaustion of cytokine production impacted the T cell polarizing process. Soon after stimulation DCs primed strong TH1 responses, whereas at later time points the same cells preferentially primed TH2 and nonpolarized T cells. These findings indicate that during an immune response, T cell priming conditions may change in the lymph nodes, suggesting another mechanism for the regulation of effector and memory T cells.
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PMID:Kinetics of dendritic cell activation: impact on priming of TH1, TH2 and nonpolarized T cells. 1101 2

The gene that encodes nuclear factor kappaB (NF-kappaB) essential modulator (or NEMO, also known as IKKgamma) is required for activation of the transcription factor NF-kappaB. We describe mutations in the putative zinc-finger domain of NEMO that result in an X-linked primary immunodeficiency characterized by hyper-IgM syndrome and hypohydrotic ectodermal dysplasia (XHM-ED). These mutations prevent CD40 ligand (CD40L)-mediated degradation of inhibitor of NF-kappaB alpha (IkappaB-alpha) and account for the following observations: B cells from XHM-ED patients are unable to undergo immunoglobulin class-switch recombination and antigen-presenting cells (APCs) are unable to synthesize the NF-kappaB-regulated cytokines interleukin 12 (IL-12) or tumor necrosis factor alpha (TNF-alpha) when stimulated with CD40L. Nevertheless, innate immunity is preserved in XHM-ED patients because APCs retain the capacity to respond to stimulation by lipopolysaccharide or Staphylococcus aureus Cowan's antigen (SAC). Overall, the phenotype observed in XHM-ED patients shows that the putative zinc-finger domain of NEMO has a regulatory function and demonstrates the definite requirement of CD40-mediated NF-kappaB activation for B cell immunoglobulin class-switching.
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PMID:Specific missense mutations in NEMO result in hyper-IgM syndrome with hypohydrotic ectodermal dysplasia. 1122 21

Mice 6 days after thermal injury (TI-mice) did not respond to lipopolysaccharide (LPS) stimulation for production of serum interleukin 12 (IL-12; 2 h after LPS stimulation, <20 pg/ml in TI-mice; 1091+/-162 pg/ml in normal mice). However, 2 h after LPS stimulation, 1456+/-118 pg/ml of IL-12 were demonstrated in sera of TI-mice previously treated with a 10 mg/kg i.p. dose of glycyrrhizin (GR). IL-12 was not induced by LPS in sera of normal mice inoculated with burn-associated type 2 T cells (IL-4/IL-10-producing CD8+CD11b+TCRgamma/delta+T cells isolated from spleens of TI-mice). However, IL-12 production was induced by LPS in sera of these mice previously treated with GR or a mixture of monoclonal antibodies (mAbs) for type 2 cytokines. Also, IL-12 production was induced by LPS in TI-mice inoculated with CD4+T cells from spleens of GR-treated normal mice (GR-CD4+T cells, 5x10(6)cells/mouse). Since GR-CD4+T cells have been shown to be antagonistic cells against production of type 2 cytokines by burn-associated type 2 T cells, these results indicate that IL-12 unresponsiveness shown in TI-mice is recovered by GR through the regulation of burn-associated type 2 T cell responses.
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PMID:Glycyrrhizin restores the impaired IL-12 production in thermally injured mice. 1129 92

Dendritic cells (DCs) are specialized antigen-presenting cells characterized by their ability to migrate into target sites, process antigens, and activate naive T cells. In this study, we analyzed the biological activity and intracellular signaling of adenosine by using reverse transcriptase-polymerase chain reaction assays to investigate mRNA expression of A(1), A(2a) and A(3) adenosine receptors in immature and mature human DCs. Functional experiments on adenosine stimulation showed chemotaxis, intracellular calcium transients, and actin polymerization, but no activation of adenylate cyclase in immature DCs. Experiments with receptor isotype-selective agonists and antagonists as well as pertussis toxin revealed that chemotaxis, calcium transients, and actin polymerization were mediated via G(i-) or G(0-)protein-coupled A(1) and A(3) receptors. Maturation of DCs induced by lipopolysaccharide (LPS) resulted in down-regulation of A(1) and A(3) receptor mRNAs, although A(2a) receptor mRNA was still expressed. However, in LPS-differentiated DCs, adenosine and an A(2a) receptor agonist stimulated adenylate cyclase activity, enhanced intracellular cAMP levels, and inhibited interleukin 12 (IL-12) production. These effects could be completely prevented by pretreatment with A(2) receptor antagonist. These findings strongly suggest that adenosine has important but distinct biological effects in DCs activity as a chemotaxin for immature DCs and as a modulator of IL-12 production in mature DCs. These effects can be explained by differential expression of adenosine receptor subtypes.
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PMID:Expression and function of adenosine receptors in human dendritic cells. 1153 76

Interleukin 12 (IL-12) is a 70-kD proinflammatory cytokine produced by antigen presenting cells that is essential for the induction of T helper type 1 development. It comprises 35-kD (p35) and 40-kD (p40) polypeptides encoded by separate genes that are induced by a range of stimuli that include lipopolysaccharide (LPS), DNA, and CD40 ligand. To date, the regulation of IL-12 expression at the transcriptional level has mainly been examined in macrophages and restricted almost exclusively to the p40 gene. Here we show that in CD8(+) dendritic cells, major producers of IL-12 p70, the Rel/nuclear factor (NF)-kappaB signaling pathway is necessary for the induction of IL-12 in response to microbial stimuli. In contrast to macrophages which require c-Rel for p40 transcription, in CD8(+) dendritic cells, the induced expression of p35 rather than p40 by inactivated Staphylococcus aureus, DNA, or LPS is c-Rel dependent and regulated directly by c-Rel complexes binding to the p35 promoter. This data establishes the IL-12 p35 gene as a new target of c-Rel and shows that the regulation of IL-12 p70 expression at the transcriptional level by Rel/NF-kappaB is controlled through both the p35 and p40 genes in a cell type-specific fashion.
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PMID:c-Rel regulates interleukin 12 p70 expression in CD8(+) dendritic cells by specifically inducing p35 gene transcription. 1160 33


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