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)

The production of IL-12 by macrophages/dendritic cells (Mphi/DC) is mediated either by a T cell-dependent pathway that is induced primarily by the interaction of CD40 ligand (CD40L) on activated T cells with CD40 on IL-12-producing cells or by a T cell-independent pathway that is induced by bacteria or bacterial products and enhanced by interferon-gamma (IFN-gamma). In this study we investigated the ability of the Th2-type cytokines interleukin (IL)-10, IL-6, and IL-4 to modulate IL-12 production in Mphi/DC induced through the two pathways. IL-12 production was induced in Mphi/DC from normal mice by stimulation with the combination of IFN-gamma plus lipopolysaccharide (LPS) or Staphylococcus aureus Cowan I (a model for the T cell-independent pathway) or by co-culture with Chinese hamster ovary (CHO) cells transfected with the CD40L (a model for the T cell-dependent pathway). The effects of three Th2-type cytokines on IL-12 production by Mphi/DC through the two pathways were examined. IL-10 inhibited IL-12 production induced through both pathways, although the inhibitory effect was more potent on the (IFN-gamma + LPS)-induced pathway. IL-6 inhibited only (LPS + IFN-gamma)-induced IL-12 production. The effect of IL-4 was particularly noteworthy: this cytokine inhibited (LPS + IFN-gamma)-induced IL-12 production, whereas it potentiated the production of IL-12 induced by CD40L. Regulation of IL-12 protein production by IL-10 and IL-4 was found to correspond to the levels of mRNA accumulation for the p40 and p35 IL-12 genes, whereas the presence of IL-6 during stimulation decreased IL-12 protein production without affecting steady-state mRNA levels. These results indicate that IL-12 production in Mphi/DC induced through a T cell-dependent or -independent pathway is positively or negatively regulated by particular cytokines at various control levels.
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PMID:Regulation of T cell-dependent and -independent IL-12 production by the three Th2-type cytokines IL-10, IL-6, and IL-4. 900 May 40

The role of interleukin-12 (IL-12) in Th1 cell differentiation is well established. The heterodimer p70, composed of a p40 and a p35 chain, is the biologically active form. IL-12 production by human monocytes is enhanced by interferon-gamma (IFN-gamma) and inhibited by IL-10 and prostaglandin E2 (PGE2). Peripheral blood mononuclear cells from human immunodeficiency virus (HIV)-infected individuals reportedly have impaired IL-12 p40 and p70 production on stimulation with Staphylococcus aureus Cowan I (SAC) in vitro. Both PGE2 and IL-10 previously were proposed to be instrumental in this defect in IL-12 production. Here, we studied IL-12 p40 and p70 production in relation to IL-10 and PGE2 production in whole blood cultures from HIV-infected individuals. On stimulation with lipopolysaccharide, IL-12 production was normal. However, on stimulation with SAC, IL-12 p40 and p70 production was decreased in HIV-infected individuals and correlated significantly with decreased peripheral blood CD4+ T-cell number and T-cell reactivity to CD3 monoclonal antibody in vitro. However, IL-10 and PGE2 production in cultures from HIV-infected individuals was normal and did not relate to IL-12 production. In conclusion, IL-12 production by cells from HIV-infected individuals is impaired under certain conditions in vitro and this decrease is independent of IL-10 or PGE2 production.
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PMID:Interleukin-12 (IL-12) production in whole blood cultures from human immunodeficiency virus-infected individuals studied in relation to IL-10 and prostaglandin E2 production. 900 60

Interleukin-12 (IL-12) is a proinflammatory cytokine produced by antigen-presenting cells in response to many microbial infections. IL-12 plays an important role in the generation of T helper type-1 cells, which favor cell-mediated immune response. IL-12 is composed of two different subunits, p40 and p35, whose expression can be regulated concomitantly or differentially. Monocytic cells, the major producers of IL-12, can be primed by interferon-gamma (IFN-gamma) to produce optimal amounts of IL-12 in response to LPS stimulation as a consequence of bacterial infection. The priming effect is exerted primarily at the transcriptional level on the p40 promoter in conjunction with the effects of LPS, possibly by inducing specific transcription factors, which individually have no direct effect but which cooperatively can activate the promoter. We examined in detail one of these DNA-protein interactions observed around an Ets-2 element situated at -211/-207 of the p40 promoter, which is known to be a functionally critical site. This region interacts with a nuclear complex termed F1 that appears to be highly inducible by either IFN-gamma treatment for 16 h or lipopolysaccharide stimulation for 8 h. F1 binding to the Ets-2 site requires a considerable amount of spacing around the Ets-2 site, as revealed by gel mobility shift and in vitro methylation assays. Supershift experiments and DNA affinity purification indicated that both Ets-2 and a novel, antigenically related protein with an approximate molecular mass of 109 kDa are part of the F1 complex, together with additional components including IRF-1 and c-Rel. This novel protein is designated GLp109 for its inducibility by IFN-gamma or lipopolysaccharide. Its possible role in the activation of the IL-12 p40 promoter is discussed.
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PMID:Identification and characterization of a novel Ets-2-related nuclear complex implicated in the activation of the human interleukin-12 p40 gene promoter. 909 78

Trehalose dimycolate (TDM), a glycolipid present in the cell wall of Mycobacterium spp., is a powerful immunostimulant. TDM primes murine macrophages (Mphi) to produce nitric oxide (NO) and to develop antitumoral activity upon activation with low doses of lipopolysaccharide (LPS). In this study, we investigated the ability of TDM to induce interleukin 12 (IL-12) and the role of this cytokine in TDM-induced activation of murine Mphi. RNA isolated from peritoneal exudate cells (PEC) collected at different times after TDM injection was used to determine IL-12 (p35 and p40 subunits) and gamma interferon (IFN-gamma) mRNA levels by semiquantitative reverse transcriptase-PCR. Constitutive expression of IL-12p35 was observed in PEC from untreated as well as from TDM-injected mice. In contrast, expression of the IL-12p40 subunit was almost undetectable in control PEC but was dramatically upregulated in PEC from TDM-injected mice. IL-12p40 expression peaked at 8 h and subsided to baseline levels at 39 h postinjection. TDM was also able to induce IFN-gamma expression; however, kinetics of induction of IFN-gamma was different from that of IL-12p40. Maximal levels of IFN-gamma mRNA were reached by 24 h and did not return to baseline by 4 days. In addition, pretreatment of mice with neutralizing monoclonal antibodies directed against IL-12 (C15.6.7 and C15.1.2) blocked IFN-gamma mRNA induction in PEC from TDM-treated mice. We further determined if the induction of IL-12 and/or IFN-gamma contributes to the in vivo priming effect of TDM on peritoneal Mphi. TDM-injected mice were treated in vivo with anti-IL-12 or anti-IFN-gamma (XMG.1.6) monoclonal antibodies. TDM-primed Mphi were then activated in vitro with LPS and tested for their ability to produce NO and to develop cytostatic activity toward cocultivated L1210 tumor cells. Priming of Mphi by TDM was completely blocked by in vivo neutralization of either IL-12 or IFN-gamma as demonstrated by an absence of tumoricidal activity and NO production by TDM-elicited Mphi in the presence of LPS. Taken together our results show that TDM, a defined molecule from M. tuberculosis, induces in vivo production of IL-12. Moreover, synthesis of IL-12 mediates TDM priming of mouse peritoneal Mphi through IFN-gamma induction.
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PMID:Interleukin-12 synthesis is a required step in trehalose dimycolate-induced activation of mouse peritoneal macrophages. 911 75

Pharmacological control of interleukin-12 (IL-12) production may be a key therapeutic strategy for modulating immunological diseases dominated by type-1 cytokine responses. In this study, we investigated the effects of pentoxifylline on the production of IL-12 by human blood mononuclear cells and primary human monocytes stimulated with heat-killed Staphylococcus aureus Cowan strain I (SAC) or lipopolysaccharide (LPS). Pentoxifylline potently suppressed production of IL-12 in a concentration-dependent manner. In these same experiments, tumour necrosis factor-alpha (TNF-alpha) production was inhibited and IL-10 and prostaglandin E2 (PGE2) production was enhanced by treatment with pentoxifylline. Suppression of IL-12 production by pentoxifylline was found to be independent of several known endogenous inhibitors of IL-12, such as IL-10, transforming growth factor-beta (TGF-beta), IL-4 and PGE2. RNase protection assays revealed that pentoxifylline inhibited accumulation of both IL-12 p40 and p35 mRNA, suggesting a predominant mRNA locus for pentoxifylline-induced IL-12 inhibition. Low levels of pentoxifylline added to the suppression of IL-12 production by suboptimal inhibiting doses of dexamethasone, suggesting that this drug combination may have therapeutic utility. These results provide a firm rationale for the use of pentoxifylline in clinical trials of immunological disorders characterized by inappropriate type-1 immune responses.
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PMID:Inhibition of human interleukin-12 production by pentoxifylline. 922 17

Monophosphoryl lipid A (MPL) is a nontoxic derivative of the lipid A region of lipopolysaccharide (LPS) that is being developed as both an adjuvant and prophylactic drug for septic shock. We compared the ability of LPS and MPL to induce interleukin-10 (IL-10), IL-12 p35, IL-12 p40, gamma interferon (IFN-gamma), glucocorticoid receptor (GR), IL-1 receptor antagonist (IL-1ra), and inducible nitric oxide synthase mRNA expression in murine peritoneal macrophages. These genes were chosen for their ability to positively or negatively regulate the host immune response and thus for their potential involvement in MPL-induced adjuvanticity or in its ability to protect against sepsis. LPS was a more potent inducer of IL-12 p35, IL-12 p40, and IFN-gamma mRNA, as well as of IL-12 protein, than MPL. In contrast, MPL induced higher levels of IL-10 mRNA than did LPS from 1 to 1,000 ng/ml. In general, MPL was not a more potent inducer of negative regulatory genes, since MPL and LPS induced similar levels of GR and IL-1ra mRNA. Addition of anti-IL-10 antibody to cultures increased the induction of MPL-induced IL-12 p35, IL-12 p40, and IFN-gamma mRNA, suggesting that the enhanced production of IL-10 by MPL-stimulated macrophages contributes to decreased production of mRNA for IL-12 (p35 and p40) and IFN-gamma. Conversely, the addition of exogenous IL-10 to LPS-treated macrophages reduced the mRNA expression of these cytokine genes. These studies suggest that enhanced production of IL-10 by MPL-stimulated macrophages may contribute to the reduced toxicity of MPL through its negative action on induction of cytokines shown to enhance endotoxicity.
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PMID:Lipopolysaccharide and monophosphoryl lipid A differentially regulate interleukin-12, gamma interferon, and interleukin-10 mRNA production in murine macrophages. 923 81

Interleukin (IL)-12 is a heterodimeric cytokine consisting of 35 and 40 kDa subunits, produced primarily by phagocytic cells in response to bacteria or bacterial products. IL-12 is important in the regulation of both innate and antigen-specific immunity through its stimulatory effects on NK cells and cytotoxic lymphocytes. Reverse transcriptase-polymerase chain reaction with primers derived from human sequence was used to clone the p35 and p40 subunits of porcine IL-12. Predicted amino acid sequences for both subunits are approximately 85% homologous to their human cognates but contain a 3aa addition and a 4aa deletion in p35 and p40 subunits, respectively. The high degree of similarity indicates the proteins may be cross reactive, an important consideration in pig-human xenotransplantation. Both subunits of pIL-12 are constitutively expressed in a variety of porcine tissues. Highest levels of the p40 subunit were found in lymphoid tissues including inguinal and mesenteric lymph nodes, Peyer's patches, spleen and thymus. The p35 subunit was also detected in these tissues. Levels of mRNA encoding the p40 subunit, but not the p35 subunit, were rapidly increased in alveolar macrophages stimulated with lipopolysaccharide or killed Staphylococcus aureus. Thus, the heterodimeric subunits appear to be differentially regulated at the transcriptional level. Since p40 also self-associates to form inactive homodimers, differential expression may be a mechanism for regulating IL-12 activity.
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PMID:Molecular cloning and mRNA expression of porcine interleukin-12. 923 44

The role of interleukin-12 (IL-12) was investigated in different shock models using anti-IL-12 reagents. IL-12 is composed of two disulfide-bonded subunits, p35 and p40. The IL-12 p40 homodimer (p40)2 has been shown to be a potent IL-12 antagonist in vitro. We investigated its in vivo inhibitory capacity in different shock models of mice. We could demonstrate that (p40)2 is able to protect mice from septic shock in primarily IL-12-dependent models such as the Shwartzman reaction and lipopolysaccharide (LPS)-induced shock, whereas (p40)2 has no effect in the tumor necrosis factor alpha-dependent LPS/D-GalN shock model. In IL-12-dependent shock models, (p40)2 inhibits IL-12-induced gamma interferon production and thereby interferes with the cascade of cytokine release, finally leading to death.
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PMID:Treatment with homodimeric interleukin-12 (IL-12) p40 protects mice from IL-12-dependent shock but not from tumor necrosis factor alpha-dependent shock. 935 58

Production of interleukin-12 (IL-12) by cultured murine microglia and astrocytes was examined, by means of ELISA to detect heterodimeric p70 and RT-PCR to analyze the expression of mRNA encoding p35 and p40. Microglia, but not astrocytes, produced IL-12 p70 in response to lipopolysaccharide and interferon-gamma. The microglial cell line, Ra2, produced only p40, but not p35, upon above stimulation. Thus, it is possible that some population of microglia induce helper 1 type T cell response via producing IL-12 in the CNS. Microglia were induced to express mRNA encoding IL-12 receptors which were exclusively expressed in activated T and NK cells.
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PMID:Production of interleukin-12 and expression of its receptors by murine microglia. 951 83

Antigen-presenting cells are thought to modulate the development of Th1 and Th2 cells by the secretion of interleukin-10 (IL-10) and IL-12. Because glucocorticoids (GC) favor the development of Th2 responses, we determined whether dexamethasone (DEX) and hydrocortisone (HC) have differential effects on lipopolysaccharide-induced IL-10 and IL-12 production in whole-blood cultures. Significant inhibition of IL-12(p40) and IL-12(p70) was found with 10(-8) mol/L and 10(-9) mol/L DEX respectively, whereas IL-10 was relatively insensitive or even stimulated. Accordingly, the expression of IL-12(p40) and IL-12(p35) mRNA was more sensitive to DEX than IL-10 mRNA. The glucocorticoid receptor (GR) antagonist RU486 enhanced IL-12 production and largely abrogated the inhibition of IL-12 by GC, indicating that this suppression was mainly GR-mediated. High concentrations of RU486 were inhibitory for IL-10, suggesting that GC may exert a positive effect on IL-10. In the presence of neutralizing anti-IL-10 antibodies, DEX was still capable of IL-12 suppression whereas RU486 still enhanced IL-12 production, indicating that GC do not modulate IL-12 via IL-10 exclusively. Taken together these results indicate that GC may favor Th2 development by differential regulation of IL-10 and IL-12.
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PMID:Differential regulation of interleukin-10 (IL-10) and IL-12 by glucocorticoids in vitro. 959 74


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