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)

Diltiazem is a calcium channel blocker that suppresses the activation of a variety of immune cells, such as T and B cells, NK cells, monocytes and dendritic cells (DCs). It has been used in the treatment of cardiovascular disorders and has been widely included in clinical protocols to prevent rejection after kidney transplantation. In line with these data, we previously showed that diltiazem directly affects maturation of human DCs and the production of IL-12. Here, we extended our analysis studying the effect of diltiazem on the transcription of IL-12 p35 and p40 subunits focusing on the activity of nuclear factor-kappa B (NF-kappa B). A marked reduction of NF-kappa B binding to the kappa B sequences present within the p35 and p40 subunit promoters was observed in diltiazem-treated DCs following the stimulation with lipopolysaccharide (LPS) or CD40L. In order to examine the mechanisms by which NF-kappa B binding activity is reduced by diltiazem, we analyzed the NF-kappa B inhibitor, I kappa B alpha. No significant differences were observed in the phosphorylation and/or the degradation of I kappa B alpha. On the other hand, the subcellular distribution of NF-kappa B subunits was clearly affected in diltiazem-treated DCs following LPS stimulation, with a reduced nuclear translocation of p65, and RelB, and a nuclear accumulation of p50 subunit. Thus, all together, our data provided evidence that in addition to the inhibition of p65/p50 nuclear translocation, the selective induction and translocation of p50/p50 homodimers is an important mechanism by which diltiazem inhibits NF-kappa B activity, and in turn, IL-12 expression.
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PMID:Inhibition of interleukin-12 expression in diltiazem-treated dendritic cells through the reduction of nuclear factor-kappa B transcriptional activity. 1565 34

Sodium methyldithiocarbamate (SMD; trade name, Metam Sodium) is an abundantly used soil fumigant that can cause adverse health effects in humans, including some immunological manifestations. The mechanisms by which SMD acts, and its targets within the immune system are not fully understood. Initial experiments demonstrated that SMD administered by oral gavage substantially decreased IL-12 production and increased IL-10 production induced by lipopolysaccharide in mice. The present study was conducted to further characterize these effects and to evaluate our working hypothesis that the mechanism for these effects involves alteration in signaling through toll-like receptor 4 and that this would suppress innate immunity to infection. SMD decreased the activation of MAP kinases and AP-1 but not NF-kappaB in peritoneal macrophages. The expression of mRNA for IL-1alpha, IL-1beta, IL-18, IFN-gamma, IL-12 p35, IL-12 p40, and macrophage migration inhibitory factor (MIF) was inhibited by SMD, whereas mRNA for IL-10 was increased. SMD increased the IL-10 concentration in the peritoneal cavity and serum and decreased the concentration of IL-12 p40 in the serum, peritoneal cavity, and intracellularly in peritoneal cells (which are >80% macrophages). Similar effects on LPS-induced cytokine production were observed following dermal administration of SMD. The major breakdown product of SMD, methylisothiocyanate (MITC), caused similar effects on cytokine production at dosages as low as 17 mg/kg, a dosage relevant to human exposure levels associated with agricultural use of SMD. Treatment of mice with SMD decreased survival following challenge with non-pathogenic Escherichia coli within 24-48 h, demonstrating suppression of innate immunity.
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PMID:Sodium methyldithiocarbamate inhibits MAP kinase activation through toll-like receptor 4, alters cytokine production by mouse peritoneal macrophages, and suppresses innate immunity. 1593 25

Infection with influenza virus strongly predisposes an individual to bacterial superinfection, which is often the significant cause of morbidity and mortality during influenza epidemics. Little is known about the immunomodulating properties of the virus that lead to this phenomenon, but the effect of the viral components on the development of immune dendritic cells (DCs) may prove vital. In this study, activation of and cytokine secretion by bacterial lipopolysaccharide (LPS)-stimulated bone marrow-derived dendritic cells (BMDCs) following treatment with the influenza virus major antigen haemagglutinin (HA) were examined. HA selectively inhibits the release of LPS-induced interleukin 12 (IL12) p70, which is independent of IL10 secretion. Suppression occurs at the transcriptional level, with selective inhibition of p35- and not p40-subunit mRNA expression. The downregulation of IL12 p70 by influenza HA is a novel and unexplored pathway that may be relevant in the predisposition to bacterial superinfection associated with influenza virus infections.
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PMID:Novel mechanism of immunosuppression by influenza virus haemagglutinin: selective suppression of interleukin 12 p35 transcription in murine bone marrow-derived dendritic cells. 1595 66

The majority of adenovirus serotypes utilize the coxsackievirus-adenovirus receptor (CAR) for virus-host cell attachment, but subgroup B and subgroup D (adenovirus type 37 [Ad37]) viruses recognize CD46. CD46 is a ubiquitously expressed receptor that serves as a cofactor for the inactivation of the complement components C3b and C4b, and it also serves as a receptor for diverse microbial pathogens. A reported consequence of CD46 engagement is a reduced capability of human immune cells to express interleukin-12 (IL-12), a cytokine involved in both the innate and adaptive immune responses. Studies were thus undertaken to determine whether CD46-utilizing Ads alter the expression of proinflammatory cytokines. Subgroup B (Ad16 and -35) and Ad37, but not Ad2 or -5, significantly reduced IL-12 production by human peripheral blood mononuclear cells stimulated with gamma interferon (IFN-gamma) and lipopolysaccharide. IL-12 mRNA (p35 and p40 subunits) levels as well as other cytokine mRNA levels (IL-1alpha and -beta, IL-1Ra, and IL-6) were decreased upon interaction with CD46-utilizing Ads. Analysis of transcription factor activity required for cytokine expression indicated that CD46-utilizing Ads preferentially inhibited IFN-gamma-induced C/EBPbeta protein expression, consequently reducing its ability to form DNA complexes. Interference with IFN-gamma signaling events by CD46-utilizing Ads, but not CAR-utilizing Ads, reveals a potentially critical difference in the host immune response against distinct Ad vectors, a situation that has implications for gene delivery and vaccine development.
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PMID:CD46-utilizing adenoviruses inhibit C/EBPbeta-dependent expression of proinflammatory cytokines. 1610 78

Chlorophyllin (CHL) is a chlorophyll derivative with anticarcinogen and antioxidant activities. Despite clinical importance of CHL as a potential therapeutics for treating cancer patients, little is known about the immunological properties of CHL. In the present study, we investigated the effect of CHL on the activation of murine splenocytes stimulated with lipopolysaccharide (LPS). RT-PCR analysis showed that LPS-activated IFN-gamma expression gradually declined by CHL treatment in a dose dependent manner while mRNA production of TNF-alpha, IL-2, and FasL was not changed. CHL also suppressed IL-12 production (p70, a heterodimer of p40 and p35) and the mRNA expression of IL-12 p40 and IL-12 receptors (both IL-12Rbeta1 and IL-12Rbeta2), which are involved in the induction of IFN-gamma expression. Furthermore, an electrophoretic mobility shift assay showed that CHL inhibited DNA binding activity of NF-kappaB, STAT-3, and STAT-4 to their cognate DNA recognition motifs, all of which contribute to the IL-12-induced IFN-gamma transcription. Exogenous addition of recombinant IL-12 abrogated the inhibitory effect of CHL on IFN-gamma and its mRNA expression in LPS-activated splenocytes. Collectively, these results show that CHL inhibits IFN-gamma production by LPS-stimulated splenic mononuclear cells due to down-regulation of IL-12 production.
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PMID:Chlorophyllin attenuates IFN-gamma expression in lipopolysaccharide-stimulated murine splenic mononuclear cells via suppressing IL-12 production. 1627 27

To investigate the influence of oxidative stress on the immune response, mice were injected with H(2)O(2), and peritoneal macrophages were isolated and stimulated in vitro with lipopolysaccharide (LPS). H(2)O(2) significantly augmented both interleukin (IL)-12p40 and IL-12p70 production and increased the p40/p70 molecular ratio. This was confirmed by mRNA analysis, which showed that H(2)O(2) increased LPS-induced mRNA expression of both IL-12p40 and IL-12p35 subunits with an increased p40/p35 ratio. Analysis of anti-ovalbumin (OVA) antibodies revealed that H(2)O(2) injection significantly increased the production of type 2 helper T cell (Th2)-associated antibody classes [immunoglobulin (Ig)E and IgG1] but not a Th1-associated antibody class (IgG2a). To confirm the Th2-predominant immune response, we analyzed the profile of cytokine production by spleen T cells of OVA-immunized and H(2)O(2)-injected mice. H(2)O(2) significantly increased the production of IL-4 but not that of interferon-gamma. Together, these results suggest that H(2)O(2)-induced overproduction of IL-12p40 promotes the Th2-predominant response through increased production of IL-12p40-homodimers, which could serve as an antagonist of the Th1-inducing cytokine IL-12p70.
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PMID:Hydrogen peroxide increases interleukin-12 p40/p70 molecular ratio and induces Th2-predominant responses in mice. 1647 11

Both antibodies and T cells contribute to immunity against influenza virus infection. However, the generation of strong Th1 immunity is crucial for viral clearance. Interestingly, we found that human dendritic cells (DCs) infected with influenza A virus have lower allospecific Th1-cell stimulatory abilities than DCs activated by other stimuli, such as lipopolysaccharide and Newcastle disease virus infection. This weak stimulatory activity correlates with a suboptimal maturation of the DCs following infection with influenza A virus. We next investigated whether the influenza A virus NS1 protein could be responsible for the low levels of DC maturation after influenza virus infection. The NS1 protein is an important virulence factor associated with the suppression of innate immunity via the inhibition of type I interferon (IFN) production in infected cells. Using recombinant influenza and Newcastle disease viruses, with or without the NS1 gene from influenza virus, we found that the induction of a genetic program underlying DC maturation, migration, and T-cell stimulatory activity is specifically suppressed by the expression of the NS1 protein. Among the genes affected by NS1 are those coding for macrophage inflammatory protein 1beta, interleukin-12 p35 (IL-12 p35), IL-23 p19, RANTES, IL-8, IFN-alpha/beta, and CCR7. These results indicate that the influenza A virus NS1 protein is a bifunctional viral immunosuppressor which inhibits innate immunity by preventing type I IFN release and inhibits adaptive immunity by attenuating human DC maturation and the capacity of DCs to induce T-cell responses. Our observations also support the potential use of NS1 mutant influenza viruses as live attenuated influenza virus vaccines.
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PMID:Influenza virus evades innate and adaptive immunity via the NS1 protein. 1677 17

Interleukin-12 (IL-12) functions as a representative lipopolysaccharide (LPS) mediator in both innate and adaptive immunity. We investigated the regulation of LPS-induced IL-12 production by mouse macrophages. In response to LPS, peritoneal macrophages produced bioactive IL-12 p70, a heterodimer (p40/p35) of subunits, but macrophage lines such as J774.1 and RAW264.7 did not. Induction of the p35 subunit was impaired in both cell lines, and additional impairment of p40 induction was observed in RAW264.7 cells. These results suggest that some negative regulatory mechanisms against LPS-induced IL-12 p40 production are constitutively functioning in RAW264.7 cells but not in the other types of cells. Activation of GA-12 (a repressor element of IL-12 p40), rather than suppression of promoter elements, such as binding sites for NF-kappaB, AP-1, and IRF-1, was detected in LPS-stimulated RAW264.7 cells, accompanying hyperactivation of extracellular signal-related kinase (ERK). When ERK activation was suppressed by an inhibitor (U0126), production of p40 rose from an undetectable to a substantial level and GA-12 activation decreased. In peritoneal macrophages, stimulation with a high dose of LPS reduced p40 production with enhanced activation of ERK. Pretreatment of the cells with phorbol myristate acetate to enhance ERK activation reduced p40 production in response to the optimal LPS stimulation. Taken together, these results demonstrate that hyperactivation of the ERK pathway plays a role in upstream signaling for the activation of GA-12, leading to the repression of IL-12 p40 production in mouse macrophages.
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PMID:Regulation of lipopolysaccharide-induced interleukin-12 production by activation of repressor element GA-12 through hyperactivation of the ERK pathway. 1689 87

Interleukin-12 (IL-12) p70 is an important cytokine secreted by antigen-presenting cells in response to antigenic stimulation; it is a heterodimer of p35 and p40 subunits. Here, we report a new, highly sensitive, and reliable method that employs fluorometric sandwich ELISA for quantification of the mouse IL-12 (moIL-12) p70 protein. Our method could quantify moIL-12 p70 in the range of approximately 0.5 to 500 pg/ml. In the assay, no signals were produced by the moIL-12 p40 monomer, homodimer [(p40)2], or mouse IL-23 even up to a concentration of 500 pg/ml; this ensures that our assay has a high specificity for moIL-12 p70. To demonstrate that our method can determine natural moIL-12 in real physiological/pathological samples, we monitored the moIL-12 p70 secretion from peritoneal exudative cells after lipopolysaccharide (LPS) stimulation. IL-12 p70 secretion as early as 3h after LPS stimulation was reliably detected due to the high sensitivity of the method.
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PMID:A sensitive and reliable quantification method for mouse interleukin-12 p70 based on fluorometric sandwich ELISA (FS-ELISA). 1714 87

Interleukin-12 (IL-12), a heterodimeric cytokine (p35/p40) produced mainly from macrophages and dendritic cells, is an important regulator of T-helper 1 cell responses and for host defense. We found that interferon (IFN) consensus sequence binding protein (ICSBP), which is a transcription factor essential for the expression of p40, was expressed in mouse bone marrow-derived mast cells (BMMCs). The transcription levels of p35 and p40 were increased by stimulation of BMMCs with IFN-gamma/lipopolysaccharide (LPS). IL-12 was secreted from BMMCs in response to LPS but not by FcepsilonRI cross-linking. The p40 levels in the peritoneal cavity of mast cell-deficient W/W(v) and W/W(v) reconstituted with p40(-/-) BMMCs were significantly lower than those of WBB6F(1)(+/+) and wild-type (WT) BMMC-reconstituted W/W(v) in the acute septic peritonitis model. The survival rate of W/W(v) reconstituted with p40(-/-) BMMCs was significantly decreased compared to those of WBB6F(1)(+/+) and WT-BMMC-reconstituted W/W(v), which was due to reduced production of IFN-gamma and subsequent impaired activation of neutrophils in the peritoneal cavity. Survival rate of p40(-/-) mice was also restored by adoptive transfer of WT-BMMCs. These results demonstrate that mast cells play a significant role in the production of IL-12 required for host defense. This is the first report to demonstrate that mast cells are a crucial source of functional IL-12.
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PMID:Involvement of mast cells in IL-12/23 p40 production is essential for survival from polymicrobial infections. 1728 16


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