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)

Histone deacetylase (HDAC) inhibitors reduce development of graft-versus-host disease (GVHD) following allogeneic bone marrow transplantation (BMT). Administration of the HDAC inhibitor suberonylanilide hydroxamic acid (SAHA) resulted in a significantly reduced GVHD-dependent mortality following fully major histocompatibility complex-mismatched allogeneic BMT. However, SAHA treatment did not affect T-cell activation or T-cell expansion in vitro and in vivo. Therefore, we focused on the effects of SAHA treatment on cytokine production and intracellular signaling events in vitro and in vivo following GVHD induction. Cultivation in the presence of SAHA broadly inhibited lipopolysaccharide (LPS) and alloantigen-induced cytokine/chemokine production in vitro and led also to a significant decrease in interferon-gamma and tumor necrosis factor-alpha levels in vivo following induction of GVHD. Concomitantly, SAHA treatment inhibited phosphorylation of STAT1 and STAT3 in response to LPS and alloactivation in vitro. Induction of GVHD led to a rapid phosphorylation of STAT 1 in the liver and spleen, which was markedly reduced by SAHA treatment. In conclusion, GVHD is associated with a marked induction of phosphorylation of STAT1 in the liver and spleen, and SAHA-dependent reduction of GVHD is associated with systemic and local inhibition of phosphorylated STAT1 and blunting proinflammatory cytokine production during the initiation phase of GVHD.
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PMID:Reduction of graft-versus-host disease by histone deacetylase inhibitor suberonylanilide hydroxamic acid is associated with modulation of inflammatory cytokine milieu and involves inhibition of STAT1. 1672 83

The mitogen-activated protein kinase (MAPK) pathway is frequently activated in human cancers, leading to malignant phenotypes such as autonomous cellular proliferation. Here, we demonstrate a novel role of the activated MAPK pathway in immune evasion by melanoma cells with the mutation of BRAF, which encodes a MAPKKs, (BRAF(V600E)). MEK inhibitor U0126 or RNA interference (RNAi) for BRAF(V600E) decreased production of the immunosuppressive soluble factors interleukin (IL)-10, VEGF, or IL-6 from melanoma cells to levels comparable to those after signal transducer and activator of transcription (STAT)3 inactivation. The suppressive activity of the culture supernatants from the melanoma cells on the production of inflammatory cytokines IL-12 and tumor necrosis factor alpha by dendritic cells upon lipopolysaccharide stimulation was markedly reduced after transduction with BRAF(V600E) RNAi, comparable to the effects observed with STAT3 RNAi transduction. No additive or synergistic effects were observed by the simultaneous transduction of RNAi for both BRAF(V600E) and STAT3. Furthermore, specific DNA binding and transcriptional activity of STAT3 were not affected by down-regulation of the MAPK signaling with the BRAF RNAi. These results indicate that the MAPK signal, along with the STAT3 signal, is essential for immune evasion by human melanomas that have constitutively active MAPK signaling and is a potential molecular target for overcoming melanoma cell evasion of the immune system.
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PMID:The BRAF-MAPK signaling pathway is essential for cancer-immune evasion in human melanoma cells. 1680 97

Lactobacillus rhamnosus is a human commensal with known immunomodulatory properties. To date the mechanism of these immunomodulatory effects is not well understood. To unravel the immunomodulatory signalling mechanism, we investigated the effects of two strains of L. rhamnosus, L. rhamnosus GG and GR-1, in modulating production of tumour necrosis factor-alpha (TNF) in human monocytic cell line THP-1 and mouse macrophages. Live L. rhamnosus GG and GR-1 or their spent culture supernatant induced minuscule amounts of TNF production but large quantities of granulocyte-colony stimulating factor (G-CSF) in macrophages compared with those induced by pathogenic Escherichia coli GR-12 and Enterococcus faecalis. By using neutralizing antibodies and G-CSF receptor knockout mice, we demonstrated that G-CSF secreted from L. rhamnosus GG- and GR-1-exposed macrophages suppressed TNF production induced by E. coli- or lipopolysaccharide-activated macrophages through a paracrine route. The suppression of TNF production by G-CSF was mediated through activation of STAT3 and subsequent inhibition of c-Jun-N-terminal kinases (JNKs). The inhibition of JNK activation required STAT3alpha-mediated de novo protein synthesis. This demonstrates a novel role of G-CSF in L. rhamnosus-triggered anti-inflammatory effects and its mechanism in the suppression of TNF production in macrophages.
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PMID:G-CSF-mediated inhibition of JNK is a key mechanism for Lactobacillus rhamnosus-induced suppression of TNF production in macrophages. 1688 27

Interleukin-10 (IL-10) is an anti-inflammatory cytokine that modulates innate and adaptive immunity. IL-10 transcripts and the protein were induced in murine bone marrow-derived dendritic cells (BMDCs) after toll-like receptor (TLR) stimulation. IL-10 induction was TLR ligand selective, in that CpG DNA, imidazoquinolin, peptidoglycan, and zymosan but not lipopolysaccharide (LPS) and poly I:C led to IL-10 production. IL-10 induction was, however, completely absent in MyD88(/) DCs that lacked a TLR adaptor showing that IL-10 induction depends on TLR signaling. Kinetic analysis of IL-10 induction by CpG and imidazoquinolin revealed a prolonged lag phase prior to a measurable rise in transcript levels, which peaked at 12-24 h after stimulation. Stat3, implicated in IL-10 gene transcription, was also induced after TLR stimulation with the kinetics similar to those of IL-10 induction. Further, Stat3 was phosphorylated and bound to the IL-10 promoter in TLR-stimulated DCs. Supporting a link with IL-10 induction, STAT3 induction was absent in MyD88(/) DCs. These data suggest a two-step model where the initial TLR signaling induced proinflammatory cytokines, which then activated Stat3, leading to the induction of IL-10. TLR-stimulated IL-10 production may regulate DC maturation steps, thereby influencing the ensuing immune responses.
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PMID:Induction of an anti-inflammatory cytokine, IL-10, in dendritic cells after toll-like receptor signaling. 1723 32

Interleukin-22 (IL-22) is a recently discovered proinflammatory cytokine, structurally related to IL-10. Since IL-22 is induced by lipopolysaccharide in vivo, we studied the role of IL-22 in a model of polymicrobial peritonitis. Quantitative real-time reverse transcription-PCR analysis showed marked induction of IL-22 and IL-22 receptor in spleen and kidney during the course of sepsis. The biological activity of IL-22 is modulated by IL-22-binding protein (IL-22BP), which is considered a natural antagonist of IL-22. To further analyze the role of IL-22 during septic peritonitis, mice were treated with recombinant IL-22BP generated as Fcgamma2a fusion protein. IL-22BP-Fc completely blocked IL-22-induced STAT3 activation in hepatocytes in vitro. Treatment of mice with IL-22BP-Fc 4 h before sepsis induction led to enhanced accumulation of neutrophils and mononuclear phagocytes and a reduced bacterial load at the site of infection. In addition, IL-22 blockade led to an enhanced bacterial clearance in liver and kidney and reduced kidney injury. These results imply an important proinflammatory role of IL-22 during septic peritonitis, contributing to bacterial spread and organ failure. IL-22 therefore appears to play an important role in the regulation of inflammatory processes in vivo.
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PMID:Inhibition of interleukin-22 attenuates bacterial load and organ failure during acute polymicrobial sepsis. 1726 6

A multifunctional protein metallothionein (MT) is induced by various chemicals and cytokines. We have found novel functions of MT as follows: 1) Cytokine expression such as IL-1alpha, IL-6, and TNFalpha responding to lipopolysaccharide is reduced in MT-deficient macrophages compared with in wild-type cells. 2) Nitric oxide production responding to TNFalpha and LPS is reduced in MT-deficient macrophages compared with in wild-type cells. 3) M-CSF expression responding to zinc is reduced in MT-deficient fibroblasts compared with in wild-type cells, and increased in MT-overexpressed fibroblasts compared with in control cells. 4) LIF, a STAT3 activating cytokine, protects the heart from ischemia/reperfusion injury. Transgenic mice overexpressing STAT3 have tolerance to ischemia/reperfusion-induced damage, whereas MT-null mutation cancels the myocardial protection. In this review, we discuss the relation of MT and stress responses from the point of view of cytokine-induced expression of MT and modulation of cytokine expression by MT.
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PMID:[Cytokine-induced metallothionein expression and modulation of cytokine expression by metallothionein]. 1740 98

Suppressor of cytokine signaling 3 (SOCS3), a negative regulator of cytokine signaling, is expressed in breast cancer cells where it can modify sensitivity and responsiveness to cytokine signaling through the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways. Although it is widely accepted that SOCS3 expression is in itself regulated by STATs, we and others have shown that prostaglandins can also up-regulate SOCS3 expression. Here we used T47D breast cancer cells treated with prostaglandin E2 (PGE2) to examine this pathway. T47D cells responded to PGE2 stimulation with a significant increase in SOCS3 mRNA that was independent of de novo protein synthesis. PGE2 stimulation resulted in STAT3 serine and tyrosine phosphorylation, although mutation of either of the two previously characterized STAT response elements on the SOCS3 promoter did not affect SOCS3 promoter activation by PGE2. In addition, overexpression of STAT3 wild-type, constitutively active or dominant-negative constructs did not affect PGE2-induced SOCS3 promoter activation, indicating that STATs are unlikely mediators of this pathway in these cells. PGE2 is a known activator of the cAMP/protein kinase A (PKA) pathway, and in T47D cells, up-regulation of SOCS3 mRNA by PGE2 was abolished by pretreatment with H89, a PKA inhibitor and increased by cAMP and forskolin treatment. Consistent with this, PGE2 treatment increased cAMP response element (CRE)-binding protein serine phosphorylation. However, mutation of the activator protein 1/CRE on the promoter did not affect basal or PGE2-stimulated activation, suggesting a role for cAMP/PKA that is independent of CRE-binding protein binding. Mutation of the GC-rich region of the SOCS3 promoter, a putative Sp1/Sp3 binding site, abolished both basal and PGE2-stimulated activation. Gel-shift assays showed increased complex formation after treatment, and this was inhibited by the addition of an Sp1 antibody or pretreatment with PKA inhibitor. Chromatin immunoprecipitation assay verified Sp1 binding to the promoter in response to PGE2. Sp1 overexpression increased SOCS3 promoter activation, and both basal and PGE2-induced SOCS3 mRNA expression was prevented by mithramycin, an inhibitor of Sp1 DNA binding. Finally, a physiological role for PGE2 was demonstrated with PGE2 pretreatment reducing lipopolysaccharide-induced STAT3 activation. Collectively, this study details a novel mechanism of SOCS3 up-regulation by PGE2 in breast cancer cells that appears to be STAT independent and involve Sp1 binding to the promoter. This process has possible implications for cytokine responsiveness and tumor progression.
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PMID:Characterization of the SOCS3 promoter response to prostaglandin E2 in T47D cells. 1763 39

Interleukin-6 (IL-6) via its signal transducer gp130 is an important mediator of liver regeneration involved in protecting from lipopolysaccharide (LPS)-induced liver injury after partial hepatectomy (PH). Here we generated mice either defective (Delta) in hepatocyte-specific gp130-dependent Ras or STAT activation to define their role during liver regeneration. Deletion of gp130-dependent signaling had major impact on acute phase gene (APG) regulation after PH. APG expression was blocked in gp130-DeltaSTAT animals, whereas gp130-DeltaRas mice showed an enhanced APG response and stronger SOCS3 regulation correlating with delayed hepatocyte proliferation. To define the role of SOCS3 during hepatocyte proliferation, primary hepatocytes were co-stimulated with IL-6 and hepatocyte growth factor. Higher SOCS3 expression in gp130-DeltaRas hepatocytes correlated with delayed hepatocyte proliferation. Next, we tested the impact of LPS, mimicking bacterial infection, on liver regeneration. LPS and PH induced SOCS3 and APG in all animal strains and delayed cell cycle progression. Additionally, IL-6/gp130-dependent STAT3 activation in hepatocytes was essential in mediating protection and thus required for maximal proliferation. Unexpectedly, oncostatin M was most strongly induced in gp130-DeltaSTAT animals after PH/LPS-induced stress and was associated with hepatocyte proliferation in this strain. In summary, gp130-dependent STAT3 activation and concomitant SOCS3 during liver regeneration is involved in timing of DNA synthesis and protects hepatocyte proliferation during stress conditions.
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PMID:Molecular dissection of gp130-dependent pathways in hepatocytes during liver regeneration. 1821 23

This study aimed to address the relative contributions of the proinflammatory cytokine interleukin-6 (IL-6) and the cytokine-like hormone leptin to the genomic activation of brain cells during lipopolysaccharide (LPS)-induced systemic inflammation. Wildtype and IL-6KO mice were injected with LPS (50 microg/kg, intraperitoneally) and the brains analyzed by immunohistochemistry and reverse-transcriptase polymerase chain reaction (RT-PCR). LPS induced a pronounced nuclear translocation of the signal transducer and activator of transcription (STAT3) throughout the brains of wildtype mice, an effect that was significantly diminished, but not abolished, in the IL-6KOs. The remnant STAT3-activation, although still observed within some of the same areas activated by IL-6, was most intense in ependymal and meningial cells and along distinct blood vessels throughout the brain. This expression was almost totally abolished in the presence of an anti-leptin antiserum. Interestingly, the induction of cyclooxygenase 2 and microsomal prostaglandin E synthase (mPGES), the rate-limiting enzymes for synthesis of PGE2 by LPS, was diminished to a degree that correlated with the absence of IL-6 but not entirely with leptin. These results demonstrate that the induction of the inflammatory pathway in the brain is mediated by both IL-6 and leptin, which appear to work in tandem. Unlike IL-6, however, the contribution of leptin to this response was limited to distinct cell types/brain areas and STAT3-responsive target genes implicated in the brain-controlled sickness-type response. The physiological significance of leptin's action on meningeal and endothelial cells remains to be clarified but might reflect a role in LPS-induced immune cell infiltration into the brain.
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PMID:Selective contribution of interleukin-6 and leptin to brain inflammatory signals induced by systemic LPS injection in mice. 1880 40

Sickness behaviour is an adaptive behavioural response to the activation of the innate immune system. It is mediated by brain cytokine production and action, especially interleukin-6 (IL-6). Polyunsaturated fatty acids (PUFA) are essential fatty acids that are highly incorporated in brain cell membranes and display immunomodulating properties. We hypothesized that a decrease in n-3 (also known as omega3) PUFA brain level by dietary means impacts on lipopolysaccharide (LPS)-induced IL-6 production and sickness behaviour. Our results show that mice exposed throughout life to a diet containing n-3 PUFA (n-3/n-6 diet) display a decrease in social interaction that does not occur in mice submitted to a diet devoid of n-3 PUFA (n-6 diet). LPS induced high IL-6 plasma levels as well as expression of IL-6 mRNA in the hippocampus and cFos mRNA in the brainstem of mice fed either diet, indicating intact immune-to-brain communication. However, STAT3 and STAT1 activation, a hallmark of the IL-6 signalling pathway, was lower in the hippocampus of LPS-treated n-6 mice than n-3/n-6 mice. In addition, LPS did not reduce social interaction in IL-6-knockout (IL-6-KO) mice and failed to induce STAT3 activation in the brain of IL-6-KO mice. Altogether, these findings point to alteration in brain STAT3 as a key mechanism for the lack of effect of LPS on social interaction in mice fed with the n-6 PUFA diet. The relative deficiency of Western diets in n-3 PUFA could impact on behavioural aspects of the host response to infection.
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PMID:Uncoupling of interleukin-6 from its signalling pathway by dietary n-3-polyunsaturated fatty acid deprivation alters sickness behaviour in mice. 1897 1


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