Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study set out to clarify whether the inhibition of sterol or nonsterol derivatives arising from mevalonate biotransformation plays a major role in the in vivo anti-inflammatory action of statins. Hepatic synthesis of all these derivatives was inhibited in mice by administered statins, whereas squalestatin inhibited only sterol derivatives. Using a short-term treatment schedule, we found that statins reduced the hepatic activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase without affecting blood cholesterol. This treatment inhibited lipopolysaccharide- and carrageenan-induced pouch leukocyte recruitment and the exudate production of interleukin-6, monocyte chemotactic protein-1, and RANTES. Coadministration of mevalonate reversed the effect of statin on leukocyte recruitment. The inhibition of sterol synthesis by squalestatin did not have any anti-inflammatory effect, indicating that the biosynthesis of nonsterol compounds arising from mevalonate is crucial for the in vivo regulation of cytokine and chemokine production by statins. Their inhibition by statins may account for the reported anti-inflammatory effects of these drugs and may provide a biochemical basis for the recently reported effects of statins in the prevention of cardiovascular disease and mortality.
 ...
PMID:In vivo anti-inflammatory effect of statins is mediated by nonsterol mevalonate products. 1149 48

Takayasu's arteritis is an inflammatory disease of the arteries that involves large vessels. The inflammatory lesions in Takayasu's arteritis originate in the vasa vasorum and are followed by cellular infiltration, mainly composed of T cells (gammadelta lymphocytes, cytotoxic T lymphocytes, T helper cells), but also of natural killer cells, dendritic cells, monocytes and granulocytes, invading the outer layer of the media and/or its neighbouring adventitia. At this stage, positive production of inflammatory cytokines and/or adhesion molecules around these areas is remarkable. According to data available--in Takayasu's arteritis--interleukin-6, interleukin-1 and RANTES are released in large amounts by infiltrating inflammatory cells within damaged tissue, as well as by circulating inflammatory cells, and very likely help maintain the aberrant immune activation, by promoting endothelial cells activation and by inducing lymphocyte infiltration. Although the nature of the antigen that triggers the auto-immune process is still unknown, the infiltrating T lymphocytes may recognize one or a few self-antigens processed and presented in association with HLA. A considerable percentage of patients with Takayasu's arteritis have immune complexes in sera; moreover, on peripheral blood lymphocyte, Fc receptors and antibodies reactive against human endothelial cells (AECA) have been detected. This observation raised the possibility that AECA might have a role in endothelial cell activation and expression of adhesion molecules, which will facilitate leukocyte traffic.
 ...
PMID:Pathogenesis of Takayasu's arteritis. 1178 7

Inflammation of the synovial membrane in rheumatoid arthritis is mediated by specialized cells necessary for immune response. The most prominent features are the accumulation of mononuclear phagocytes, lymphocytes and leukocytes in the proliferating tissue. Pro-inflammatory and proliferative signals are transmitted to the bone marrow and to the synovial membrane. The result is a monoclonal stimulation of specific cell lines, and synovial proliferation in the inflamed joint. Angiogenesis, synovial hypertrophy, and increased perfusion facilitate the accumulation of inflammatory cells. Components of the autoimmune reaction are described in the international system of classification, the CD-System (cluster of differentiation). Pro-inflammatory signals are mediated by metabolites of arachidonic acid. Prostaglandins, leukotrienes, lipoxines and hydroxy fatty acids, derived from this PUFA, stimulate the formation and the activity of adhesion molecules (integrines), cytokines (gamma-interferon, interleukin-1, interleukin-6, tumor-necrosis factor), chemokines (interleukine-8, macrophage-chemotactic peptide, RANTES and colony -stimulating factors ((CSF, granulocytes/ monocytes-CSF, Multi-CSF (= IL-3)). Dietary means to mitigate inflammation comprise reduction of arachidonic acid, and increased intake of eicosapentaenoic acid and antioxidants. In the literature 12 randomized, placebo-controlled double-blind studies, fulfilling GCP-criteria, demonstrate a moderate but consistent improvement of clinical findings and laboratory parameters in patients with RA. A dose-response relationship was established up to an daily dose of 2.6 gram fish oil, equivalent to about 1.6 gram EPA. In these experiments EPA was the omega-3 fatty acid responsible for improvement, with distinct effects on inhibition of cytokines formation (IL-1 to IL-6, IL-8, TFN-alpha, GM-CSF), decreased induction of proinflammatory adhesion molecules (selectines, intercellular adhesions molecule-1 (ICAM-1)), and degrading enzymes (e.g. phospholipase A2, cyclooxygenase-2, inducible NO-synthetase). Only one study reports the relevance of the background diet. From this study it became apparent that reduction of dietary arachidonic acid improves the incorporation and the clinical benefit of EPA.
 ...
PMID:Dietary fatty acids and immune reactions in synovial tissue. 1291 34

Recent data indicate that certain pro-inflammatory cytokines are transcriptionally upregulated in the spinal cords of G93A-SOD1 mice, a model of amyotrophic lateral sclerosis (ALS). We previously showed that the receptor for tumor necrosis factor alpha (TNF-R1) was notably elevated at late presymptomatic as well as symptomatic phases of disease (J. Neurochem. 82 (2002) 365). We now extend these findings by showing that message for TNFalpha, as well as mRNA for interferon gamma (IFNgamma) and transforming growth factor beta1/2 (TGFbeta1, TGFbeta2), is simultaneously increased. Furthermore, TNFalpha protein is significantly increased in G93A-SOD1 mouse spinal cords, as are protein levels for interleukin-6 (IL6), IFNgamma, and the chemokines RANTES (CCL5) and KC. The interaction of TNFalpha, IL6, and IFNgamma proteins was modeled in vitro using Walker EOC-20 murine microglia with nitrite (NO(2)(-)) efflux as a quantitative index of cell response. TNFalpha alone caused robust NO(2)(-) flux, while IL6 had a lesser effect and neither IFNgamma nor IL1beta was active when applied singly. The TNFalpha stimulus was potently magnified in the presence of IL6 or IFNgamma. When applied in combination at very low concentrations, IFNgamma co-synergized with IL6 to produce a multiplicative increase in NO(2)(-) after stimulation with TNFalpha. Taken together, these data suggest that modest increases in multiple synergistic cytokines could produce a disproportionately severe activation of microglia within the degenerating spinal cord. Our data support a model wherein TNFalpha acts as a principal driver for neuroinflammation, while several co-stimulating cytokines and chemokines act to potentiate the TNFalpha effects.
 ...
PMID:Message and protein-level elevation of tumor necrosis factor alpha (TNF alpha) and TNF alpha-modulating cytokines in spinal cords of the G93A-SOD1 mouse model for amyotrophic lateral sclerosis. 1367 68

Current evidence suggests that tumor necrosis factor alpha (TNFalpha) and the family of interferons (IFNs) synergistically regulate many cellular responses that are believed to be critical in chronic inflammatory diseases, although the underlying mechanisms of such interaction are complex, cell-specific, and not completely understood. In this study, TNFalpha in a time-dependent manner activated both janus tyrosine kinase 1 and Tyk2 tyrosine kinase and increased the nuclear translocation of interferon-regulatory factor-1, STAT1, and STAT2 in human airway smooth muscle cells. In cells transfected with a luciferase reporter, TNFalpha stimulated gamma-activated site-dependent gene transcription in a time- and concentration-dependent manner. Using neutralizing antibodies to IFNbeta and TNFalpha receptor 1, we show that TNFalpha-induced secretion of IFNbeta mediated gamma-activated site-dependent gene expression via activation of TNFalpha receptor 1. In addition, neutralizing antibody to IFNbeta also completely abrogated the activation of interferon stimulation response element-dependent gene transcription induced by TNFalpha. Secreted IFNbeta acted as a negative regulator of TNFalpha-induced interleukin-6 expression, while IFNbeta augmented TNFalpha-induced RANTES (regulated on activation normal T cell expressed and secreted) secretion but had little effect on TNFalpha-induced intercellular adhesion molecule-1 expression. Furthermore TNFalpha, a modest airway smooth muscle mitogen, markedly induced DNA synthesis when cells were treated with neutralizing anti-IFNbeta. Together these data show that TNFalpha, via the autocrine action of IFNbeta, differentially regulates the expression of proinflammatory genes and DNA synthesis.
 ...
PMID:Tumor necrosis factor alpha modulates airway smooth muscle function via the autocrine action of interferon beta. 1451 61

Orientia tsutsugamushi, an obligate intracellular bacterium, is the causative agent of scrub typhus which is histopathologically characterized by inflammatory manifestations, indicating that rickettsiae induce mechanisms that amplify the inflammatory response. To understand the pathogenesis of scrub typhus, we examined chemokine and cytokine production after infection with O. tsutsugamushi in mice. The mRNAs that were upregulated included lymphotactin, RANTES (regulated upon activation, normal T-cell expressed and secreted), macrophage inflammatory proteins 1alpha/beta (MIP-1alpha/beta), MIP-2, monocyte chemoattractant protein 1, lymphotoxin beta, tumor necrosis factor alpha, interleukin-6, gamma-interferon, transforming growth factor beta1, and migration inhibition factor. Peak expression of these chemokines and cytokines was observed between 4 and 8 days after infection. Gene induction was followed by the secretion of chemokine and cytokine proteins. Chemokine profile in infected mice was well correlated with kinetics of inflammatory cell infiltration. Thus, O. tsutsugamushi appears to be a strong inducer of chemokines and cytokines which may, by the attraction and activation of phagocytic leukocytes, significantly contribute to inflammation observed in scrub typhus.
 ...
PMID:Chemokine and cytokine production during Orientia tsutsugamushi infection in mice. 1464 40

Heat shock factor 1 (HSF1) is a major transactivator of heat shock proteins in response to heat shock, and it is also involved in oogenesis, spermatogenesis, and placental development. However, we do not know the molecular mechanisms controlling developmental processes. In this study, we found that HSF1-null mice exhibited a significant decrease in the T cell-dependent B cell response. When mice were immunized intraperitoneally with sheep red blood cells, the sheep red blood cell-specific IgG production, especially IgG2a production, in HSF1-null mice was about 50% lower than that in wild-type mice at 6 days after the immunization, whereas IgM production was normal. The number of bromodeoxyuridine-incorporated spleen cells in immunized HSF1-null mice was one-third that in immunized wild-type mice, indicating reduced proliferation of the spleen cells. We analyzed levels of cytokines and chemokines in spleen cells and in peritoneal macrophages stimulated with lipopolysaccharide and interferon-gamma and found that expression levels of interleukin-6 and CCL5 were significantly lower in HSF1-null cells than those in wild-type cells. Furthermore, we demonstrated that the IL-6 gene is a direct target gene of HSF1. These results revealed a novel molecular link between HSF1 and a gene related to immune response and inflammation.
 ...
PMID:Impaired IgG production in mice deficient for heat shock transcription factor 1. 1522 19

To characterize the roles of Porphyromonas gingivalis and its components in the disease processes, we investigated the cytokine profile induced by live P. gingivalis, its lipopolysaccharides (LPS), and its major fimbrial protein, fimbrillin (FimA). Using cytokine antibody arrays, we found that P. gingivalis LPS and FimA induced a similar profile of cytokine expression when exposed to mouse peritoneal macrophages but that this profile differed significantly in response to live P. gingivalis. In vitro, mouse peritoneal macrophages were stimulated to produce interleukin-6 (IL-6), granulocyte colony-stimulating factor, and lymphotactin by live P. gingivalis, but not by P. gingivalis LPS or FimA, while RANTES, gamma interferon, IL-17, vascular cell adhesion molecule 1 (VCAM-1), and vascular endothelial growth factor were induced by P. gingivalis LPS or FimA, but not by live P. gingivalis. In vivo, IL-6 mRNA was strongly induced only by live P. gingivalis while monocyte chemoattractant protein 1 mRNA was strongly induced only by P. gingivalis LPS and FimA in mouse calvarial scalp, further confirming the differences of cytokine profile induced in vitro. Cytokine antibody arrays using toll-like receptor 2 (TLR2)- and TLR4-deficient macrophages revealed that most of the cytokines induced by P. gingivalis LPS or FimA signal through TLR2, while most of cytokines induced by live P. gingivalis signal through both TLR2 and TLR4. Interestingly, the activation of TLR2 by live P. gingivalis inhibited the release of RANTES, VCAM-1, and IL-1alpha from mouse peritoneal macrophages. A tumor necrosis factor alpha enzyme-linked immunosorbent assay further confirmed that P. gingivalis LPS and FimA activate mouse peritoneal macrophages via TLR2. These results indicate that host immune cells sense live P. gingivalis and its components differently, which translates into the expression of different inflammatory cytokine profiles.
 ...
PMID:Cytokine profiling of macrophages exposed to Porphyromonas gingivalis, its lipopolysaccharide, or its FimA protein. 1566 35

A 49-year-old woman complained of hearing loss and diminution of left radial arterial pulsation. She had been diagnosed with sudden deafness and treated with corticosteroids. Her audibility deteriorated again after the cessation of the therapy. Angiograms showed stenosis in the bilateral carotid arteries, the left vertebral artery, the left subclavian artery, and the pulmonary arteries. She was diagnosed with Takayasu's arteritis. After steroid therapy was restarted, there were improvements in her audibility, radial arterial pulsation, and levels of inflammatory markers (erythrocyte sedimentation rate, C-reactive protein, and gamma-globulin), fibrinogen, interleukin-6, and RANTES (regulated on activation, normal T cell expressed and secreted).
 ...
PMID:Sensorineural hearing loss combined with Takayasu's arteritis. 1575 Feb 72

Herpes simplex viruses (HSV) infect human and murine dendritic cells (DCs) and interfere with their immunostimulatory functions in culture. HSV-2 infection increases human immunodeficiency virus (HIV) spread in patients, and DCs also promote HIV infection. We have studied these topics in rhesus macaque monocyte-derived DCs (moDCs) to set the stage for future studies of these issues in animals. We provide the first evidence that macaque DCs become infected by HSV-2. Structural viral proteins (ICP5 [infected cell protein 5], glycoprotein D [gD], envelope) were detected in the cell periphery, and a functional protein (infected cell protein 8 [ICP8]) was predominantly found in the nucleus after infection. Infectious HSV-2 induced apoptotic death, decreased expression of HLA-DR, CD40, CD80, CD83, and CD86, and increased release of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), macrophage inflammatory protein-1alpha (MIP-1alpha) (CCL3), and RANTES (regulated on activation normal T cells expressed and secreted) (CCL5) but not IL-12 or interferon-alpha (IFN-alpha) by macaque DCs. This coincided with HSV-2-infected DCs stimulating weak T-cell responses, including impaired SIV-specific responses. Comparable HSV-2 protein expression, DC apoptosis, as well as membrane immunophenotype and functional modifications were observed in HSV-2-exposed human moDCs. Such HSV-2-induced modifications of macaque and human DCs could augment DC-driven immunodeficiency virus infection. This work affords the basis for future macaque studies to explore how HSV-2 impacts the efficacy of strategies being developed to prevent HIV transmission.
 ...
PMID:Immunomodulatory effects of HSV-2 infection on immature macaque dendritic cells modify innate and adaptive responses. 1584 98


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>