Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Perivascular accumulation of mononuclear cells (MNCs) in the central nervous system (CNS) and high levels of myelin autoantigen-reactive T cells in blood and further enriched in cerebrospinal fluid (CSF) are characteristic for multiple sclerosis (MS) and suggest a role for immunoregulatory cytokines in MS pathogenesis. The difficulties inherent to measurements of cytokine concentrations in body fluids have been partly overcome by adopting techniques allowing cytokine determinations on cellular level. MS is associated with the parallel up-regulation of proinflammatory [interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), lymphotoxin-alpha, and interleukin (IL)-12] and immune response-down-regulating [transforming growth factor-beta (TGF-beta), IL-10] cytokines systemically. A preferential up-modulation of TNF-alpha and lymphotoxin-alpha is observed in clinical exacerbations and of TGF-beta and IL-10 in remissions. The B cell-stimulating IL-4 and IL-6 are also up-regulated in MS, as is the cytolysis-promoting perforin. Cytokine production is elevated to an even higher degree in the CSF than systemically, underlining the autonomy of the immune responses in the CSF. All cytokine abnormalities are demonstrable already in very early MS, manifested by acute unilateral optic neuritis associated with more than two MS-like lesions on brain magnetic resonance imaging and oligoclonal IgG bands in CSF. The cytokine abnormalities hitherto observed are not MS specific, because they can be found in other inflammatory CNS diseases, e.g., aseptic meningitis and even noninflammatory neurological diseases like stroke. The influence on cytokine profiles, e.g., suppressing proinflammatory cytokines and promoting TGF-beta and IL-10, could be an important way to identify new and promising treatments of MS.
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PMID:Review: cytokines and the pathogenesis of multiple sclerosis. 887 92

A growing body of evidence points out the potential role of inflammatory mechanisms in the pathophysiology of ischaemic brain damage. We have recently demonstrated that stroke patients display an intrathecal production of proinflammatory cytokines, such as IL-1beta and IL-6 already within the first 24 h after the beginning of symptoms (Tarkowski et al., 1995). The aim of the present study was to investigate patterns of local inflammatory responses as a consequence of acute stroke. Thirty stroke patients were studied prospectively on days 0-3, 7-9, 21-26 and after day 90 with clinical evaluations, radiological assessments and analysis of cerebrospinal fluid (CSF) cytokine levels. In addition, 15 healthy control CSF samples were used. Significantly increased CSF levels of IL-8, granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-10 were observed early during the stroke with a peak on day 2 for the proinflammatory cytokines IL-8 and GM-CSF, and on day 3 for the immunoregulatory cytokine IL-10. Patients with a brain infarct predominantly located in the white matter showed significantly higher levels of IL-8 in CSF than patients with an infarct mainly located in the grey matter. Also, high levels of intrathecal tumour necrosis factor-alpha (TNF-alpha) were associated with the presence of white matter disease. Our study demonstrates an intrathecal production of proinflammatory and immunoregulatory cytokines in patients with stroke, supporting the notion of localized immune response to the acute brain lesion. A better understanding of the inflammatory response in stroke may lead to new treatment strategies.
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PMID:Intrathecal release of pro- and anti-inflammatory cytokines during stroke. 940 56

The effects of the anti-inflammatory cytokine, IL-10, on brain injury following permanent focal ischemia were determined. Rats subjected to occlusion of the right middle cerebral artery (MCAO) were administered IL-10 (1 microg) centrally into the lateral ventricle 30 min and 3 h post MCAO or systemically into the tail vein (5 or 15 microg/h) starting 30 min post MCAO for 3 h. Brains were removed 24 h later and infarct size was measured. IL-10 administered centrally significantly (P < 0.01) reduced infarct size by 20.7% +/- 6.0 compared to vehicle. Systemic IL-10 administration at 5 and 15 microg/h significantly (P < 0.05) decreased infarct size (40.3% +/- 14.0 and 30.7% +/- 13.7, respectively). These studies indicate that an anti-inflammatory therapeutic approach using IL-10 can provide neuroprotection in ischemic stroke.
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PMID:IL-10 reduces rat brain injury following focal stroke. 972 75

Ischemic stroke is associated with altered systemic immune responses both early after the onset and in the recovery phase. Interleukin (IL)-10, a Th2 related cytokine, has multiple effects on different cell types, including T and B lymphocytes, monocytes, neutrophils and mast cells. IL-4 is another Th2 cytokine that inhibits the synthesis of pro-inflammatory cytokines by Th1 clones. We used enzyme-linked immunospot assays to detect and enumerate blood mononuclear cells (MNC) secreting IL-10 and IL-4 spontaneously as well as after stimulation with myelin basic protein (MBP), considered to be an autoantigen of possible pathogenic importance in, for example, multiple sclerosis, to evaluate the involvement of anti-inflammatory cytokines in ischemic stroke. All patients with ischemic stroke and cerebral hemorrhage had strongly elevated numbers of IL-10 secreting blood MNC compared with healthy individuals. Numbers of MBP-reactive IL-10 secreting blood MNC were also elevated in a proportion of the patients with stroke and hemorrhage. Levels of IL-4 secreting blood MNC did not differ in ischemic stroke versus healthy individuals. The anti-inflammatory IL-10 could play a pivotal role in ischemic stroke as well as cerebral hemorrhage.
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PMID:High levels of IL-10 secreting cells are present in blood in cerebrovascular diseases. 1036 96

Cognate interactions between human adult microglia and activated T lymphocytes induce the production of inflammatory cytokines. Since this interaction can occur in a non-antigen-dependent manner, it is relevant to a variety of CNS diseases where activated T cells, regardless of specificities, come into contact with microglia; these disorders include multiple sclerosis, trauma, stroke and Alzheimer's disease. A model cell line would facilitate studies of the engagement between T cells and human adult microglia, since the latter are difficult to obtain in substantial quantity or frequency. This study shows that the PMA/IFN gamma-treated U937 cell line shows similarities to microglia in its interaction with activated T lymphocytes, in that the production of tumor necrosis factor (TNF)-alpha, interleukin (IL)-4, IL-10 and IL-12 is induced. Morphological features and mechanisms of cytokine production resemble those observed in microglia--T cell co-cultures since CTLA-4 and CD40--CD40L blockades reduce TNF-alpha and IL-10 levels, while anti-CD23 inhibits IL-10 only in U937--T cell interactions. We propose that PMA/IFN gamma-treated U937 cells can serve as a model of human adult microglia to study cytokine generation in response to interactions with activated T cells.
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PMID:Cytokine production consequent to T cell--microglia interaction: the PMA/IFN gamma-treated U937 cells display similarities to human microglia. 1127 68

Oral tolerance is a long recognized method to induce peripheral immune tolerance. Oral tolerance has been used successfully to treat animal models of autoimmune diseases and is being tested in human diseases. Low doses of oral antigen induce active suppression, whereas high doses induce clonal anergy and deletion. Oral antigen preferentially generates a Th2(IL-4/IL-10)- or a Th3(TGF-beta)-type response. Th3-type cells are a unique T-cell subset which primarily secrete TGF-beta, provide help for IgA and have suppressive properties for Th1 and other immune cells. Th3-type cells appear distinct from the Th2 cells as CD4(+) TGF-beta-secreting cells with suppressive properties in the gut have been generated from IL-4-deficient animals. In vitro differentiation of Th3-type cells from Th0 precursors from TCR transgenic mice is enhanced by culture with TGF-beta, IL-4, IL-10 and anti-IL-12. Because regulatory T cells generated by oral antigen are triggered in an antigen-specific fashion but suppress in an antigen-nonspecific fashion, they mediate bystander suppression when they encounter the fed autoantigen at the target organ. Thus, mucosal tolerance can be used to treat inflammatory processes that are not autoimmune in nature. Mucosal antigen has also been used to treat animal models of stroke and of Alzheimer's disease. Induction of low-dose oral tolerance is enhanced by oral administration of IL-4 and IL-10. Coupling antigen to CTB or administration of Flt-3 ligand enhances oral tolerance. Anti-B7.2 but not anti-B7.1 blocks low-dose, but not high-dose oral tolerance. High-dose oral tolerance is blocked by anti-CTLA-4. CD25(+) CD4(+) regulatory T-cell function also appears to be related to TFG-beta.
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PMID:Oral tolerance: immune mechanisms and the generation of Th3-type TGF-beta-secreting regulatory cells. 1156 43

Stroke is a common cause of death and disability in our society. Stroke is associated with changes in immune responses within the central nervous system as well as systemically. The cells contributing to such changes as well as the factors contributing to formation of the inflammatory infiltrate observed in stroke remain to be clarified. In this study, blood monocytes and corresponding mononuclear cells (MNC) were separated and examined in parallel within 4 days and 1-3 months after onset of ischemic stroke. Numbers of TNF-alpha-, IL-12-, IL-6-, and IL-10-secreting cells and of cells expressing mRNA for matrix metalloproteinase (MMP)-1, -2, -7, -9 and tissue inhibitor of MMP (TIMP)-1 were studied. The TNF-alpha-, IL-12-, and IL-6-secreting monocytes and MNC were elevated during the acute phase compared to healthy controls. Such differences were not observed when stroke patients were examined during convalescence. The IL-10-secreting monocytes did not change over the course of stroke. Levels of monocytes expressing MMP-1, MMP-7 and TIMP-1 mRNA were elevated in the acute phase of stroke patients compared to convalescence and healthy controls, as were levels of MMP-1, -2, -7, -9 and TIMP-1 mRNA expressing blood MNC. The MMP-2 and -9 activity as measured by zymography also was higher in MNC supernatants in the acute phase of stroke compared to convalescence. The high levels of proinflammatory cytokines and MMPs in blood monocytes and MNC further demonstrate the presence of systemic aberrations in the acute phase of stroke. Such changes may contribute to the influx of blood-borne cells into the ischemic lesions during the acute phase of stroke.
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PMID:Matrix metalloproteinase and cytokine profiles in monocytes over the course of stroke. 1172 9

Interleukin (IL)-10 is synthesized in the central nervous system (CNS) and acts to limit clinical symptoms of stroke, multiple sclerosis, Alzheimer's disease, meningitis, and the behavioral changes that occur during bacterial infections. Expression of IL-10 is elevated during the course of most major diseases in the CNS and promotes survival of neurons and all glial cells in the brain by blocking the effects of proapoptotic cytokines and by promoting expression of cell survival signals. Stimulation of IL-10 receptors regulates numerous life- or death-signaling pathways--including Jak1/Stat3, PI 3-kinase, MAPK, SOCS, and NF-kappaB--ultimately promoting cell survival by inhibiting both ligand- and mitochondrial-induced apoptotic pathways. IL-10 also limits inflammation in the brain; it does so by three major pathways: (1) reducing synthesis of proinflammatory cytokines, (2) suppressing cytokine receptor expression, and (3) inhibiting receptor activation. Finally, IL-10 induces anergy in brain-infiltrating T cells by inhibiting cell signaling through the costimulatory CD28-CD80/86 pathway. The multiple functions of IL-10 in the brain will create new and intriguing vistas that will promote a better understanding of neurodegenerative diseases. These discoveries could lead to development of innovative approaches for the use of antiinflammatory cytokines in major debilitating diseases of the CNS.
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PMID:Interleukin-10 in the brain. 1194 58

Enriched populations of human microglial cells were isolated from mixed cell cultures prepared from embryonic human telencephalon tissues. Human microglial cells exhibited cell type-specific antigens for macrophage-microglia lineage cells including CD11b (Mac-1), CD68, B7-2 (CD86), HLA-ABC, HLA-DR and ricinus communis aggulutinin lectin-1 (RCA-1), and actively phagocytosed latex beads. Gene expression and protein production of cytokines, chemokines and cytokine/chemokine receptors were investigated in the purified populations of human microglia. Normal unstimulated human microglia expressed constitutively mRNA transcripts for interleukin- 1beta (IL-1beta) -6, -8, -10, -12, -15, tumor necrosis factor-alpha (TNF-alpha), macrophage inflammatory protein-1alpha (MIP-1alpha), MIP-1beta, and monocyte chemoattractant protein-1 (MCP-1), while treatment with lipopolysaccharide (LPS) or amyloid beta peptides (Abeta) led to increased expression of mRNA levels of IL-8, IL-10, IL-12, TNF-alpha, MIP-1alpha, MIP-1beta, and MCP-1. Human microglia, in addition, expressed mRNA transcripts for IL-1RI, IL-1RII, IL-5R, IL-6R, IL-8R, IL-9R, IL-10R, IL-12R, IL-13R, and IL-15R. Enzyme-linked immunosorbent assays (ELISA) showed increased protein levels in culture media of IL-1beta, IL-8, TNF-alpha, and MIP-1alpha in human microglia following treatment with LPS or Abeta. Increased TNF-alpha release from human microglia following LPS treatment was completely inhibited with IL-10 pretreatment, but not with IL-6, IL-9, IL-12, IL-13, or transforming growth factor-beta (TGF-beta). Present results should help in understanding the basic microglial biology, but also the pathophysiology of activated microglia in neurological diseases such as Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, stroke, and neurotrauma.
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PMID:Cytokines, chemokines, and cytokine receptors in human microglia. 1211 20

We sought to assess the anti-inflammatory properties of unfractionated heparin (UFH) in patients with ischemic stroke treated within 24 h from the onset of symptoms. We studied prospectively 167 patients that received 1000 IU/h intravenous UFH (n=70) or 300 mg oral aspirin (n=97) at a mean treatment delay of 6.7 h. Repeated plasma levels of interleukin (IL)-6, IL-10, IL-4, tumor necrosis factor (TNF)-alpha, soluble intercellular adhesion molecule-1 (sICAM-1), and soluble vascular cell adhesion molecule-1 (sVCAM-1) were compared in both groups using multivariate analyses. Whereas TNF-alpha and sICAM-1 decreased at 48 h, IL-6, IL-4, and sVCAM-1 increased compared with baseline values (P<0.01). The rise of sVCAM-1 levels at 48 h was significantly lower in patients treated with UFH (P=0.017) and a two-fold increase of baseline sVCAM-1 was an independent predictor of poor outcome (odds ratio, 2.19, 1.1-4.39). These results suggest that adjusted high-dose UFH has anti-inflammatory effects which might improve recovery if administered early after stroke onset.
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PMID:Unfractionated heparin is associated with a lower rise of serum vascular cell adhesion molecule-1 in acute ischemic stroke patients. 1214 13


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