Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10145 (IL-8)
 23,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nuclear factor-kappa B (NF-kappaB) is a transcription factor that resides in the cytoplasm of every cell and translocates to the nucleus when activated. Its activation is induced by a wide variety of agents including stress, cigarette smoke, viruses, bacteria, inflammatory stimuli, cytokines, free radicals, carcinogens, tumor promoters, and endotoxins. On activation, NF-kappaB regulates the expression of almost 400 different genes, which include enzymes (e.g., COX-2, 5-LOX, and iNOS), cytokines (such as TNF, IL-1, IL-6, IL-8, and chemokines), adhesion molecules, cell cycle regulatory molecules, viral proteins, and angiogenic factors. The constitutive activation of NF-kappaB has been linked with a wide variety of human diseases, including asthma, atherosclerosis, AIDS, rheumatoid arthritis, diabetes, osteoporosis, Alzheimer's disease, and cancer. Several agents are known to suppress NF-kappaB activation, including Th2 cytokines (IL-4, IL-13, and IL-10), interferons, endocrine hormones (LH, HCG, MSH, and GH), phytochemicals, corticosteroids, and immunosuppressive agents. Because of the strong link of NF-kappaB with different stress signals, it has been called a "smoke-sensor" of the body.
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PMID:Transcription factor NF-kappaB: a sensor for smoke and stress signals. 1638 90

The notion that microvascular abnormalities contribute to deleterious changes in the Alzheimer's disease (AD) brain is supported by work from our laboratory and others demonstrating biochemical and functional alterations of the microcirculation in AD. The objective of this study is to determine whether levels of neurotoxic (thrombin) and inflammatory (interleukin 8 (IL-8), integrins alphaVbeta3 and alphaVbeta5) proteins are altered in microvessels isolated from AD patients compared to levels in vessels obtained from non-demented age-matched controls. We also evaluate in AD and control microvessels expression of the transcription factor hypoxia-inducible factor 1-alpha(HIF1-alpha), which regulates pro-inflammatory gene expression, and the regulation of HIF1-alpha expression by thrombin in cultured brain endothelial cells. Our results indicate that in AD there are high levels of expression of the neurotoxic protease thrombin and the inflammation-associated proteins IL-8 and alphaVbeta3 and alphaVbeta5 integrins. HIF1-alpha is higher in AD microvessels compared to control and thrombin treatment of cultured brain endothelial cells results in increased expression of HIF1-alpha. These data suggest that in AD the cerebral microcirculation is a source of neurotoxic and inflammatory mediators and as such contributory to pathologic processes ongoing in the AD brain.
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PMID:Thrombin and inflammatory proteins are elevated in Alzheimer's disease microvessels: implications for disease pathogenesis. 1662 34

Jeongshintang (JST) is a Korean herbal prescription, which has been successfully used for cerebral diseases. However, the anti-inflammatory effect of JST on Alzheimer's disease (AD) is still not fully understood. In this study, we investigated the effects of JST in attenuating the inflammatory response induced by interleukin (IL)-1beta plus beta-amyloid [1-42] fragment (A beta) in the human astrocyte cell line, U373MG. The production of IL-6, IL-8, and prostaglandin (PG)E2 was significantly increased by IL-1beta plus A beta (1-42) in a time-dependent manner (P < 0.05). JST significantly inhibited the IL-1beta plus A beta (1-42)-induced IL-6, IL-8, and PGE2 production at 24 h (P < 0.05). Maximal inhibition rate of IL-6, IL-8, and PGE2 production by JST was about 54.40%, 56.01%, and 44.06% respectively. JST (0.01-1 mg/ml) also attenuated the expression of cyclooxygenase (COX)-2 and activation of p38 MAPK induced by IL-1beta and A beta (1-42). These results demonstrated that JST has an anti-inflammatory effect, which might explain its beneficial effect in the treatment of various neurodegenerative diseases such as AD.
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PMID:Anti-inflammatory effect of jeongshintang through suppression of p38 activation in human astrocytoma, U373MG cells. 1669 13

Recent studies indicate that chronic inflammation plays a pathogenic role in both the central nervous system (CNS) and periphery in Alzheimer's disease (AD). We have screened for cytokines differentially produced by peripheral blood mononuclear cells (PBMCs) isolated from subjects with mild cognitive impairment (MCI) and mild AD subjects who had progressed from MCI using a commercially available cytokine array. Following determination of expressed cytokines, we quantified levels of the proinflammatory cytokines TNF-alpha, IL-6, and IL-8, and the anti-inflammatory cytokine IL-10 using flow cytometry. We have found a significant increase in the levels of IL-6, IL-8, and IL-10 produced by PBMCs stimulated for 24 h with phytohemagglutinin (PHA) in MCI subjects compared to healthy elderly controls. However, in PBMCs stimulated for 48 h with lipopolysaccharide (LPS), lower TNF-alpha/IL-10, IL-6/IL-10, and IL-8/IL-10 ratios were seen in MCI subjects. There were no differences in plasma levels of IL-8 between aged controls, MCI, and mild AD, and the levels of circulating IL-6 and IL-10 were below detection limits. Our data indicate that changes in cytokine production by PBMCs may be detected early in MCI, and an alteration of the immune response may precede clinical AD.
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PMID:Increased production of inflammatory cytokines in mild cognitive impairment. 1708 1

We investigated the modulating actions of the nonselective K(+) channel blocker 4-aminopyridine (4-AP) on amyloid beta (Abeta(1-42))-induced human microglial signaling pathways and functional processes. Whole-cell patch-clamp studies showed acute application of Abeta(1-42) (5 mum) to human microglia led to rapid expression of a 4-AP-sensitive, non-inactivating outwardly rectifying K(+) current (I(K)). Intracellular application of the nonhydrolyzable analog of GTP, GTPgammaS, induced an outward K(+) current with similar properties to the Abeta(1-42)-induced I(K) including sensitivity to 4-AP (IC(50) = 5 mm). Reverse transcriptase-PCR showed a rapid expression of a delayed rectifier Kv3.1 channel in Abeta(1-42)-treated microglia. Abeta(1-42) peptide also caused a slow, progressive increase in levels of [Ca(2+)](i) (intracellular calcium) that was partially blocked by 4-AP. Chronic exposure of human microglia to Abeta(1-42) led to enhanced p38 mitogen-activated protein kinase and nuclear factor kappaB expression with factors inhibited by 4-AP. Abeta(1-42) also induced the expression and production of the pro-inflammatory cytokines interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha, the chemokine IL-8, and the enzyme cyclooxygenase-2; 4-AP was effective in reducing all of these pro-inflammatory mediators. Additionally, toxicity of supernatant from Abeta(1-42)-treated microglia on cultured rat hippocampal neurons was reduced if 4-AP was included with peptide. In vivo, injection of Abeta(1-42) into rat hippocampus induced neuronal damage and increased microglial activation. Daily administration of 1 mg/kg 4-AP was found to suppress microglial activation and exhibited neuroprotection. The overall results suggest that 4-AP modulation of an Abeta(1-42)-induced I(K) (candidate channel Kv3.1) and intracellular signaling pathways in human microglia could serve as a therapeutic strategy for neuroprotection in Alzheimer's disease pathology.
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PMID:Broad-spectrum effects of 4-aminopyridine to modulate amyloid beta1-42-induced cell signaling and functional responses in human microglia. 1709 87

Curcumin (diferuloylmethane) is an orange-yellow component of turmeric (Curcuma longa), a spice often found in curry powder. Traditionally known for its an antiinflammatory effects, curcumin has been shown in the last two decades to be a potent immunomodulatory agent that can modulate the activation of T cells, B cells, macrophages, neutrophils, natural killer cells, and dendritic cells. Curcumin can also downregulate the expression of various proinflammatory cytokines including TNF, IL-1, IL-2, IL-6, IL-8, IL-12, and chemokines, most likely through inactivation of the transcription factor NF-kappaB. Interestingly, however, curcumin at low doses can also enhance antibody responses. This suggests that curcumin's reported beneficial effects in arthritis, allergy, asthma, atherosclerosis, heart disease, Alzheimer's disease, diabetes, and cancer might be due in part to its ability to modulate the immune system. Together, these findings warrant further consideration of curcumin as a therapy for immune disorders.
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PMID:"Spicing up" of the immune system by curcumin. 1721 25

Epigallocatechin-3-gallate (EGCG) is the major polyphenol component of green tea and is primarily responsible for the green tea effect. EGCG possesses two triphenolic groups in its structure. These groups are reported to be important with respect to anticarcinogenic and antioxidant effects. However, the anti-inflammatory effect of EGCG on Alzheimer's disease (AD) is still not fully understood. In this study, we investigated the effects of EGCG in attenuating the inflammatory response induced by interleukin (IL)-1beta+beta-amyloid (25-35) fragment (Abeta) in human astrocytoma, U373MG cells. EGCG significantly inhibited the IL-1beta+Abeta (25-35)-induced IL-6, IL-8, vascular endothelial growth factor (VEGF) and prostaglandin (PG)E(2) production at 24 h (P<.01). The maximal inhibition rate of IL-6, IL-8, VEGF and PGE(2) production by EGCG was approximately 54.40%, 56.01%, 69.06% and 47.03%, respectively. EGCG also attenuated the expression of cyclooxygenase-2 and activation of nuclear factor-kappaB induced by IL-1beta+Abeta (25-35). We demonstrated that EGCG suppresses IL-1beta+Abeta (25-35)-induced phosphorylation of the mitogen-activated protein kinase p38 and the c-Jun N-terminal kinase. In addition, EGCG induced the expression of mitogen-activated protein kinase phosphatase-1. These results provide new insight into the pharmacological actions of EGCG and its potential therapeutic application to various neurodegenerative diseases such as AD.
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PMID:Epigallocatechin-3-gallate suppresses NF-kappaB activation and phosphorylation of p38 MAPK and JNK in human astrocytoma U373MG cells. 1744 59

Inflammatory mediators are highly expressed in the Alzheimer's disease (AD) brain. We have shown that in AD the cerebral microcirculation is a rich source of cytokines and chemokines including interleukins (IL) 1beta, IL-6, IL-8, tumor necrosis factor-alpha, and monocyte chemoattractant protein-1. However, the factors that regulate expression of these inflammatory proteins have not been defined. The objective of this study is to compare expression of macrophage inflammatory protein 1-alpha (MIP-1alpha) in brain microvessels isolated from AD patients to vessels from age-matched controls and further to determine whether expression of MIP-1alpha in brain endothelial cells is altered by oxidative stress. The data show that brain AD-derived microvessels express high levels of MIP-1alpha mRNA and release high levels of MIP-1alpha protein compared to brain microvessels isolated from controls. Treatment of brain endothelial cell cultures with menadione, a superoxide releasing compound, hydrogen peroxide, lipopolysacharride, or oxidatively modified low density lipoproteins (LDL) (Ox-LDL, HNE-LDL) results in a dose- dependent increase in MIP-1alpha mRNA levels and MIP-1alpha release into the media. These results suggest that oxidative and lipid insults to the brain microvasculature are likely to contribute to the inflammatory milieu of the AD brain.
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PMID:Expression of macrophage inflammatory protein 1-alpha is elevated in Alzheimer's vessels and is regulated by oxidative stress. 1765 23

Neuronal cell loss is a critical feature of age-related neurodegenerative diseases such as Alzheimer's disease (AD). In the AD brain, a marked increase in pro-inflammatory cytokines and chemokines, including IL-8, has been documented. The objective of this study was to determine the effect of IL-8 on cell viability and expression of neurotoxic, apoptotic, and cell cycle proteins in cultured neurons. Incubation of cultured neurons with IL-8 for 24 h resulted in neuronal cell death. RT-PCR analysis of primary rat neuronal cultures treated with IL-8 for 24 h showed induction of genes for matrix metalloproteinases (MMP-2 and MMP-9), proinflammatory proteases with neurotoxic properties. Gelatin zymography demonstrated IL-8 induced MMP-2 and MMP-9 activity. Western blot analysis showed that IL-8 also increased levels of the pro-apoptotic protein Bim (Bcl-2-interacting mediator of cell death). In addition, message levels of the cell cycle protein cyclin D1, an early marker for G1/S transition and a protein implicated as a regulator of neuronal apoptosis, were elevated after IL-8 exposure. These results suggest that IL-8 could be an important mediator of neuronal death in AD both via its effects on release of neurotoxins such as MMPs as well as by induction of cell cycle and pro-apoptotic proteins.
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PMID:IL-8 induces expression of matrix metalloproteinases, cell cycle and pro-apoptotic proteins, and cell death in cultured neurons. 1785 Nov 81

The role of chronic inflammation in the pathogenesis of Alzheimer's disease (AD) has been implied in a plethora of studies. The objective of the present study was to evaluate the immune alterations and the immunological markers in patients suffering from AD. IL-1alpha, IL-2, IL-6, IL-8, IL-10, TNF-alpha cytokine and helper/inducer (CD4), suppressor/cytotoxic (CD8) T lymphocyte levels were investigated in patients with various degrees of cognitive impairment (mild-moderate and severe stage), as well as in age-matched non demented controls. Cytokines were measured using the ELISA immunoassay method and lymphocytes using flow cytometry. Results showed a significant TNF-alpha increase in patients of severe stage serum compared to controls as well as a significant decrease of CD4 lymphocyte subpopulation levels in patients of severe stage compared to those of mild-moderate stage patients and controls. No significant differences were observed on IL-1alpha, IL-2, IL-6, IL-8, IL-10 cytokine levels and on CD8, CD4/CD8 lymphocyte subpopulations levels between patients and controls neither between mild moderate and severe stage patients. CD4 lymphocyte subpopulation and cytokine IL-2 were revealed as having a significant relationship (positive and negative respectively) with the MMSE score of patients. Data suggest the existence of detectable changes of peripheral immune system in AD.
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PMID:Systemic immune aberrations in Alzheimer's disease patients. 1803 2


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