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

ATP is abundantly released from stressed or damaged cells in response to mechanical stimulation, bacteria, or noxious agents. In this study, we have investigated the possible involvement of P2 receptors (receptor for extracellular nucleotides) in the expression and release of inflammatory mediators by human keratinocytes. Notably, extracellular ATP displayed a complex regulation of IFN-gamma-stimulated chemokine expression, with upregulation of CC chemokine ligand 2 (CCL2), CCL5 and CXC chemokine ligand 8 (CXCL8), and suppression of the receptor CXC chemokine receptor 3 (CXCR3), CXCL9, CXCL10, and CXCL11. The effect of ATP was mimicked by ADP and adenosine-5'-O-3-thiotriphosphate, whereas 2',3'-O-(4-benzoylbenzoyl) ATP (BzATP) downmodulated all chemokines investigated. UTP had no effect on IFN-gamma-stimulated chemokine secretion. The broad-spectrum P2 receptor antagonist suramin and the selective P2Y1 inhibitor adenosine 3'-phosphate 5'-phosphosulfate counteracted the effect of ATP on secretion of all the chemokines examined, whereas pyridoxal phosphate 6-azophenyl 2',4'-disulfonic acid and KN62 (1-[N,O-bis(5-isoquinoline sulfonyl)-N-methyl-L-tyrosyl] 4 phenylpiperazine) partially prevented the inhibitory effect of ATP on CXCL10 secretion, but on the other hand potentiated the ATP-stimulatory effect on CCL5, CCL2, and CXCL8 release. In lesional skin of psoriasis and atopic dermatitis patients, intense P2X7 reactivity was confined to the cell membrane of the basal layer, whereas diffuse P2Y1 immunostaining was found throughout the epidermis. Collectively, our data suggest that the orchestrated activation of distinct P2Y and P2X receptors modulates skin inflammation.
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PMID:Stimulation of purinergic receptors modulates chemokine expression in human keratinocytes. 1703 39

Type 2 diabetes is associated with decreased levels of the glycosphingolipid sulfatide, as well as a state of low-grade inflammation. Sulfatide is reported to have anti-inflammatory properties in other cell-types. In the present study, the effects of sulfatide on adipokine (adiponectin, TNF-alpha, IL-6, and IL-8) production in human adipose tissue (AT) was investigated in vitro. Isolated human adipocytes and AT cultures were incubated with sulfatide isolated from pig brain [sulfatide containing a variety of fatty acids or isoforms of sulfatide with defined, saturated fatty acids with 16 (C16:0) or 24 (C24:0) carbon atoms]. Adiponectin production was increased 50-80%, by all sulfatide preparations. Only the C16:0 isoform decreased TNF-alpha, IL-6, and IL-8 production 20-30%. The C16:0 sulfatide has been shown to activate potassium channels in beta-cells, and glibenclamide, an ATP-sensitive K+-(KATP) channel blocker, reversed the C16:0-induced decrement in stimulated TNF-alpha, IL-6, and IL-8 release in adipocytes. Glibenclamide on its own was without effect on the production of adiponectin, TNF-alpha, IL-6, and IL-8. In conclusion, this study shows that, sulfatide exerts anti-inflammatory effects in human adipocytes and AT in vitro. Accordingly, the reported low serum levels of sulfatide in patients with type 2 diabetes might be of importance in relation to the chronic low-grade inflammatory state found in this disease.
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PMID:Sulfatide increases adiponectin and decreases TNF-alpha, IL-6, and IL-8 in human adipose tissue in vitro. 1709 22

Sirolimus is a potent immunosuppressive agent and has an anti-atherosclerotic effect through its anti-proliferative property. The present study was undertaken to investigate the effect of sirolimus on intracellular cholesterol homeostasis in human vascular smooth muscle cells (VSMCs) in the presence of inflammatory cytokine IL-1 beta. We explored the effect of sirolimus on the lipid accumulation of VSMCs in the presence of IL-1 beta, using Oil Red O staining and quantitative measurement of intracellular cholesterol. The effect of sirolimus on the gene and protein expression of lipoprotein receptors and ATP binding cassettes (ABCA1 and ABCG1) was examined by real-time PCR and Western blotting, respectively. Furthermore, the effect of sirolimus on cholesterol efflux from VSMCs in the presence or absence of IL-1 beta was also investigated using [(3)H] cholesterol efflux. Finally, we examined the effect of sirolimus on the production of inflammatory cytokines in VSMCs using ELISA. Sirolimus reduced intracellular lipid accumulation in VSMCs mediated by IL-1 beta possibly due to the reduction of expression of low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) receptors. Sirolimus increased cholesterol efflux from VSMCs and overrode the suppression of cholesterol efflux induced by IL-1 beta. Sirolimus also increased ABCA1 and ABCG1 genes expression, even in the presence of IL-1 beta. We further confirmed that sirolimus inhibited mRNA and protein expression of inflammatory cytokines IL-6, tumor necrosis factor-alpha, IL-8, and monocyte chemoattractant protein-1. Inhibition of lipid uptake together with increasing cholesterol efflux and the inhibition of inflammatory cytokines are all important aspects of the anti-atherosclerotic effects of sirolimus on VSMCs.
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PMID:Anti-atherosclerotic effects of sirolimus on human vascular smooth muscle cells. 1732 16

Histone chaperones assemble and disassemble nucleosomes in an ATP-independent manner and thus regulate the most fundamental step in the alteration of chromatin structure. The molecular mechanisms underlying histone chaperone activity remain unclear. To gain insights into these mechanisms, we solved the crystal structure of the functional domain of SET/TAF-Ibeta/INHAT at a resolution of 2.3 A. We found that SET/TAF-Ibeta/INHAT formed a dimer that assumed a "headphone"-like structure. Each subunit of the SET/TAF-Ibeta/INHAT dimer consisted of an N terminus, a backbone helix, and an "earmuff" domain. It resembles the structure of the related protein NAP-1. Comparison of the crystal structures of SET/TAF-Ibeta/INHAT and NAP-1 revealed that the two proteins were folded similarly except for an inserted helix. However, their backbone helices were shaped differently, and the relative dispositions of the backbone helix and the earmuff domain between the two proteins differed by approximately 40 degrees . Our biochemical analyses of mutants revealed that the region of SET/TAF-Ibeta/INHAT that is engaged in histone chaperone activity is the bottom surface of the earmuff domain, because this surface bound both core histones and double-stranded DNA. This overlap or closeness of the activity surface and the binding surfaces suggests that the specific association among SET/TAF-Ibeta/INHAT, core histones, and double-stranded DNA is requisite for histone chaperone activity. These findings provide insights into the possible mechanisms by which histone chaperones assemble and disassemble nucleosome structures.
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PMID:Relationship between the structure of SET/TAF-Ibeta/INHAT and its histone chaperone activity. 1736 May 16

Previous reports have shown that cellular functions could be influenced by visual light (400-700 nm). Recent evidence indicates that cellular proliferation could be triggered by the interaction of a helium-neon laser (He-Ne laser, 632.8 nm) with the mitochondrial photoacceptor-cytochrome c oxidase. Our previous studies demonstrated that He-Ne irradiation induced an increase in cell proliferation, but not migration, in the melanoma cell line A2058 cell. The aim of this study was to investigate the underlying mechanisms involved in photostimulatory effects induced by an He-Ne laser. Using the A2058 cell as a model for cell proliferation, the photobiologic effects induced by an He-Ne laser were studied. He-Ne irradiation immediately induced an increase in mitochondrial membrane potential (delta psi(mt)), ATP, and cAMP via enhanced cytochrome c oxidase activity and promoted phosphorylation of Jun N-terminal kinase (JNK)/activator protein-1 (AP-1) expressions. He-Ne irradiation-induced A2058 cell proliferation was significantly abrogated by the addition of delta psi(mt) and JNK inhibitors. Moreover, treatment with an He-Ne laser resulted in delayed effects on IL-8 and transforming growth factor-beta1 release from A2058 cells. These results suggest that He-Ne irradiation elicits photostimulatory effects in mitochondria processes, which involve JNK/AP-1 activation and enhanced growth factor release, and ultimately lead to A2058 cell proliferation.
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PMID:Helium-neon laser irradiation stimulates cell proliferation through photostimulatory effects in mitochondria. 1744

The neuroendocrine system affects the immune system through the neuroendocrine humoral outflow via the pituitary, and through direct neuronal influences via the sympathetic, parasympathetic (cholinergic) and peptidergic/sensory innervation of peripheral tissues. Circulating hormones or locally released neurotransmitters and neuropeptides regulate major immune functions, such as antigen presentation, antibody production, lymphocyte activity, proliferation and traffic, and the secretion of cytokines including the selection of T helper (Th)1 or Th2 cytokine responses. During inflammation, the activation of the stress system, through induction of a Th2 shift protects the organism from systemic "overshooting" with Th1/pro-inflammatory cytokines. Under certain conditions, however, stress hormones, substance P, ATP and the activation of the corticotropin-releasing hormone/substance P-histamine axis may actually facilitate inflammation, through induction of interleukin (IL)-1, IL-6, IL-8, IL-18, tumor necrosis factor (TNF)-alpha and CRP production. Thus, a dysfunctional neuroendocrine-immune interface associated with abnormalities of the 'systemic anti-inflammatory feedback' and/or 'hyperactivity' of the local pro-inflammatory factors may play a role in the pathogenesis of atopic/allergic and autoimmune diseases, obesity, depression and atherosclerosis. Better understanding of the neuroendocrine control of inflammation may provide critical insights into mechanisms underlying a variety of common human immune-related diseases.
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PMID:Neurohormonal-cytokine interactions: implications for inflammation, common human diseases and well-being. 1771 84

We tested whether cystic fibrosis (CF) airway epithelia have larger innate immune responses than non-CF or cystic fibrosis transmembrane conductance regulator (CFTR)-corrected cells, perhaps resulting from ER stress due to retention of DeltaF508CFTR in the endoplasmic reticulum (ER) and activation of cytosolic Ca(2+) (Ca(i)) and nuclear factor (NF)-kappaB signaling. Adenovirus infections of a human CF (DeltaF508/DeltaF508) nasal cell line (CF15) provided isogenic comparisons of wild-type (wt) CFTR and DeltaF508CFTR. In the absence of bacteria, there were no or only small differences among CF15, CF15-lacZ (beta-galactosidase-expressing), CF15-wtCFTR (wtCFTR-corrected), and CF15-DeltaF508CFTR (to test ER retention of DeltaF508CFTR) cells in NF-kappaB activity, interleukin (IL)-8 secretion, Ca(i) responses, and ER stress. Non-CF and CF primary cultures of human bronchial epithelial cells (HBE) secreted IL-8 equivalently. Upon infection with Pseudomonas aeruginosa (PA) or flagellin (key activator for airway epithelia), CF15, CF15-lacZ, CF15-wtCFTR, and CF15DeltaF508CFTR cells exhibited equal PA binding, NF-kappaB activity, and IL-8 secretion; cells also responded similarly to flagellin when both CFTR (forskolin) and Ca(i) signaling (ATP) were activated. CF and non-CF HBE responded similarly to flagellin + ATP. Thapsigargin (Tg, releases ER Ca(2+)) increased flagellin-stimulated NF-kappaB and ER stress similarly in all cells. We conclude that ER stress, Ca(i), and NF-kappaB signaling and IL-8 secretion were unaffected by wt- or DeltaF508CFTR in control and during exposure to PA, flagellin, flagellin + ATP, or flagellin + ATP + forskolin. Tg, but not wt- or DeltaF508CFTR, triggered ER stress. Previous measurements showing hyperinflammatory responses in CF airway epithelia may have resulted from cell-specific, rather than CFTR- or DeltaF508CFTR-specific effects.
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PMID:Effects of cystic fibrosis transmembrane conductance regulator and DeltaF508CFTR on inflammatory response, ER stress, and Ca2+ of airway epithelia. 1782 50

RecA family proteins engage in an ATP-dependent DNA strand exchange reaction that includes a ssDNA nucleoprotein helical filament and a homologous dsDNA sequence. In spite of more than 20 years of efforts, the molecular mechanism of homology pairing and strand exchange is still not fully understood. Here we report a crystal structure of Sulfolobus solfataricus RadA overwound right-handed filament with three monomers per helical pitch. This structure reveals conformational details of the first ssDNA binding disordered loop (denoted L1 motif) and the dsDNA binding N-terminal domain (NTD). L1 and NTD together form an outwardly open palm structure on the outer surface of the helical filament. Inside this palm structure, five conserved basic amino acid residues (K27, K60, R117, R223 and R229) surround a 25 A pocket that is wide enough to accommodate anionic ssDNA, dsDNA or both. Biochemical analyses demonstrate that these five positively charged residues are essential for DNA binding and for RadA-catalyzed D-loop formation. We suggest that the overwound right-handed RadA filament represents a functional conformation in the homology search and pairing reaction. A new structural model is proposed for the homologous interactions between a RadA-ssDNA nucleoprotein filament and its dsDNA target.
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PMID:Structural and functional analyses of five conserved positively charged residues in the L1 and N-terminal DNA binding motifs of archaeal RADA protein. 1784 89

Our results demonstrate the first findings of expression and function of the purinergic P2X7 receptor (P2X7R) in rat C6 glioma cells. P2X7R mRNA and protein were present in unstimulated C6 cells and were up-regulated by cell exposure to the P2X7R agonist, 2',3'-(benzoyl-4-benzoyl)-ATP (BzATP). Activation of P2X7R in C6 in response to BzATP led to increased mobilization of intracellular calcium [Ca2+]i and formation of large pores. Chronic exposure of C6 cells to BzATP enhanced the expression of pro-inflammatory factors including MCP-1, IL-8 and VEGF. In a scratch-wound migration assay, the P2X7R was shown to regulate cell mobility. The overall results suggest that P2X7R activation in C6 is linked with increased pro-inflammatory factors and tumor cell migration.
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PMID:Expression and function of the P2X(7) receptor in rat C6 glioma cells. 1803 56

Dendritic cells (DCs), including Langerhans cells (LCs), play a critical role in the induction phase of allergic contact hypersensitivity. Following exposure to chemical allergens in the skin, LCs undergo a maturation process leading to the up-regulation of expression of co-stimulatory molecules, such as CD86, CD54 and CD40. Our previous study revealed that chemical allergens induce phenotype alterations (e.g., CD86, CD54 and CD40) and cytokine production (TNF-alpha and IL-8) in THP-1 cells that possibly reflect the maturation of dendritic cells during skin sensitization. However, the physiological signals for phenotypic alterations by chemical allergens are still not fully understood. Therefore, in this study, we investigated the effect of TNF-alpha and extracellular ATP on THP-1 cell activation induced by chemical allergens. Kinetic studies revealed that TNF-alpha and IL-8 release occurred in a time-dependent manner with release of two cytokines beginning at 3 hr post-exposure to well-known haptens, DNCB and NiSO(4). While recombinant human TNF-alpha augmented CD54 and CD40 expression in a dose-dependent manner, rhTNF-alpha did not increase CD86 expression. Furthermore, neutralization of TNF-alpha activity strongly inhibited CD54 and CD40 expression induced by allergens. On the contrary, extracellular ATP induced the up-regulation of both CD86 and CD54 expression. In the presence of the P2 receptor antagonist suramin, the up-regulation of CD86 and CD54 expression by allergens was in part suppressed. Therefore, we postulate that not only TNF-alpha but also extracellular ATP may contribute to cell activation following allergen stimulation, which might reflect the mechanism by which DCs respond to allergens.
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PMID:Role of TNF-alpha and extracellular ATP in THP-1 cell activation following allergen exposure. 1830 86


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