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)

Chemokines are key mediators of the selective migration of leukocytes that occurs in neurodegenerative diseases and related inflammatory processes. Astrocytes, the most abundant cell type in the CNS, have an active role in brain inflammation. To ascertain the role of astrocytes during neuropathological processes, we have investigated in two models of primary cells (human fetal and simian adult astrocytes) the repertoire of chemokines and their receptors expressed in response to inflammatory stimuli. We demonstrated that, in the absence of any stimulation, human fetal and simian adult astrocytes express mRNA for receptors APJ, BOB/GPR15, Bonzo/CXCR6, CCR2, CCR3, CCR5, CCR8, ChemR23, CXCR3/GPR9, CXCR4, GPR1, and V28/CX3CR1. Moreover, TNFalpha and IL-1beta significantly increase BOB/GPR15, CCR2, and V28/CX3CR1 mRNA levels in both models. Furthermore, TNFalpha and IFNgamma act synergistically to induce expression of the major coreceptors for HIV infection, CXCR4 and CCR5, at both the mRNA and protein levels in human and simian astrocytes, whereas CCR3 expression was not affected by cytokine treatment. Finally, TNFalpha/IFNgamma was the most significant cytokine combination in leading to a pronounced upregulation in a comparable, time-dependent manner of the production of chemokines IP-10/CXCL10, RANTES/CCL5, MIG/CXCL9, MCP-1/CCL2, and IL-8/CXCL8. In summary, these data suggest that astrocytes serve as an important source of chemokines under the dependence of a complex cytokine regulation, and TNFalpha and IFNgamma are important modulators of chemokines and chemokine receptor expression in human as well as simian astrocytes. Finally, with the conditions we used, there was no difference between species or age of tissue.
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PMID:Expression of chemokines and their receptors in human and simian astrocytes: evidence for a central role of TNF alpha and IFN gamma in CXCR4 and CCR5 modulation. 1255 3

Within the brain, quinolinic acid (QUIN) is an important neurotoxin, especially in AIDS dementia complex (ADC). Its production by monocytic lineage cells is increased in the context of inflammation. However, it is not known whether QUIN promotes inflammation. Astrocytes are important in immunoregulation within the brain and so we chose to examine the effects of QUIN on the astrocyte. Using purified primary human fetal astrocyte cultures, we determined chemokine production using ELISA assays and RT-PCR and chemokine receptor expression using immunocytochemistry and RT-PCR with QUIN in comparison to TNFalpha, IL-1beta, and IFNgamma. We found that QUIN induces astrocytes to produce large quantities of MCP-1 (CCL2) and lesser amounts of RANTES (CCL5) and IL-8 (CXCL8). QUIN also increases SDF-1alpha (CXCL12), HuMIG (CXCL9), and fractalkine (CX(3)CL1) mRNA expression. Moreover, QUIN leads to upregulation of the chemokine receptor expression of CXCR4, CCR5, and CCR3 in human fetal astrocytes. Most of these effects were comparable to those induced by TNFalpha, IL-1beta, and IFNgamma. The present work represents the first evidence that QUIN induces chemokine and chemokine receptor expression in astrocytes and is at least as potent as classical mediators such as inflammatory cytokines. These results suggest that QUIN may be critical in the amplification of brain inflammation, particularly in ADC.
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PMID:Quinolinic acid upregulates chemokine production and chemokine receptor expression in astrocytes. 1255 4

Toll-like receptors (TLRs) are pattern recognition receptors that serve an important function in detecting pathogens and initiating inflammatory responses. Upon encounter with foreign Ag, dendritic cells (DCs) go through a maturation process characterized by an increase in surface expression of MHC class II and costimulatory molecules, which leads to initiation of an effective immune response in naive T cells. The innate immune response to bacterial flagellin is mediated by TLR5, which is expressed on human DCs. Therefore, we sought to investigate whether flagellin could induce DC maturation. Immature DCs were cultured in the absence or presence of flagellin and monitored for expression of cell surface maturation markers. Stimulation with flagellin induced increased surface expression of CD83, CD80, CD86, MHC class II, and the lymph node-homing chemokine receptor CCR7. Flagellin stimulated the expression of chemokines active on neutrophils (IL-8/CXC chemokine ligand (CXCL)8, GRO-alpha/CXCL1, GRO-beta/CXCL2, GRO-gamma/CXCL3), monocytes (monocyte chemoattractant protein-1/CC chemokine ligand (CCL)2), and immature DCs (macrophage-inflammatory protein-1 alpha/CCL3, macrophage-inflammatory protein-1 beta/CCL4), but not chemokines active on effector T cells (IFN-inducible protein-10 kDa/CXCL10, monokine induced by IFN-gamma/CXCL9, IFN-inducible T cell alpha chemoattractant/CXCL11). However, stimulating DCs with both flagellin and IFN-inducible protein-10 kDa, monokine induced by IFN-gamma, and IFN-inducible T cell alpha chemoattractant expression, whereas stimulation with IFN-beta or flagellin alone failed to induce these chemokines. In functional assays, flagellin-matured DCs displayed enhanced T cell stimulatory activity with a concomitant decrease in endocytic activity. Finally, DCs isolated from mouse spleens or bone marrows were shown to not express TLR5 and were not responsive to flagellin stimulation. These results demonstrate that flagellin can directly stimulate human but not murine DC maturation, providing an additional mechanism by which motile bacteria can initiate an acquired immune response.
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PMID:The Toll-like receptor 5 stimulus bacterial flagellin induces maturation and chemokine production in human dendritic cells. 1273 64

Macrophages have a central role in innate-immune responses to bacteria. In the present work, we show that infection of human macrophages with Gram-positive pathogenic Streptococcus pyogenes or nonpathogenic Lactobacillus rhamnosus GG enhances mRNA expression of inflammatory chemokine ligands CCL2/monocyte chemoattractant protein-1 (MCP-1), CCL3/macrophage-inflammatory protein-1alpha (MIP-1alpha), CCL5/regulated on activation, normal T expressed and secreted, CCL7/MCP-3, CCL19/MIP-3beta, and CCL20/MIP-3alpha and CXC chemokine ligands CXCL8/interleukin (IL)-8, CXCL9/monokine induced by interferon-gamma (IFN-gamma), and CXCL10/IFN-inducible protein 10. Bacteria-induced CCL2, CCL7, CXCL9, and CXCL10 mRNA expression was partially dependent on ongoing protein synthesis. The expression of these chemokines and of CCL19 was dependent on bacteria-induced IFN-alpha/beta production. CCL19 and CCL20 mRNA expression was up-regulated by IL-1beta or tumor necrosis factor alpha (TNF-alpha), and in addition, IFN-alpha together with TNF-alpha further enhanced CCL19 gene expression. Synergy between IFN-alpha and TNF-alpha was also seen for CXCL9 and CXCL10 mRNA expression. Bacteria-stimulated macrophage supernatants induced the migration of T helper cell type 1 (Th1) cells, suggesting that in human macrophages, these bacteria can stimulate efficient inflammatory chemokine gene expression including those that recruit Th1 cells to the site of inflammation. Furthermore, L. rhamnosus-induced Th1 chemokine production could in part explain the proposed antiallergenic properties of this bacterium.
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PMID:Lactobacilli and streptococci induce inflammatory chemokine production in human macrophages that stimulates Th1 cell chemotaxis. 1294 43

Proteolytic processing is an important regulatory mechanism for chemokines. Matrix metalloproteinases (MMPs), such as gelatinase A/MMP-2 and gelatinase B/MMP-9, are known to process the aminoterminal end of various chemokines, including interleukin-8 (IL-8/CXCL-8) and monocyte chemotactic protein-3 (MCP-3/CXCL-7). In the present study, two proteases, gelatinase B and neutrophil collagenase/MMP-8, are shown for the first time to process the carboxyterminal end of two chemokines, monokine induced by interferon (IFN)-gamma (MIG/CXCL-9) and IFN-inducible protein-10 (IP-10/CXCL-10). Neutrophil collagenase degrades MIG into small fragments and cleaves IP-10 behind positions 71 and 73. Gelatinase B degrades IP-10 and cleaves MIG at three different sites in its extended carboxyterminal region. This results in the formation of MIG(1-94), MIG(1-93), and MIG(1-90). In general, gelatinase B was more efficient than neutrophil collagenase in processing these chemokines. Alignment of the CXC chemokines with the respective cleavage sites by both MMPs identified the ELR motif as a possible determinant for amino terminal cleavage by these MMPs.
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PMID:Carboxyterminal cleavage of the chemokines MIG and IP-10 by gelatinase B and neutrophil collagenase. 1455 Feb 88

CXC chemokines modulate host immunity, neovascularization, growth and invasive behaviour of tumours. Despite their relevance in tumour biology, chemokine expression in intestinal- and diffuse-type gastric carcinoma, which exhibit a completely different growth pattern, has not been investigated in detail. In this study, expression of the CXC chemokines CXCL8 [interleukin (IL)-8], CXCL1 [growth-related oncogene alpha (Gro alpha)], CXCL9 [monokine induced by interferon (IFN)-gamma] and CXCL10 [IFN-gamma-inducible protein-10 (IP-10)] and the corresponding chemokine receptors CXCR1-3 was investigated by immunohistochemistry in intestinal- and diffuse-type gastric carcinoma. Tumour cells of all patients expressed CXCL8. CXCL8 expression was significantly stronger in tumour cells of diffuse- rather than intestinal-type gastric carcinoma (P < 0.01) as determined by a semiquantitative score. CXCL1 was expressed almost exclusively by diffuse- but not intestinal-type carcinoma cells. The corresponding chemokine receptors, CXCR1 and CXCR2, were found on carcinoma cells. Furthermore, CXCL8 expression correlated with number of tumour vessels (P < 0.01), suggesting an angiogenetic function in gastric carcinoma not only in vitro but also in vivo. CXCL10 and CXCL9, attractants for T cells, were expressed by peritumorous macrophages in close proximity to IFN-gamma-producing CXCR3-positive T cells in both tumour types. These chemokines may attract gastric carcinoma-infiltrating T cells via an IFN-gamma-mediated pathway and enhance host immunity against the tumour. In gastric carcinoma a complex interplay between CXC-chemokine signals derived from both tumour cells and tumour-infiltrating immune cells may exhibit pleiotropic effects in tumour biology that go far beyond their originally described functions as leucocyte chemoattractants. Because CXCL8 and CXCL1, which are known to increase growth and invasive behaviour of malignant tumours, are significantly stronger expressed in diffuse- than intestinal-type gastric carcinoma, one may speculate that these chemokines influence the different growth pattern of gastric carcinoma types.
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PMID:Pleiotropic effects of CXC chemokines in gastric carcinoma: differences in CXCL8 and CXCL1 expression between diffuse and intestinal types of gastric carcinoma. 1463 59

The synovial cavity constitutes the ideal stage to study the interplay between microbial Toll-like receptor (TLR) ligands and cytokines. Infiltrated leukocytes and synovial fibroblasts produce cytokine- and chemokine-induced proteases for remodeling the extracellular matrix. The regulation of chemokine function for attraction and activation of leukocytes constitutes a key feature in host immunity and resolution of inflammation after infection. Enhanced levels of the CXC chemokine ligand (CXCL9)/monokine induced by interferon-gamma (IFN-gamma) and CXCL11/IFN-inducible T cell alpha chemoattractant, two chemoattractants for activated T cells and natural killer cells, and ligands for CXC chemokine receptor 3 (CXCR3) were detected in the synovial fluid of septic arthritis compared with osteo- and crystal arthritis patients. In vitro, IFN-gamma and TLR3 ligation by double-stranded RNA (dsRNA) induced the expression of CXCL9 and CXCL11 in leukocytes and skin-muscle fibroblasts, whereas ligation of TLR2, TLR4, TLR5, and TLR9 by peptidoglycan (PGN), lipopolysaccharide (LPS), flagellin, and unmethylated CpG oligonucleotides, respectively, did not. PGN and LPS, but not unmethylated CpG oligonucleotides, even inhibited IFN-gamma-induced CXCL9 and CXCL11 expression in leukocytes. In sharp contrast, in fibroblasts, the TLR ligands PGN, dsRNA, LPS, and flagellin synergized with IFN-gamma for the production of CXCL9 and CXCL11. Although TLR ligands stimulate leukocytes to produce CXCL8/interleukin-8 during the early innate defense, they contribute less to the production of CXCR3 ligands, whereas fibroblasts are important sources of CXCR3 ligands. These results illustrate the complex interaction between cytokines and TLR ligands in infection.
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PMID:Synergistic induction of CXCL9 and CXCL11 by Toll-like receptor ligands and interferon-gamma in fibroblasts correlates with elevated levels of CXCR3 ligands in septic arthritis synovial fluids. 1499 26

Tumour necrosis factor (TNF)-alpha is thought to play a major role in the pathophysiology of psoriasis. Good clinical responses of psoriasis to anti-TNF-alpha-based therapies have recently been demonstrated. We studied the effect of infliximab, a monoclonal antibody against TNF-alpha, on chemokine expression in pustular psoriasis. A 61-year-old man with a 2-year history of severe pustular psoriasis of von Zumbusch type who did not respond to conventional therapies responded rapidly to treatment with infliximab. The clinical response was reflected by an immediate and effective reduction of the neutrophil-attractant chemokines interleukin (IL)-8 and growth-related oncogene (Gro)-alpha as well as of monocyte chemoattractant protein (MCP)-1, as determined by mRNA in situ hybridization of lesional skin. No expression before or after treatment was seen for monokine induced by interferon (IFN)-gamma (MIG) and IFN-inducible protein (IP)-10. Thus, in pustular psoriasis the chemokine expression pattern is dominated by neutrophil-attractant chemokines and MCP-1 while, in contrast to plaque psoriasis, IFN-gamma-inducible lymphocyte-attractant chemokines such as IP-10 and MIG are not abundant. We conclude that anti-TNF-alpha treatment with infliximab is an effective therapy in severe pustular psoriasis which is reflected by downregulation of disease-promoting chemokines such as IL-8, Gro-alpha and MCP-1.
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PMID:Treatment of recalcitrant pustular psoriasis with infliximab: effective reduction of chemokine expression. 1514 18

Within the brain, quinolinic acid (QUIN) is an important neurotoxin, especially in AIDS dementia complex (ADC). Its production by monocytic lineage cells is increased in the context of inflammation. However, it is not known whether QUIN promotes inflammation. Astrocytes are important in immuno-regulation within the brain and so we chose to examine the effects of QUIN on the astrocyte. Using purified cultures of primary human foetal astrocyte, we determined chemokine production using ELISA assays and RT-PCR, and chemokine receptor expression using immunocytochemistry and RT-PCR with QUIN in comparison to TNF-alpha/IFN-gamma. We found that QUIN induces astrocytes to produce large quantities of MCP-1 (CCL2), and lesser amounts of RANTES (CCL5), IL-8 (CXCL8). QUIN also increases SDF-1alpha (CXCL12), HuMIG (CXCL9) and fractalkine (CX3CL1) mRNA expression. Moreover, QUIN leads to up-regulation of the chemokine receptor expression of CXCR4, CCR5, and CCR3 in human foetal astrocytes. Most of these effects were comparable to those induced by TNF-alpha/IFN-gamma. The present work represents the first evidence that QUIN induces chemokine and chemokine receptor expression in astrocytes and is at least as potent as classical mediators such as inflammatory cytokines. These results suggest that QUIN may be critical in the amplification of brain inflammation particularly in ADC.
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PMID:Quinolinic acid up-regulates chemokine production and chemokine receptor expression in astrocytes. 1520 14

CXCL11 (ITAC) is one of three chemokines known to bind the receptor CXCR3, the two others being CXCL9 (Mig) and CXCL10 (IP-10). CXCL11 differs from the other CXCR3 ligands in both the strength and the particularities of its receptor interactions: It has a higher affinity, is a stronger agonist, and behaves differently when critical N-terminal residues are deleted. The structure of CXCL11 was determined using solution NMR to allow comparison with that of CXCL10 and help elucidate the source of the differences. CXCL11 takes on the canonical chemokine fold but exhibits greater conformational flexibility than has been observed for related chemokines under the same sample conditions. Unlike related chemokines such as IP-10 and IL-8, ITAC does not appear to form dimers at millimolar concentrations. The origin for this behavior can be found in the solution structure, which indicates a beta-bulge in beta-strand 1 that distorts the dimerization interface used by other CXC chemokines.
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PMID:NMR structure of CXCR3 binding chemokine CXCL11 (ITAC). 1527 3


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