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)

In a study of the structural basis for leukocyte specificity of chemoattractants, we determined the complete amino acid sequence of human glioma-derived monocyte chemotactic factor (GDCF-2), a peptide that attracts human monocytes but not neutrophils. The choice of a tumor cell product for analysis was dictated by its relative abundance and an amino acid composition indistinguishable from that of lymphocyte-derived chemotactic factor (LDCF), the agonist thought to account for monocyte accumulation in cellular immune reactions. By a combination of Edman degradation and mass spectrometry, it was established that GDCF-2 comprises 76 amino acid residues, commencing at the N terminus with pyroglutamic acid. The peptide contains four half-cystines, at positions 11, 12, 36, and 52, which create a pair of loops, clustered at the disulfide bridges. The relative positions of the half-cystines are almost identical to those of monocyte-derived neutrophil chemotactic factor (MDNCF), a peptide of similar mass but with only 24% sequence identity to GDCF. Thus, GDCF and MDNCF have a similar gross secondary structure because of the loops formed by the clustered disulfides, and their different leukocyte specificities are most likely determined by the large differences in primary sequence.
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PMID:Complete amino acid sequence of a human monocyte chemoattractant, a putative mediator of cellular immune reactions. 264 85

Neutrophils from 13 children who received G-CSF for the collection of peripheral blood progenitors while they were in haematological steady state were studied at various times after G-CSF injection for Fc gammaR expression (Fc gammaRI or CD64, Fc gammaRII or CD32, and Fc gammaRIII or CD16) and for their ability to exert antibody-dependent cell cytotoxicity (ADCC) through Fc gammaRI. Changes in IFNgamma, IL8, IL10, MCP1 and TNF alpha mRNA levels in peripheral blood cells were also studied 4 h and 24 h after the first G-CSF injection. Fc gammaRI expression increased strongly after 24 h and then remained at the same level throughout treatment. In contrast, Fc gammaRIII expression sharply decreased at day 1 and diminished even further thereafter. No change in Fc gammaRII was observed. ADCC exerted by neutrophils through Fc gammaRI started to increase after 24 h with the peak level at day 5. Cytokine mRNA analyses indicated a reproducible and strong increase of IL8 mRNA (11/13 children) after 24 h, whereas the changes in the mRNA levels of the other cytokines tested were more heterogenous (TFNgamma: three; IL10: six; MCP1: five: TNF alpha: four, of the 13 children). Therefore this study opens the way to an optimized therapeutic schedule for the combined use of G-CSF and monoclonal antibodies in adjuvant immuno-intervention.
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PMID:In vivo induction of functional Fc gammaRI (CD64) on neutrophils and modulation of blood cytokine mRNA levels in cancer patients treated with G-CSF (rMetHuG-CSF). 950 38

Matrix metalloproteinases (MMPs) are a family of zinc-dependent enzymes, capable of degrading proteins found in the extracellular matrix. MMPs 2 and 9 are known to be produced by microglia, the resident macrophages of the central nervous system. The control of the secretion of these proteases and the activation of proenzymes by other proteases such as plasmin, as well as the balance between MMP secretion and the secretion of their natural inhibitors (TIMPs), have an important relevance in the pathogenesis of multiple sclerosis (MS). The in vitro control of MMPs 2 and 9, TIMPs 1 and 2, and urokinase-type plasminogen activator by microglia was examined in response to a panel of chemokines (chemotactic cytokines), using ELISA and zymography techniques. The chemokines MCP1, MIP1beta, RANTES, IL-8, and Fractalkine were all found significantly to increase the secretion of MMPs and TIMPs by a human foetal microglial cell line, CHME3, after 24 h stimulation. The chemokines tested, MCP1, MIP1beta, and Fractalkine, were also shown to increase MMP9 secretion by primary isolated rat brain microglia in vitro. MCP1, MIP1alpha/beta, and RANTES significantly decreased the secretion of uPA into culture supernatants in ELISA experiments. These findings suggest an important potential role for the involvement of chemokines in the breakdown of the blood-brain barrier and also the destruction of myelin basic protein in MS.
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PMID:Chemokine modulation of matrix metalloproteinase and TIMP production in adult rat brain microglia and a human microglial cell line in vitro. 1055 77

Paired synovial tissue samples were obtained from both clinically uninvolved (CU) and clinically involved (CI) knee joints of eight rheumatoid arthritis (RA) patients. In addition, biopsies were taken from five control subjects. We observed the expression of the chemokines CXCL8, CXCL9, CXCL10, CCL2 and CCL4 in CI and CU joints of RA patients. In particular, CXCL8 protein levels were specifically increased in CI joints compared with CU joints, which was confirmed by immunohistochemistry and in situ hybridization.
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PMID:The development of clinical signs of rheumatoid synovial inflammation is associated with increased synthesis of the chemokine CXCL8 (interleukin-8). 1117 28

Chemokines are attractants and regulators of cell activation. Several CXC family chemokine members induce angiogenesis and promote tumor growth. In contrast, the only CC chemokine, reported to play a direct role in angiogenesis is monocyte-chemotactic protein-1. Here we report that another CC chemokine, eotaxin (also known as CCL11), also induced chemotaxis of human microvascular endothelial cells. CCL11-induced chemotactic responses were comparable with those induced by monocyte-chemotactic protein-1 (CCL2), but lower than those induced by stroma-derived factor-1alpha (CXCL12) and IL-8 (CXCL8). The chemotactic activity was consistent with the expression of CCR3, the receptor for CCL11, on human microvascular endothelial cells and was inhibited by mAbs to either human CCL11 or human CCR3. CCL11 also induced the formation of blood vessels in vivo as assessed by the chick chorioallantoic membrane and Matrigel plug assays. The angiogenic response induced by CCL11 was about one-half of that induced by basic fibroblast factor, and it was accompanied by an inflammatory infiltrate, which consisted predominantly of eosinophils. Because the rat aortic sprouting assay, which is not infiltrated by eosinophils, yielded a positive response to CCL11, this angiogenic response appears to be direct and is not mediated by eosinophil products. This suggests that CCL11 may contribute to angiogenesis in conditions characterized by increased CCL11 production and eosinophil infiltration such as Hodgkin's lymphoma, nasal polyposis, endometriosis, and allergic diathesis.
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PMID:Eotaxin (CCL11) induces in vivo angiogenic responses by human CCR3+ endothelial cells. 1139 May 13

The essential in pathogenesis of RA is induction of incorrect immunological response against synovial and connective tissue antigens, which depends of CD4+ T-cells activation by specific antigen. This stimulation leads to releasing Th1 lymphokines. The most important cytokine is TNF-alpha. An increased level of TNF-alpha, IL-1, IL-6, GM-CSF, IL-8 was observed in patients with RA. PDGF, FGF, TGF, C-X-C a chemokines (IL-GRO-alpha, ENA78) and CCb chemokines (RANTES, MCP1 MIP1 alpha) are also involved in synovial hyperplasia in RA. During a pregnancy a clinical improvement in women with RA is frequent. The reason of this fact is probably connected with Th2 predominance (IL-4, IL-10) caused by presence of fetal tissues. Specific, cell-mediated immunity is suppressed and changed to Th2 by progesterone and PGE2. During a pregnancy a higher sensitivity of lymphocytes to progesterone was found. Progesterone stimulates T cells to PIBF production, which decreases NK activity. Th2 cytokines (Il-6, IL-10, IL-13, TGF) are expressed on decidua and inhibit secretion of Th1 cytokines (IL-2, INF gamma, TNF-alpha, IL-1 alpha, IL-1 beta). Immunosuppression caused by pregnancy probably decreases inflammatory and destructive reactions in tissues women with RA. The first attack of this disease frequently observed during puerperium is connected with a high level of prolactin and a low of estrogens, which causes a increased release of IL-2 and has a main influence on initiation and increasing of inflammatory process in RA.
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PMID:[Current opinions on immunological processes in rheumatoid arthritis during pregnancy]. 1150 69

The recruitment of T cells into the skin is regulated by chemokines released by resident cells. In this study, we found that normal human keratinocytes activated with Th1-derived supernatant (sup) expressed early (6-12 h) IP-10/CXCL10, MCP-1/CCL2, IL-8/CXCL8, and I-309/CCL1 mRNAs and with slower kinetics (24-96 h), RANTES/CCL5 and MDC/CCL22 mRNAs. Upon stimulation with the Th1 sup, keratinocytes secreted high levels of RANTES, IP-10, MCP-1, and IL-8 and moderate levels of I-309 and MDC. Although much less efficiently, Th2 sup could also induce keratinocyte expression of IL-8, IP-10, RANTES, and MCP-1 but not of I-309 and MDC. TARC/CCL17 was not significantly induced by any stimuli. Sup from keratinocytes activated with Th1-derived cytokines elicited a strong migratory response of Th1 cells and a limited migration of Th2 cells, whereas sup from Th2-activated keratinocytes promoted a moderate migration of Th1 and Th2 lymphocytes. Thus, keratinocytes appear considerably more sensitive to Th1- than to Th2-derived lymphokines in terms of chemokine release and can support the preferential accumulation of Th1 lymphocytes in the skin.
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PMID:A cytokine-to-chemokine axis between T lymphocytes and keratinocytes can favor Th1 cell accumulation in chronic inflammatory skin diseases. 1159 Jan 99

Rheumatoid arthritis (RA) is characterized by proliferation of synoviocytes that produce inflammatory cytokines and chemokines. The expressed chemokines are thought to be involved in the migration of inflammatory cells into the synovium. In this study we show that CCL2/monocyte chemotactic protein-1, CCL5/RANTES, and CXCL12/stromal cell-derived factor-1 enhanced IL-6 and IL-8 production by fibroblast-like synoviocytes (FLS) from patients with RA, and their corresponding receptors, CCR2, CCR5, and CXCR4, respectively, were expressed by RA FLS. The chemokines stimulated RA FLS more effectively than skin fibroblasts. Culture with CCL2 enhanced phosphorylation of extracellular signal-related kinase 1 (ERK1) and ERK2, but not phosphorylation of p38 or Src. Moreover, activation of ERK1/2 was inhibited by pertussis toxin, a G(i)-coupled protein inhibitor, and RS-504393, CCR2 antagonist, suggesting that ERK1/2 was activated by CCL2 via CCR2 and G(i)-coupled protein. On the other hand, CCL2, CCL5, and CXCL12 were expressed on RA FLS, and their production was regulated by TNF-alpha, IL-1beta, and TGF-beta1. Our results indicate that the chemokines not only play a role in inflammatory cell migration, but are also involved in the activation of FLS in RA synovium, possibly in an autocrine or paracrine manner.
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PMID:Chemokines regulate IL-6 and IL-8 production by fibroblast-like synoviocytes from patients with rheumatoid arthritis. 1167 56

Chemokines are mediators of innate and acquired immunity. CCL18, also designated pulmonary and activation-regulated chemokine (PARC), dendritic cell-derived CC chemokine-1 (DC-CK1), alternative macrophage activation-associated CC chemokine-1 (AMAC-1) and macrophage inflammatory protein-4 (MIP-4), was for the first time isolated from peripheral blood mononuclear cells (PBMC) and biochemically characterized. We found that CCL18/PARC protein is spontaneously secreted by PBMC and is selectively induced in PBMC by staphylococcal enterotoxins (SEA, SEB) and IL-4, but not by IFN-gamma and the CXCL8/IL-8 inducers lipopolysaccharide (LPS) or Concanavalin A. Human fibroblasts, chondrocytes and endothelial cells did not produce CCL18/PARC in response to inflammatory mediators such as measles virus, double-stranded RNA, LPS or IL-1beta, whereas up to 150 ng/ml of CCL2/MCP-1 was induced under these conditions. In synovial fluids from septic and rheumatoid arthritis patients, fourfold-enhanced CCL18/PARC levels (150 ng/ml) were detected compared to those in crystal-induced arthritis and osteoarthritis. In septic arthritis, the synovial levels of CCL18/PARC were fivefold higher than those of CXCL8/IL-8. Immunochemistry revealed CD68(+) monocytes/macrophages as the main CCL18/PARC-producing cell type in both PBMC and arthritic synovial tissue. In addition, CD1a(+) blood dendritic cells expressed CCL18/PARC. These findings suggest that monocytic cells respond to Gram-positive bacterial infection by the production of CCL18/PARC in the synovial cavity.
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PMID:Selective induction of CCL18/PARC by staphylococcal enterotoxins in mononuclear cells and enhanced levels in septic and rheumatoid arthritis. 1174 96

Natural killer (NK) cells participate in innate and adaptive immune responses to obligate intracellular pathogens and malignant tumors. Two major NK cell subsets have been identified in humans: CD56(dim) CD16+ and CD56(bright) CD16-. Resting CD56(dim) CD16+ NK cells express CXCR1, CXCR2, CXCR3, CXCR4, and CX3CR1 but no detectable levels of CC chemokine receptors on the cell surface. They migrate vigorously in response to CXCL12 and CXC3L1. In contrast, resting CD56(bright) CD16- NK cells express little CXCR1, CXCR2, and CXC3R1 but high levels of CCR5 and CCR7. Chemotaxis of CD56(bright) CD16- NK cells is stimulated most potently by CCL19, CCL21, CXCL10, CXCL11, and CXCL12. Following activation, NK cells can migrate in response to additional CC and CXC chemokines. Cytolytic activity of NK cells is augmented by CCL2, CCL3, CCL4, CCL5, CCL10, and CXC3L1. Moreover, proliferation of CD56(dim) CD16+ NK cells is costimulated by CCL19 and CCL21. Activated NK cells produce XCL1, CCL1, CCL3, CCL4, CCL5, CCL22, and CXCL8. Chemokines secreted by NK cells may recruit other effector cells during immune responses. Furthermore, CCL3, CCL4, and CCL5 produced by NK cells can inhibit in vitro replication of HIV. CCL3 and CXL10 expression appear to be required for protective NK cell responses in vivo to murine cytomegalovirus or Leishmania major, respectively. Moreover, NK cells participate in the in vivo rejection of transduced tumor cells that produce CCL19 or CCL21. Thus, chemokines appear to play an important role in afferent and efferent NK cell responses to infected and neoplastic cells.
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PMID:Role of chemokines in the biology of natural killer cells. 1181 37


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