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 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

Chemokines are important in leukocyte homeostasis, inflammation, angiogenesis, and metastasis. Here, the molecular diversity of chemokines present in ovarian carcinoma was studied by purifying the proteins to homogeneity from ascitic fluid. Biologically active intact CCL2 and processed CXCL8, CCL3, and CCL18 isoforms were recovered. CCL7 and CCL20 were also purified, but their levels were 10-fold lower compared with CXCL8, CCL2, and CCL3 and even 100-fold lower than the amounts of CCL18 isolated. In ascitic fluids from patients with ovarian carcinoma (n = 12), significantly higher levels of CXCL8 and CCL18 (2.0 versus 0.7 ng/ml (p = 0.01) and 120 versus 44 ng/ml (p = 0.0002), respectively) were detected compared with those in nonovarian carcinoma patients (n = 12). In contrast to CXCL8, CCL18 was not inducible in carcinoma cell lines. Immunostaining showed CCL18 expression in tumor-infiltrating cells with monocyte/macrophage morphology but not in the ovarian carcinoma cells. Our data demonstrate that biochemically heterogenous but biologically active forms of several chemokines are present at different concentrations in ovarian carcinoma ascitic fluid. This points to a delicate balance of chemokines in epithelial ovarian cancer and to a potentially major role for CXCL8 and CCL18 in this tumor.
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PMID:Identification of biologically active chemokine isoforms from ascitic fluid and elevated levels of CCL18/pulmonary and activation-regulated chemokine in ovarian carcinoma. 1197 86

Chemokines play an important role in leukocyte mobilization, hematopoiesis, and angiogenesis. Tissue-specific expression of particular chemokines also influences tumor growth and metastasis. Here, the CC chemokine pulmonary and activation-regulated chemokine (PARC)/CCL18 was measured in pediatric patients with acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML). Surprisingly, PARC immunoreactivity was consistently detected in plasma from healthy donors. After purification to homogeneity, the presence of intact PARC (1-69) and processed PARC (1-68) in normal human plasma was confirmed by sequence and mass spectrometry analysis. Furthermore, PARC serum levels were significantly increased in children with T-ALL and prepreB-ALL compared to control serum samples, whereas serum levels in AML and preB-ALL patients were not significantly different from controls. In contrast, the hemofiltrate CC chemokine-1 (HCC-1)/CCL14 was not found to be a biomarker in any of these patients' strata, whereas the cytokine interleukin-6 (IL-6) was significantly decreased in AML and prepreB-ALL. Stimulated leukocytic cell lines or lymphoblasts from patients produced IL-8/CXCL8 or macrophage inflammatory protein-1alpha (MIP-1alpha/CCL3) but not PARC, not even after IL-4 or IL-10 treatment. However, PARC was produced by superantigen or IL-4 stimulated monocytes co-cultured with lymphocytes or lymphoblastic cells. Serum PARC levels thus constitute a novel leukemia marker, possibly reflecting tumor/host cell interactions in the circulation.
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PMID:PARC/CCL18 is a plasma CC chemokine with increased levels in childhood acute lymphoblastic leukemia. 1457 5

CCL16 is a CC chemokine originally identified as a liver-expressed chemokine. Its expression has been detected in activated monocytes where it is up-regulated by stimulation with IL-10. This is in contrast with IL-10's inhibition of the expression of most chemokines. CCL16 is chemotactic for monocytes, lymphocyte and dendritic cells. We investigated whether CCL16 displays biological activities other than chemotaxis and whether IL-10 affects monocyte response to CCL16. We show that CCL16 induces the expression of CCL2 at the mRNA and protein level, but does not affect that of CCL5, CCL18 and proinflammatory cytokines. This effect was prevented by treatment with pertussis toxin and may thus be mediated by G-protein-coupled receptors. IL-10 markedly increased CCL2 production induced by CCL16, but suppressed that of CXCL8. It also enhanced the chemotactic response to CCL16. Addition of antibodies blocking CCR1, but not CCR8, prevented this enhanced chemotactic response and suggested that CCR1 is primarily involved. We propose that IL-10 modulates the effects of CCL16 on monocytes by increasing their CCR1-dependent response. The coordinated secretion of CCL16 and IL-10 may thus enhance monocyte infiltration.
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PMID:IL-10 enhances CCL2 release and chemotaxis induced by CCL16 in human monocytes. 1588 56

Monocyte-derived dendritic cell functions have been explored for identification of contact allergens in vitro. Current methods, including measurement of changes in cell surface marker expression (e.g. CD83, CD86) do not provide a sensitive method for detecting the sensitising potential of a chemical. In this study, we investigated whether chemokine production by monocyte-derived dendritic cells is increased upon maturation and whether chemokine production can provide methodology for the detection of allergens. Monocyte-derived dendritic cells were exposed to allergens (nickel sulphate, cobalt chloride, palladium chloride, copper sulphate, chrome-(III)-chloride, potassium dichromate, p-phenylenediamine and dinitrochlorobenzene) and irritants (sodium dodecyl sulphate, dimethylsulphoxide, benzalkoniumchloride and propane-1-ol). CD83 and CD86 expression was analysed by flow cytometry and chemokine production (CXCL8, CCL5, CCL17, CCL18, CCL19, CCL20, CCL22) was determined by ELISA. Significant up regulation of CD83 and CD86 expression could only be induced by three out of seven and five out of seven allergens, respectively. In contrast, CXCL8 production was significantly increased after stimulation with all allergens tested, whereas irritant exposure led to decreased CXCL8 production. All other chemokines tested, failed in identifying contact allergens. In conclusion, CXCL8 production, next to CD83 and CD86 up regulation, by monocyte-derived dendritic cells provides a promising in vitro tool for discrimination between allergens and irritants.
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PMID:CXCL8 secretion by dendritic cells predicts contact allergens from irritants. 1609 35

Interactions between periprosthetic cells and prosthetic wear debris have been recognized as an important event in the development of osteolysis and aseptic loosening. Although the ability of wear debris to activate pro-inflammatory macrophage signaling has been documented, the full repertoire of macrophage responses to wear particles has not been established. Here, we examined the involvement of alternative macrophage activation and defective osteogenic signaling in osteolysis. Using real-time RT-PCR analysis of periprosthetic soft tissue from osteolysis patients, we detected elevated levels of expression of alternative macrophage activation markers (CHIT1, CCL18), chemokines (IL8, MIP1 alpha) and markers of osteoclast precursor cell differentiation and multinucleation (Cathepsin K, TRAP, DC-STAMP) relative to osteoarthritis controls. The presence of cathepsin K positive multinuclear cells was confirmed by immunohistochemistry. Reduced expression levels of the osteogenic signaling components BMP4 and FGF18 were detected. Expression levels of TNF-alpha, IL-6, and RANKL were unchanged, while the anti-osteoclastogenic cytokine OPG was reduced in osteolysis patients, resulting in elevated RANKL:OPG ratios. In vitro studies confirmed the role of particulate debris in alternative macrophage activation and inhibition of osteogenic signaling. Taken together, these results suggest involvement in osteolysis of alternative macrophage activation, accompanied by elevated levels of various chemokines. Increased recruitment and maturation of osteoclast precursors is also observed, as is reduced osteogenesis. These findings provide new insights into the molecular pathogenesis of osteolysis, and identify new potential candidate markers for disease progression and therapeutic targeting.
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PMID:Expression profiling reveals alternative macrophage activation and impaired osteogenesis in periprosthetic osteolysis. 1772 2

Rheumatoid arthritis (RA) is characterized by the recruitment of leukocytes and the accumulation of inflammatory mediators within the synovial compartment. Release of the chemokine CCL18 has been widely attributed to antigen-presenting cells, including macrophages and dendritic cells. This study investigates the production of CCL18 in polymorphonuclear neutrophils (PMN), the predominant cell type recruited into synovial fluid (SF). Microarray analysis, semiquantitative and quantitative reverse transcriptase polymerase chain reaction identified SF PMN from patients with RA as a novel source for CCL18 in diseased joints. Highly upregulated expression of other chemokine genes was observed for CCL3, CXCL8 and CXCL10, whereas CCL21 was downregulated. The chemokine receptor genes were differentially expressed, with upregulation of CXCR4, CCRL2 and CCR5 and downregulation of CXCR1 and CXCR2. In cell culture experiments, expression of CCL18 mRNA in blood PMN was induced by tumor necrosis factor alpha, whereas synthesis of CCL18 protein required additional stimulation with a combination of IL-10 and vitamin D3. In comparison, recruited SF PMN from patients with RA were sensitized for CCL18 production, because IL-10 alone was sufficient to induce CCL18 release. These results suggest a release of the T cell-attracting CCL18 by PMN when recruited to diseased joints. However, its production is tightly regulated at the levels of mRNA expression and protein synthesis.
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PMID:Expression and regulation of CCL18 in synovial fluid neutrophils of patients with rheumatoid arthritis. 1787 2

We compared gene expression in blood neutrophils (polymorphonuclear leukocytes, or PMNs) collected from healthy subjects with those of cystic fibrosis (CF) patients devoid of bacterial colonization. Macroarray analysis of 1050 genes revealed upregulation of 62 genes and downregulation expression of 27 genes in CF blood PMNs. Among upregulated genes were those coding for vitronectin, some chemokines (particularly CCL17 and CCL18), some interleukin (IL) receptors (IL-3, IL-8, IL-10, IL-12), all three colony-stimulating factors (G-, M-, GM-CSF), numerous genes coding for molecules involved in signal transduction, and a few genes under the control of gamma-interferon. In contrast, none of the genes coding for adhesion molecules were modulated. The upregulation of six genes in CF PMNs (coding for thrombospondin-1, G-CSF, CXCL10, CCL17, IKKvarepsilon, IL-10Ra) was further confirmed by qPCR. In addition, the increased presence of G-CSF, CCL17, and CXCL10 was confirmed by ELISA in supernatants of neutrophils from CF patients. When comparison was performed between blood and airway PMNs of CF patients, there was a limited difference in terms of gene expression. Only the mRNA expression of amphiregulin and tumor necrosis factor (TNF) receptor p55 were significantly higher in airway PMNs. The presence of amphiregulin was confirmed by ELISA in the sputum of CF patients, suggesting for the first time a role of amphiregulin in cystic fibrosis. Altogether, this study clearly demonstrates that blood PMNs from CF patients display a profound modification of gene expression profile associated with the disease, suggesting a state of activation of these cells.
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PMID:Neutrophils in cystic fibrosis display a distinct gene expression pattern. 1802 71

CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) are potent suppressors of the adaptive immune system, but their effects on innate immune cells are less well known. Here we demonstrate a previously uncharacterized function of Tregs, namely their ability to steer monocyte differentiation toward alternatively activated macrophages (AAM). AAM are cells with strong antiinflammatory potential involved in immune regulation, tissue remodeling, parasite killing, and tumor promotion. We show that, after coculture with Tregs, monocytes/macrophages display typical features of AAM, including up-regulated expression of CD206 (macrophage mannose receptor) and CD163 (hemoglobin scavenger receptor), an increased production of CCL18, and an enhanced phagocytic capacity. In addition, the monocytes/macrophages have reduced expression of HLA-DR and a strongly reduced capacity to respond to LPS in terms of proinflammatory mediator production (IL-1beta, IL-6, IL-8, MIP-1alpha, TNF-alpha), NFkappaB activation, and tyrosine phosphorylation. Mechanistic studies reveal that CD4(+)CD25(+)CD127(low)Foxp3(+) Tregs produce IL-10, IL-4, and IL-13 and that these cytokines are the critical factors involved in the suppression of the proinflammatory cytokine response. In contrast, the Treg-mediated induction of CD206 is entirely cytokine-independent, whereas the up-regulation of CD163, CCL18, and phagocytosis are (partly) dependent on IL-10 but not on IL-4/IL-13. Together these data demonstrate a previously unrecognized function of CD4(+)CD25(+)Foxp3(+) Tregs, namely their ability to induce alternative activation of monocytes/macrophages. Moreover, the data suggest that the Treg-mediated induction of AAM partly involves a novel, cytokine-independent pathway.
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PMID:CD4+CD25+Foxp3+ regulatory T cells induce alternative activation of human monocytes/macrophages. 1804 19

Coxiella burnetii is an obligate intracellular bacterium, responsible for Q fever, which survives in macrophages by interfering with their microbicidal competence. As functional polarization of macrophages is critical for their microbicidal activity, we studied the activation program of monocyte-derived macrophages (MDM) stimulated with C. burnetii. This program was markedly distinct from that induced by lipopolysaccharides (LPS), a canonical inducer of M1 polarization. Indeed, C. burnetii up-regulated the expression of genes associated with M2 polarization, including TGF-beta1, IL-1 receptor antagonist (IL-1ra), CCL18, the mannose receptor and arginase-1, and only up-regulated the expression of two genes associated with M1 polarization, namely IL-6 and CXCL8. In contrast, C. burnetii down-regulated the expression of genes associated with M1 polarization such as TNF, CD80, CCR7 and TLR-2. Functional analyses showed that C. burnetii-stimulated MDM produced high levels of TGF-beta1 and CCL18, and expressed the mannose receptor and arginase-1, the latter being associated with the prevention of nitric oxide production by MDM. Finally, C. burnetii induced the release of IL-6 and CXCL8 at a lower level than LPS-stimulated MDM. Our results suggest that C. burnetii stimulated an atypical M2 activation program that may account for the persistence of C. burnetii in macrophages.
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PMID:Coxiella burnetii, the agent of Q fever, stimulates an atypical M2 activation program in human macrophages. 1835 May 41


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