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)

Currently available prognostic tools are inadequate to discern the molecular basis of the heterogenic response in hepatitis C virus (HCV)-infected patients treated with the current standard of therapy. The expression and biological function of immune mediators have been shown to be critical in all phases of the immune response to HCV infection and likely therefore influence host response. Herein, a biometric multiplex serum cytokine assay was utilized to characterize the immunomodulatory effects of host response in 10 HCV patients. Serum levels of 17 cytokines were compared before and after 1 month of treatment and against controls. Overall serum cytokine levels were significantly higher in patients (P < 0.05) than controls. Additionally, viral titers decreased in all patients after 1 month of therapy, as did overall serum cytokine levels in the cohort (P < 0.05). To assess relationships between changes in cytokine levels and changes in viral titer, the cohort was divided into three statistically distinct subgroups based on changes in viral titers. Specific sets of cytokines decreased in each group: decreases in CCL4, interleukin (IL)-2, CXCL8, and IL-1beta correlated with the greatest drops in viral titer, decreases in IL-5, granulocyte colony stimulating factor (G-CSF), and CCL4 correlated with moderate drops in viral titer, and only CCL2 correlated with the lowest drops in viral titer. Interestingly, decreases in CCL4 levels correlated with decreases in viral titers in all patients. CCL4 controls leukocyte influx and thus propagates inflammation. In conclusion, these data raise the possibility that characteristic changes in host response modulate the therapeutic response, demonstrating the prognostic power of serum cytokine profiling in chronic HCV.
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PMID:Multiplex cytokine profiling of initial therapeutic response in patients with chronic hepatitis C virus infection. 1618 76

Rearrangements of the RET receptor tyrosine kinase gene generating RET/PTC oncogenes are specific to papillary thyroid carcinoma (PTC), the most frequent thyroid tumor. Here, we show that the RET/PTC1 oncogene, when exogenously expressed in primary normal human thyrocytes, induces the expression of a large set of genes involved in inflammation and tumor invasion, including those encoding chemokines (CCL2, CCL20, CXCL8, and CXCL12), chemokine receptors (CXCR4), cytokines (IL1B, CSF-1, GM-CSF, and G-CSF), matrix-degrading enzymes (metalloproteases and urokinase-type plasminogen activator and its receptor), and adhesion molecules (L-selectin). This effect is strictly dependent on the presence of the RET/PTC1 Tyr-451 (corresponding to RET Tyr-1062 multidocking site). Selected relevant genes (CCL20, CCL2, CXCL8, CXCR4, L-selectin, GM-CSF, IL1B, MMP9, UPA, and SPP1/OPN) were found up-regulated also in clinical samples of PTC, particularly those characterized by RET/PTC activation, local extrathyroid spread, and lymph node metastases, when compared with normal thyroid tissue or follicular thyroid carcinoma. These results, demonstrating that the RET/PTC1 oncogene activates a proinflammatory program, provide a direct link between a transforming human oncogene, inflammation, and malignant behavior.
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PMID:Induction of a proinflammatory program in normal human thyrocytes by the RET/PTC1 oncogene. 1620 90

We have recently shown that several proinflammatory chemokines can be stored in secretory granules of endothelial cells (ECs). Subsequent regulated exocytosis of such chemokines may then enable rapid recruitment of leukocytes to inflammatory sites. Although IL-8/CXCL8 and eotaxin-3/CCL26 are sorted to the rod-shaped Weibel-Palade body (WPB), we found that GROalpha/CXCL1 and MCP-1/CCL2 reside in small granules that, similarly to the WPB, respond to secretagogue stimuli. In the present study, we report that GROalpha and MCP-1 colocalized in 50- to 100-nm granules, which occur throughout the cytoplasm and at the cell cortex. Immunofluorescence confocal microscopy revealed no colocalization with multimerin or tissue plasminogen activator, i.e., proteins that are released from small granules of ECs by regulated exocytosis. Moreover, the GROalpha/MCP-1-containing granules were Rab27-negative, contrasting the Rab27-positive, WPB. The secretagogues PMA, histamine, and forskolin triggered distinct dose and time-dependent responses of GROalpha release. Furthermore, GROalpha release was more sensitive than IL-8 release to inhibitors and activators of PKA and PKC but not to an activator of Epac, a cAMP-regulated GTPase exchange factor, indicating that GROalpha release is regulated by molecular adaptors different from those regulating exocytosis of the WPB. On the basis of these findings, we designated the GROalpha/MCP-1-containing compartment the type 2 granule of regulated secretion in ECs, considering the WPB the type 1 compartment. In conclusion, we propose that the GROalpha/MCP-1-containing type 2 granule shows preferential responsiveness to important mediators of EC activation, pointing to the existence of selective agonists that would allow differential release of selected chemokines.
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PMID:Characterization of a novel chemokine-containing storage granule in endothelial cells: evidence for preferential exocytosis mediated by protein kinase A and diacylglycerol. 1621 Jun 42

Immunosuppression associated with measles virus (MV) can be demonstrated by cytokine production failure in subacute sclerosing panencephalitis (SSPE) and may have implications on the pathogenesis of the disease. Cytokines (IL-12, IL-10, IL-4, IL-17, IL-18, IFN-alpha, IFN-gamma) and chemokines (CXCL8, CXCL10, CCL2 and CCL5) were measured in the cerebrospinal fluid (CSF) and serum samples from 60 patients with SSPE, 36 patients with infectious and/or inflammatory (IN) and 28 with other non-inflammatory (NIN) neurological diseases by ELISA. IL-12 p70+p40 was elevated in CSF and sera of SSPE when compared to the NIN group. However, the CSF levels of IL-12 p70 alone were not increased, indicating an increase of p40. The CSF of SSPE patients also showed relatively higher levels of IL-10 than that of the NIN group. CXCL10 levels in CSF were significantly higher in SSPE, whereas CXCL8 was increased in sera compared to NIN. No difference was detected in IFN-gamma, IFN-alpha, IL-17, IL-18, IL-4 or CCL2 and CCL5 levels. These results demonstrate that immune response against MV in SSPE may be impaired, although some T cell/Th1 inducing stimulations are present.
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PMID:Elevated interleukin-12 and CXCL10 in subacute sclerosing panencephalitis. 1622 66

Lung epithelial cells are the primary cellular targets for respiratory virus pathogens such as influenza and parainfluenza viruses. Here, we have analyzed influenza A, influenza B and Sendai virus-induced chemokine response in human A549 lung epithelial cells. Influenza virus infection resulted in low CCL2/MCP-1, CCL5/RANTES, CXCL8/IL-8 and CXCL10/IP-10 production at late times of infection. However, when cells were pretreated with TNF-alpha or IFN-alpha, influenza-A-virus-induced chemokine production was greatly enhanced. Cytokine pretreatment resulted in enhanced expression of RIG-I, IKKepsilon, interferon regulatory factor (IRF)1, IRF7 and p50 proteins. Most importantly, influenza-A-virus-induced DNA binding of IRF1, IRF3, IRF7 and NF-kappaB onto CXCL10 ISRE and NF-kappaB elements, respectively, was markedly enhanced in cytokine-pretreated cells. Our results suggest that IFN-alpha and TNF-alpha have a significant role in priming epithelial cells for higher cytokine and chemokine production in influenza A virus infection.
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PMID:TNF-alpha and IFN-alpha enhance influenza-A-virus-induced chemokine gene expression in human A549 lung epithelial cells. 1625 3

Guinea pigs exposed to very small numbers of virulent tubercle bacilli by the respiratory route develop a disease which mimics many of the important features of the pathogenesis of human tuberculosis (TB), including the expression of strong protective immunity following vaccination with BCG. In order to elucidate the precise immunological mechanisms of vaccine-induced resistance in this model, both mRNA and protein assays for several guinea pig cytokines and chemokines have been developed. The coordinated expression of cytokine and chemokine mRNA and protein was examined in various leukocyte populations and in inflammatory cells and fluid collected following the induction of tuberculous pleurisy in BCG-vaccinated guinea pigs. Real-time RT-PCR assays revealed that the mRNA levels for IFNgamma, TNFalpha, and IL-8 rose over the first few days of TB pleuritis and then declined over the 9 days of the study. Injection of anti-TGFbeta on day 8 following pleurisy induction resulted in significant changes in cytokine mRNA levels and PPD-induced proliferation in pleural effusion lymphocytes taken 24h later. BCG vaccination induced significantly higher levels of bioactive TNFalpha protein in the supernatants of alveolar, peritoneal and splenic cells from BCG-vaccinated guinea pigs cultured in the presence of attenuated or virulent mycobacteria. In sharp contrast, following virulent challenge, all three cell types from BCG-vaccinated guinea pigs produced significantly less TNFalpha. Thus, BCG vaccination appears to modulate the potentially harmful effects of TNFalpha in this model of pulmonary TB. Levels of mRNA for IL-12p40 were upregulated by exposure of infected and uninfected macrophages to recombinant guinea pig (rgp)TNFalpha. The intracellular survival of mycobacteria was enhanced when endogeous TNFalpha activity was neutralized with anti-rgpTNFalpha antiserum. rgp RANTES (CCL5) upregulated mRNA levels for TNFalpha, IL-1beta, MCP-1 (CCL2), and IL-8 (CXCL8) in alveolar and peritoneal macrophages. These results illustrate the profound effects of prior vaccination with BCG on the cytokine and chemokine responses of distinct cell populations in the guinea pig following exposure to attenuated and virulent strains of M. tuberculosis.
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PMID:Vaccine-induced cytokine responses in a guinea pig model of pulmonary tuberculosis. 1625 58

Stromal cells isolated from bone marrow (BMSCs), often referred to as mesenchymal stem cells, are currently under investigation for a variety of therapeutic applications. However, limited data are available regarding receptors that can influence their homing to and positioning within the bone marrow. In the present study, we found that second passage BMSCs express a unique set of chemokine receptors: three CC chemokine receptors (CCR1, CCR7, and CCR9) and three CXC chemokine receptors (CXCR4, CXCR5, and CXCR6). BMSCs cultured in serum-free medium secrete several chemokine ligands (CCL2, CCL4, CCL5, CCL20, CXCL12, CXCL8, and CX3CL1). The surface-expressed chemokine receptors were functional by several criteria. Stimulation of BMSCs with chemokine ligands triggers phosphorylation of the mitogen-activated protein kinase (e.g., extracellular signal-related kinase [ERK]-1 and ERK-2) and focal adhesion kinase signaling pathways. In addition, CXCL12 selectively activates signal transducer and activator of transcription (STAT)-5 whereas CCL5 activates STAT-1. In cell biologic assays, all of the chemokines tested stimulate chemotaxis of BMSCs, and CXCL12 induces cytoskeleton F-actin polymerization. Studies of culture-expanded BMSCs, for example, 12-16 passages, indicate loss of surface expression of all chemokine receptors and lack of chemotactic response to chemokines. The loss in chemokine receptor expression is accompanied by a decrease in expression of adhesion molecules (ICAM-1, ICAM-2, and vascular cell adhesion molecule 1) and CD157, while expression of CD90 and CD105 is maintained. The change in BMSC phenotype is associated with slowing of cell growth and increased spontaneous apoptosis. These findings suggest that several chemokine axes may operate in BMSC biology and may be important parameters in the validation of cultured BMSCs intended for cell therapy.
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PMID:Human bone marrow stromal cells express a distinct set of biologically functional chemokine receptors. 1625 81

Psoriasis is an immune-mediated skin disease characterized by lymphocytic infiltration and altered keratinocyte differentiation. Using immunohistochemical techniques we found that the cellular infiltrate in acute psoriatic plaques includes 5-8% CD3(-)CD56(+) natural killer (NK) cells, mostly localized in the mid and papillary dermis. NK lymphocytes isolated from punch biopsy specimens of psoriatic plaques showed a CD56(bright)CD16(-)CD158b(-) phenotype, failed to express the skin homing cutaneous lymphocyte-associated antigen and released abundant IFN-gamma upon stimulation. Supernatants from psoriatic NK cells induced MHC class II and ICAM-1 expression and release of CXCL10 and CCL5 by cultured psoriatic keratinocytes. Skin NK cells expressed high levels of the chemokines receptors CXCR3 and CCR5, intermediate amounts of CXCR1, CCR6 and CCR8, and low levels of CCR1, CCR2, CCR4, CCR7 and CX3CR1. In addition, they promptly migrated in vitro toward CXCL10, CCL5, supernatants of IFN-gamma-activated psoriatic keratinocytes and, to a lower extent, CCL20 and CCL4. In contrast, they failed to migrate toward CXCL8, CCL1, CCL2, CCL3, CCL17, CCL19 and CX3CL1. Taken together, our results implicate NK lymphocytes as newly identified protagonists in the pathogenesis of psoriasis. Their distinctive homing properties should be taken into account in the design of specific therapy aimed at blocking pathogenic cell accumulation in the skin.
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PMID:CD56brightCD16(-) NK cells accumulate in psoriatic skin in response to CXCL10 and CCL5 and exacerbate skin inflammation. 1632 44

We tested the hypothesis that cholinergic stimulation and cyclic stretch regulate inflammatory gene expression in intact airway smooth muscle by measuring mRNA expression in bovine tracheal smooth muscle using limited microarray analysis and RT-PCR. Carbachol (1 microM) induced significant increases in the expression of cyclooxygenase (COX)-1, COX-2, IL-8, and plasminogen activator, urokinase type (PLAU) to levels ranging from 1.3- to 3.1-fold of control. Sinusoidal length oscillation at an amplitude of 10% muscle length and a frequency of 1 Hz induced significant increases in the expression of CCL-2, COX-2, IL-1 beta, and IL-6 to levels ranging from 12- to 206-fold of control. Decreasing the oscillatory amplitude by 50% did not significantly change inflammatory gene expression. In contrast, decreasing the oscillatory frequency by 50% significantly attenuated inflammatory gene expression by 76-93%. Nifedipine (1 microM) had an insignificant effect on carbachol-induced gene expression, but significantly inhibited sinusoidal length oscillation-induced inflammatory gene expression by 40-78%. Correlation analysis revealed two groups of genes with differential responses to sinusoidal length oscillation. The highly responsive group included COX-2, IL-6, and IL-8, which exhibited 45- to 364-fold increases in gene expression in response to sinusoidal length oscillation. The moderately responsive group included CCL2 and PLAU, which exhibited 13- to 19-fold increases in gene expression in response to sinusoidal oscillation. These findings suggest that cyclic stretch regulates inflammatory gene expression in intact airway smooth muscle in an amplitude- and frequency-dependent manner by modulating the activity of L-type voltage-gated calcium channels.
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PMID:Cholinergic receptor and cyclic stretch-mediated inflammatory gene expression in intact ASM. 1633 98

Pertussis toxin B-oligomer (PTX-B) inhibits HIV replication in T lymphocytes and monocyte-derived macrophages by interfering with multiple steps of the HIV life cycle. PTX-B prevents CCR5-dependent (R5) virus entry in a noncompetitive manner, and it also exerts suppressive effects on both R5- and CXCR4-dependent HIV expression at a less-characterized postentry level. We demonstrate in this study that PTX-B profoundly inhibits HIV expression in chronically infected promonocytic U1 cells stimulated with several cytokines and, particularly, the IL-6-mediated effect, a cytokine that triggers viral production in these cells independently of NF-kappaB activation. From U1 cells we have subcloned a cell line, named U1-CR1, with increased responsiveness to IL-6. In these cells, PTX-B neither down-regulated the IL-6R nor prevented IL-6 induced signaling in terms of STAT3 phosphorylation and DNA binding. In contrast, PTX-B inhibited AP-1 binding to target DNA and modified its composition with a proportional increases in FosB, Fra2, and ATF2. PTX-B inhibited IL-6-induced HIV-1 long-terminal repeat-driven transcription from A, C, E, and F viral subtypes, which contain functional AP-1 binding sites, but failed to inhibit transcription from subtypes B and D LTR devoid of these sites. In addition, PTX-B inhibited the secretion of IL-6-induced, AP-1-dependent genes, including urokinase-type plasminogen activator, CXCL8/IL-8, and CCL2/monocyte chemotactic protein-1. Thus, PTX-B suppression of IL-6 induced expression of HIV and cellular genes in chronically infected promonocytic cells is strongly correlated to inhibition of AP-1.
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PMID:Pertussis toxin B-oligomer suppresses IL-6 induced HIV-1 and chemokine expression in chronically infected U1 cells via inhibition of activator protein 1. 1639 86


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