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)

The identification of chemokines has profoundly changed the way we interpret the immune response, elucidating the mechanism by which inflammatory cells are recruited to the site of infection by local secretion of chemoattractants such as CXC chemokine ligand 8 (CXCL8)/interleukin-8, chemokine ligand 2 (CCL2)/monocyte chemoattractant protein 1. This novel view of the immune response has been remodeled further following observations that lymphoid tissue development derives from the coordinated secretion of homeostatic chemokines such as CCL19, CCL21, and CXCL13, which mediate recruitment and clustering of the cells involved in lymphoid organogenesis. The study of primary immunodeficiencies has demonstrated that the number of circulating leukocytes is dependent on migration amongst bone marrow, blood circulation, and inflamed tissues. Defects of leukocyte adhesion and chemotaxis as a result of mutations of beta2-integrins lead to abnormal leukocytosis and susceptibility to skin infections, as observed in leukocyte adhesion deficiency. Conversely, neutropenia in children with myelokathexis is a result of leukocyte retention in the bone marrow because of the mutations of CXC chemokine receptor 4, which affect the capacity of cells to recirculate between blood and bone marrow. Moreover, the identification of the genetic basis of primary immunodeficiencies has shown that many primary immunodeficiencies such as Wiskott-Aldrich syndrome and common variable immunodeficiencies are characterized by altered migration of leukocytes and/or disregulation of cellular response to chemokines. This paper will be focused on the interpretation of primary immunodeficiencies as defects in leukocyte circulation between blood and primary and secondary organs.
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PMID:Leukocyte circulation: one-way or round-trip? Lessons from primary immunodeficiency patients. 1507 52

Human T lymphotrophic virus type-I (HTLV-I), a human retrovirus, infects CD4(+) lymphocytes and is thought to modify their function and a possible association with pulmonary diseases has also been suggested. However, little is known about the influence of HTLV-I on diffuse pan-bronchiolitis (DPB), a chronic inflammatory lung disease with infiltration of lymphocytes and hyperplasia of the bronchus-associated lymphoid tissue. In this study, 35 DPB patients with and without HTLV-I infection were examined. HTLV-I positive DPB patients were likely to have a larger affected area with lower FEV(1). The CD3(+)/CD25(+) lymphocyte percentage was significantly higher in the BALF of HTLV-I positive patients than in negative patients. MIP-1 alpha, IP-10 and levels in BALF were also significantly higher in HTLV-I positive patients than in negative patients. The levels of MCP-1 and IL-8 were not significantly different. In HTLV-I positive patients, the MIP-1 alpha and IP-10 levels showed a significant positive correlation with the percentage of CD3(+)/CD25 lymphocytes. BALF cells of all HTLV-I positive DPB patients showed expression of p40(tax) mRNA. We suggest that HTLV-I infection may modify DPB pathogenesis via activation of T cells. We also found that the frequency of ATL development in HTLV-I positive DPB patients was significantly higher than in all HTLV-I positive patients (OR = 8.22, 95% CI = 2.61-25.9, P < 0.01). The levels of TGF-beta in patients who developed ATL were significantly lower than in patients who did not develop ATL. Sensitivity and specificity were 80% and 85.7%, respectively (cut-off = 20 pg/ml). We also propose that these features should be taken into consideration in the treatment of DPB in HTLV-I infected individuals.
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PMID:Influence of human T lymphotrophic virus type I on diffuse pan-bronchiolitis. 1514 54

Uridine nucleotides are endogenous nucleotides which are released into the extracellular space from mechanical stressed endothelial and epithelial cells as well as lipopolysaccharide (lps)-stimulated monocytes. Here, we studied the biological activity of the selective purinoreceptor P2Y6 (P2YR6) agonist Uridine 5'diphosphate (UDP) as well as the P2YR2- and P2YR4-activating uridine 5'triphosphate (UTP) on human dendritic cells (DC). These cells in their immature state have the ability to migrate from blood to peripheral target sites where they sense dangerous signals and capture potential antigens. Moreover, mature DC induce innate immune responses and migrate from peripheral tissues to secondary lymphoid organs in order to activate naive T cells and initiate adaptive immunity. Here, we were able to show that uridine nucleotides stimulated Ca(2+) transients, actin polymerization, and chemotaxis in immature DC. Experiments with pertussis toxin, the stable pyrimidine agonist uridine 5'-O-(2-thiodiphosphate) (UDPgammaS) and receptor antagonists, as well as desensitization studies suggested that these uridine nucleotides activities were mediated by different G(i) protein-coupled receptors. During lps-induced maturation, DC lost their ability to respond towards uridine nucleotides with these activities. Instead, UDP, but not UTP, stimulated the release of the CXC-chemokine 8 (CXCL8) from mature DC in a reactive blue sensitive manner. Moreover, our study indicates that UDP stimulates different signaling pathways in immature and mature DC in order to favor the accumulation of immature DC and to augment the capacity to secrete CXCL8 in mature DC.
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PMID:Characterization of the biological activities of uridine diphosphate in human dendritic cells: Influence on chemotaxis and CXCL8 release. 1533 63

To study the early stages of development from stem cells of the CD56+ cell population [which includes natural killer (NK) cells], granulocyte-colony stimulating factor-mobilized peripheral blood CD34+ cells from healthy donors were sorted to >99% purity and cultured in the presence of stem cell factor and interleukin (IL)-2. After 3 weeks in culture, the majority of cells acquired CD33, with or without human leukocyte antigen-DR and CD14. In 20 stem cell donors tested, 8.7 +/- 8.8% of cells were CD56+. Two major CD56+ subsets were identified: CD56(bright), mainly CD33- cells (7+/-10%, n=11) with large, granular lymphocyte morphology, and CD56dim, mainly CD33+ (2.5+/-2, n=11) cells with macrophage morphology. The CD56bright population had cytoplasmic granzyme A but lacked killer inhibitory receptor, suggesting they were immature NK cells. The CD56dim, CD33+, population lacked NK markers. They may represent a minor subset of normal monocytes at a developmental stage comparable with the rare CD56+ CD33+ hybrid myeloid/NK cell leukemia. Consistent with a monocyte nature, CD56dimCD33+ proliferated and produced a variety of cytokines upon lipopolysaccharide stimulation, including IL-8, IL-6, monocyte chemoattractant protein-1, and macrophage-derived chemokine but not interferon-gamma. In a short-term cytotoxicity assay, they failed to kill but powerfully inhibited the proliferation of the NK-resistant cell line P815. The generation of CD56+ cells was negatively regulated by hyaluronic acid and IL-4, indicating that extracellular matrix may play an important role in the commitment of CD34+ cells into CD56 myeloid and lymphoid lineages.
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PMID:G-CSF-mobilized CD34+ cells cultured in interleukin-2 and stem cell factor generate a phenotypically novel monocyte. 1534 23

Natural killer (NK) cells comprise a set of lymphocytes that is capable of mediating innate immune responses to viral infections, malignancies, and allogeneic bone marrow grafts. This review summarizes what is known about the mechanisms NK cells use to arrive at their sites of action. NK cells express a wide array of adhesion molecules including alphaLbeta2, alphaMbeta2, alphaXbeta2, and alpha4beta1 integrins, ICAM-1, PSGL-1, and L-selectin. Like other immune and inflammatory cells, NK cells use the blood circulation to enter tissues and organs, which requires that they interact with the vessel wall under flow conditions, arrest, and transmigrate. NK cells are able to chemotax to a variety of cytokines and chemokines, including IL-12, IFN-(alpha/beta, CCL2, 3, 4, 5, 7, 8, CXCL8, and CX3CL1. In many cases, NK cells appear to migrate towards these soluble factors without any kind of priming. These cells also appear to distribute in secondary and tertiary lymphoid sites (i.e., spleen, bone marrow, liver, lung, and lymph nodes) both with and without stimulation. In addition to their ability to move throughout the body in an unprimed state, activated NK cells may have increased specificity in homing to sites of inflammation. NK cells not only react to, but also produce IFN-gamma, TNF-alpha, GM-CSF, CCL3, CCL4, and CCL5, enabling them to recruit various immune cells to sites of immune response.
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PMID:Trafficking of natural killer cells. 1535 73

Resveratrol, trans-3,5,4'-trihydroxystilbene, was first isolated in 1940 as a constituent of the roots of white hellebore (Veratrum grandiflorum O. Loes), but has since been found in various plants, including grapes, berries and peanuts. Besides cardioprotective effects, resveratrol exhibits anticancer properties, as suggested by its ability to suppress proliferation of a wide variety of tumor cells, including lymphoid and myeloid cancers; multiple myeloma; cancers of the breast, prostate, stomach, colon, pancreas, and thyroid; melanoma; head and neck squamous cell carcinoma; ovarian carcinoma; and cervical carcinoma. The growth-inhibitory effects of resveratrol are mediated through cell-cycle arrest; upregulation of p21Cip1/WAF1, p53 and Bax; down-regulation of survivin, cyclin D1, cyclin E, Bcl-2, Bcl-xL and clAPs; and activation of caspases. Resveratrol has been shown to suppress the activation of several transcription factors, including NF-kappaB, AP-1 and Egr-1; to inhibit protein kinases including IkappaBalpha kinase, JNK, MAPK, Akt, PKC, PKD and casein kinase II; and to down-regulate products of genes such as COX-2, 5-LOX, VEGF, IL-1, IL-6, IL-8, AR and PSA. These activities account for the suppression of angiogenesis by this stilbene. Resveratrol also has been shown to potentiate the apoptotic effects of cytokines (e.g., TRAIL), chemotherapeutic agents and gamma-radiation. Phamacokinetic studies revealed that the target organs of resveratrol are liver and kidney, where it is concentrated after absorption and is mainly converted to a sulfated form and a glucuronide conjugate. In vivo, resveratrol blocks the multistep process of carcinogenesis at various stages: it blocks carcinogen activation by inhibiting aryl hydrocarbon-induced CYP1A1 expression and activity, and suppresses tumor initiation, promotion and progression. Besides chemopreventive effects, resveratrol appears to exhibit therapeutic effects against cancer. Limited data in humans have revealed that resveratrol is pharmacologically quite safe. Currently, structural analogues of resveratrol with improved bioavailability are being pursued as potential therapeutic agents for cancer.
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PMID:Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies. 1551 85

Asymptomatic Salmonella enterica serovar Enteritidis carrier state in poultry has serious consequences on food safety and public health due to the risks of food poisoning following consumption of contaminated products. An understanding the mechanisms of persistence of Salmonella in the digestive tract of chicken can be achieved by a better knowledge of the defects in the control of infection in susceptible versus resistant animals. The gene expression of innate immune response factors including anti-microbial molecules, inflammatory and anti-infectious cytokines was studied in the caecal lymphoid tissue associated with the carrier state. Expression levels of these genes were assessed by real-time PCR and were compared in two inbred lines of chickens differing in resistance to the carrier state following oral inoculation of S. enterica serovar Enteritidis at 1 week of age. No correlation was observed between resistance/susceptibility to caecal carrier state and level of interleukin (IL)-1beta, IL-8, IL-18, inducible NO synthase (iNOS) and natural resistance associated macrophage protein 1 (NRAMP1). A high baseline level of defensin gene expression was recorded in young animals from the susceptible line. In contrast, a significantly low expression of interferon-gamma (IFN-gamma) gene was observed in these susceptible infected animals in comparison to resistant ones and healthy counterparts. IFN-gamma expression level represents a valuable indication of immunodeficiency associated with persistence of Salmonella in the chicken digestive tract, and IFN-gamma thus represents a factor to consider in the development of prophylactic measures for the reduction of Salmonella carrier state.
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PMID:Salmonella carrier state in chicken: comparison of expression of immune response genes between susceptible and resistant animals. 1555 34

Ubiquitination affects various immune processes and E3 ubiquitin ligases (E3) play an important role in determining substrate specificity. We identified 11 human E3 ligase genes of potential importance in pathogenesis of autoimmune diseases by search of public databases and screened them for candidacy of biological investigation with case-control linkage disequilibrium tests on multiple SNPs in the genes using rheumatoid arthritis (RA) as a model of autoimmune diseases. Significant association with RA was observed in an SNP in intron 3 of Cullin 1 (CUL1) that affected transcriptional efficiency of the promoter activity in lymphocytic cell lines. Quantitative expression analysis revealed that CUL1 mRNA was highly detected in lymphoid tissues including spleen and tonsil, and was specifically expressed in T and B lymphocytes in fractionated peripheral leukocytes. Histological evaluation of tonsils indicated that CUL1 protein expression was relatively specific for maturing germinal centers. Suppression of CUL1 expression had influence on the phenotype of T-cell line, that is, it inhibited IL-8 induction, which is known to play an important role in the migration of inflammatory cells into the affected area seen in RA. Our data suggest that the regulation of CUL1 expression in immunological tissues may affect the susceptibility of RA via altering lymphocyte signal transduction.
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PMID:CUL1, a component of E3 ubiquitin ligase, alters lymphocyte signal transduction with possible effect on rheumatoid arthritis. 1575 13

In the course of a clinical trial consisting of intratumoral injections of dendritic cells (DCs) transfected to produce interleukin-12, the use of (111)In-labeled tracing doses of DCs showed that most DCs remained inside tumor tissue, instead of migrating out. In search for factors that could explain this retention, it was found that tumors from patients suffering hepatocellular carcinoma, colorectal or pancreatic cancer were producing IL-8 and that this chemokine attracted monocyte-derived dendritic cells that uniformly express both IL-8 receptors CXCR1 and CXCR2. Accordingly, neutralizing antihuman IL-8 monoclonal antibodies blocked the chemotactic attraction of DCs by recombinant IL-8, as well as by the serum of the patients or culture supernatants of human colorectal carcinomas. In addition, tissue culture supernatants of colon carcinoma cells inhibited DC migration induced by MIP-3beta in an IL-8-dependent fashion. IL-8 production in malignant tissue and the responsiveness of DCs to IL-8 are a likely explanation of the clinical images, which suggest retention of DCs inside human malignant lesions. Impairment of DC migration toward lymphoid tissue could be involved in cancer immune evasion.
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PMID:Dendritic cells delivered inside human carcinomas are sequestered by interleukin-8. 1580 Sep 14

Chlamydia pneumoniae infection of lymphocytes in blood has been documented, and it is apparent that control of this pathogen in lymphocytes as well as immune functions of the infected lymphocytes may be critical in the development of chronic inflammatory diseases associated with infection by this bacterium. Since immune function of lymphocytes infected with C. pneumoniae has not been well studied, the cytokine response of lymphocytes infected with this pathogen was analyzed using an in vitro infection model of the Molt-4 human lymphoid cell line. C. pneumoniae infection of the cells showed a persistent infection without any vigorous growth of the bacteria. Analysis of the cytokine response of the cells persistently infected with C. pneumoniae showed minimum induction of inflammatory cytokine TNF-alpha message, determined by real-time reverse transcription (RT)-PCR in the lymphocytes, even though the infection of THP-1 monocytic cells showed a marked induction of this cytokine messages. BIC (a lymphocyte activation marker gene) as well as IFN-gamma messages were also minimally induced by the infection in Molt-4 lymphocytes. In contrast, constitutive expression of interleukin 8 (IL-8) messages of Molt-4 cells was suppressed by the infection. Thus, these results suggest that lymphocytes persistently infected with C. pneumoniae may have attenuated cytokine responses.
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PMID:Cytokine response of lymphocytes persistently infected with Chlamydia pneumoniae. 1588 75


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