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)

Procathepsin D (pCD) is a major secreted protein in estrogen receptor-positive (ER+) breast cancer cell lines. Several independent studies have documented pronounced mitogenic effect of secreted pCD on cancer tissue-derived cell lines, including those from breast, lung, and prostate cancer. It has also been shown that the proliferative effect of pCD involves both autocrine and paracrine modes of action. Recent studies have suggested that pCD could act as a key paracrine communicator between cancer and stromal cells. We have shown earlier that the proliferative activity of pCD depends on the activation peptide sequence of pCD. The present study casts light on the mechanism by which pCD influences the proliferation of cancer cells expressing the ER. Results described in the current paper clearly show that pCD initiates secretion of cytokines interleukin-4 (IL-4), IL-8, IL-10, IL-13, macrophage inflammatory protein-1beta and (MIP-1beta) from such tumor cells. Secreted cytokines take part in the proliferation of the cancer cells, as proven by selective inhibition using antibodies. In addition, expression of cytokine receptors on tested cell lines corresponded to the effects of individual cytokines. An analogous pattern was also observed for fibroblasts, which, under physiologic conditions, are the cells in closest contact with the tumor tissue and play a role in tumor growth and invasion. Our observations were further supported by coculture experiments that are in agreement. Although very similar in response to addition of pCD, the invasive ER- cells do not secrete cytokines. Together with previous in vivo results, these data point to pCD as one of key molecules for therapeutic attack in breast cancer.
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PMID:Secretion of cytokines in breast cancer cells: the molecular mechanism of procathepsin D proliferative effects. 1734 17

The chemokine receptor CXCR4 plays an important role in tumor growth, angiogenesis and metastasis. Our previous studies showed that Nordy, a synthetic chiral compound of nordihydroguaiaretic acid, inhibited the growth and angiogenesis of various malignant tumors. In this study we examined the capacity of Nordy to regulate CXCR4-mediated production of angiogenic factors by human glioblastoma cells. We found that Nordy potently inhibited CXCR4 ligand SDF-1-induced production of IL-8 and vascular endothelial cell growth factor, two important angiogenic factors implicated in the progression of malignant tumors. Further study revealed that the effect of Nordy was attributable to its down-regulation of the expression of functional CXCR4 in glioblastoma cells. These results suggest that the anti-cancer activity of Nordy is due, at least in part, to its suppression of the chemokine receptor CXCR4 thus reducing the production of angiogenic factors by tumor cells.
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PMID:The anti-cancer compound Nordy inhibits CXCR4-mediated production of IL-8 and VEGF by malignant human glioma cells. 1741 25

Cytokines produced by tumor cells may have various effects on antitumor immune responses and tumor growth. In the present study, the cytokine production of 31 lung cancer cell lines was evaluated, while any correlation with the histological type, the induction of tumor-specific cytotoxic T lymphocytes (CTL) in vitro, and angiogenesis and the infiltration of inflammatory cells in tumor tissues were also examined. Production of interleukin (IL)-1alpha, IL-1beta, IL-4, IL-6, IL-8, IL-10, tumor necrosis factor (TNF)-alpha, granulocyte macrophage colony stimulating factor (GM-CSF), granulocyte colony stimulating factor, transforming growth factor (TGF)-beta and vascular endothelial growth factor (VEGF) in the culture supernatant was measured using enzyme-linked immunosorbent assay. Each cytokine was produced in a substantial number of the tumor cell lines. In particular, IL-6, IL-8, TGF-beta and VEGF were produced in 18 (55%), 29 (94%), 31 (100%) and 28 (90%) of 31 cell lines, respectively. However, neither IL-4 nor TNF-alpha was produced at all by any tumor cell line. TGF-beta production was significantly higher in adenocarcinoma than in squamous cell carcinoma (P = 0.03). Immunohistochemical staining revealed the magnitude of macrophage infiltration, and angiogenesis in surgically resected tumor tissue specimens correlated well with GM-CSF and IL-8 production from the corresponding cell lines. Among six lung cancer cell lines, CTL were induced in the three lung cancer cell lines that produced a lower amount of TGF-beta (<100 pg/mL). These findings suggested that TGF-beta produced by tumor cells could inhibit the induction of CTL in vitro. The present results suggest that the production of various cytokines from tumor cells might exert various paracrine effects both in vivo and in vitro.
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PMID:Cytokine production of lung cancer cell lines: Correlation between their production and the inflammatory/immunological responses both in vivo and in vitro. 1751 73

Edible berries, a potential source of natural anthocyanin antioxidants, have demonstrated a broad spectrum of biomedical functions. These include cardiovascular disorders, advancing age-induced oxidative stress, inflammatory responses, and diverse degenerative diseases. Berry anthocyanins also improve neuronal and cognitive brain functions, ocular health as well as protect genomic DNA integrity. This chapter demonstrates the beneficial effects of wild blueberry, bilberry, cranberry, elderberry, raspberry seeds, and strawberry in human health and disease prevention. Furthermore, this chapter will discuss the pharmacological benefits of a novel combination of selected berry extracts known as OptiBerry, a combination of wild blueberry, wild bilberry, cranberry, elderberry, raspberry seeds, and strawberry, and its potential benefit over individual berries. Recent studies in our laboratories have demonstrated that OptiBerry exhibits high antioxidant efficacy as shown by its high oxygen radical absorbance capacity (ORAC) values, novel antiangiogenic and antiatherosclerotic activities, and potential cytotoxicity towards Helicobacter pylori, a noxious pathogen responsible for various gastrointestinal disorders including duodenal ulcer and gastric cancer, as compared to individual berry extracts. OptiBerry also significantly inhibited basal MCP-1 and inducible NF-kappabeta transcriptions as well as the inflammatory biomarker IL-8, and significantly reduced the ability to form hemangioma and markedly decreased EOMA cell-induced tumor growth in an in vivo model. Overall, berry anthocyanins trigger genetic signaling in promoting human health and disease prevention.
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PMID:Berry anthocyanins as novel antioxidants in human health and disease prevention. 1832 May 75

The objective of the current study was to characterize the systemic and local innate immune response of dairy cows to IMI with Mycoplasma bovis, a pathogen of growing concern to the dairy industry. Ten Holstein cows were each infused in 1 quarter with M. bovis and studied for a 10-d period. Acute phase protein synthesis, which reflects 1 parameter of the systemic response to infection, was induced within 108 h of infection, as evidenced by increased circulating concentrations of lipopolysaccharide binding protein and serum amyloid A. Transient neutropenia was observed from 84 to 168 h postinfection, whereas a constant state of lymphopenia and thrombocytopenia was observed from 84 h until the end of the study. Milk somatic cell counts initially increased within 66 h of M. bovis infusion and remained elevated, relative to control (time 0) concentrations, for the remainder of study. Increased milk concentrations of BSA, which reflect increased permeability of the mammary epithelial-endothelial barrier, were evident within 78 h of infection and were sustained from 90 h until the end of the study. Milk concentrations of several cytokines, including IFN-gamma, IL-1beta, IL-10, IL-12, tumor growth factor-alpha, and tumor necrosis factor-alpha, were elevated in response to infection over a period of several days, whereas increases in milk IL-8 were of a more limited duration. Complement activation, reflected by increased milk concentrations of complement factor 5a, was also observed over several days. Despite the indication by these observed changes that the cows mounted a prolonged inflammatory response to M. bovis intramammary infection, all quarters remained infected throughout the study with persistently high concentrations of this bacterium. Thus, a sustained inflammatory response is not sufficient to eradicate M. bovis from the mammary gland and may reflect the ongoing struggle of the host to clear this persistent pathogen.
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PMID:Innate immune response to intramammary Mycoplasma bovis infection. 1758 19

Under normal conditions, macrophages provide essential innate immune surveillance in tissues. These cells also play key functions during wound healing and in pathological conditions. When macrophages are exposed to thrombin, an enzyme released from leaky blood vessels, they are stimulated to produce inflammatory cytokines, which are critical for wound healing and can also facilitate tumor growth and invasion. Using antibody cytokine arrays, we identified IL-8/CXCL8, a chemokine that plays important functions in inflammation and angiogenesis and consequently in healing and tumor development, as one of the cytokines that is highly stimulated in macrophages by thrombin. Here, we investigated the signal transduction mechanism by which thrombin stimulates IL-8/CXCL8 expression in THP-1-derived and primary human macrophages. We show that JNK is a crucial mediator of the thrombin signaling pathways in macrophages, and the activation of JNK is dependent on stimulation of the Rho small GTPase. The thrombin-induced Rho/JNK cascade is a novel signaling cascade for IL-8/CXCL8 transcription activation. Understanding the molecular mechanism by which thrombin controls the expression of inflammatory cytokines in macrophages can lead to therapeutic interventions, which can provide better management of healing, inflammation, and tumorigenesis.
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PMID:Molecular mechanisms of thrombin-induced interleukin-8 (IL-8/CXCL8) expression in THP-1-derived and primary human macrophages. 1758 62

The proinflammatory chemokine interleukin-8 (IL-8) is undetectable in androgen-responsive prostate cancer cells (e.g., LNCaP and LAPC-4), but it is highly expressed in androgen-independent metastatic cells, such as PC-3. In this report, we show IL-8 functions in androgen independence, chemoresistance, tumor growth, and angiogenesis. We stably transfected LNCaP and LAPC-4 cells with IL-8 cDNA and selected IL-8-secreting (IL8-S) transfectants. The IL8-S transfectants that secreted IL-8 at levels similar to that secreted by PC-3 cells (100-170 ng/10(6) cells) were characterized. Continuous or transient exposure of LNCaP and LAPC-4 cells to IL-8 reduced their dependence on androgen for growth and decreased sensitivity (>3.5x) to an antiandrogen. IL-8-induced cell proliferation was mediated through CXCR1 and was independent of androgen receptor (AR). Quantitative PCR, immunoblotting, and transfection studies showed that IL8-S cells or IL-8-treated LAPC-4 cells exhibit a 2- to 3-fold reduction in PSA and AR levels, when compared with vector transfectants. IL8-S cells expressed 2- to 3-fold higher levels of phospho-EGFR, src, Akt, and nuclear factor kappaB (NF-kappaB) and showed increased survival when treated with docetaxel. This increase was blocked by NF-kappaB and src inhibitors, but not by an Akt inhibitor. IL8-S transfectants displayed a 3- to 5-fold increased motility, invasion, matrix metalloproteinase-9 and vascular endothelial growth factor production. LNCaP IL8-S cells grew rapidly as tumors, with increased microvessel density and abnormal tumor vasculature when compared with the tumors derived from their vector-transfected counterparts. Therefore, IL-8 is a molecular determinant of androgen-independent prostate cancer growth and progression.
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PMID:Interleukin-8 is a molecular determinant of androgen independence and progression in prostate cancer. 1763 96

Embryonic development associated gene (EDAG), which is overexpressed in hematopoietic neoplasms and leukemia cell lines, has been reported to participate in the leukemia cell differentiation and proliferation. This study investigated whether retrovirus-mediated transfer of a siRNA against EDAG can reduce the growth of leukemia cells which highly express EDAG in vitro and in vivo. The stable transfected cells were identified with RT-PCR, the effect of EDAG/siRNA on the growth of the human erythroleukemia cell line HEL was analyzed by MTT assay, and angiogenic factor IL-8 release was evaluated by ELISA and RT-PCR. The results showed that EDAG/siRNA can silence the expression of EDAG in HEL cells. Down-regulation of EDAG expression by retrovirus-mediated siRNA inhibited the cell proliferation and tumor growth. Knockdown of EDAG expression by siRNA is also associated with decreased expression of the anti-angiogenic factor IL-8, suggesting that EDAG stimulates tumor growth at least in part by regulating angiogenesis. This study suggests that siRNA-mediated gene silencing of EDAG could potentially be a therapeutic strategy for EDAG over-expressing leukemia cells.
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PMID:Down-regulation of EDAG expression by retrovirus-mediated small interfering RNA inhibits the growth and IL-8 production of leukemia cells. 1767 16

Recent experiments show that vascular endothelial growth factor (VEGF) is the crucial mediator of downstream events that ultimately lead to enhanced endothelial cell survival and increased vascular density within many tumors. The newly discovered pathway involves up-regulation of the anti-apoptotic protein Bcl-2, which in turn leads to increased production of interleukin-8 (CXCL8). The VEGF-Bcl-2-CXCL8 pathway suggests new targets for the development of anti-angiogenic strategies including short interfering RNA (siRNA) that silence the CXCL8 gene and small molecule inhibitors of Bcl-2. In this paper, we present and validate a mathematical model designed to predict the effect of the therapeutic blockage of VEGF, CXCL8, and Bcl-2 at different stages of tumor progression. In agreement with experimental observations, the model predicts that curtailing the production of CXCL8 early in development can result in a delay in tumor growth and vascular development; however, it has little effect when applied at late stages of tumor progression. Numerical simulations also show that blocking Bcl-2 up-regulation, either at early stages or after the tumor has fully developed, ensures that both microvascular and tumor cell density stabilize at low values representing growth control. These results provide insight into those aspects of the VEGF-Bcl-2-CXCL8 pathway, which independently and in combination, are crucial mediators of tumor growth and vascular development. Continued quantitative modeling in this direction may have profound implications for the development of novel therapies directed against specific proteins and chemokines to alter tumor progression.
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PMID:Modeling the VEGF-Bcl-2-CXCL8 pathway in intratumoral agiogenesis. 1770 79

The objective of this study was to learn from in vitro studies how to better utilize Toll-like receptor (TLR) agonists in controlling tumor growth. One of the primary effects of TLR agonists is induction of cytokine and chemokine production. In order to identify combinations of cytokines or chemokines with optimal ability to inhibit in vitro tumor cell proliferation, a panel of 17 recombinant human or mouse cytokines that have minimal effect on primary cell survival, were tested individually or in combinations of 2, 3 or 4 on a panel of human and mouse chemotherapy sensitive and resistant tumor cell lines. A combination of high (>10 ng/ml) levels of IFNgamma with moderate concentrations of TNFalpha>IFNalpha>IL-6=IL-8 was most effective at inhibiting in vitro tumor cell viability and proliferation with minimal effect on primary cells. We also observed that similar cytokine profile could be induced in vitro PBMC culture by using certain combinations of TLR-TLR and TLR-TCR agonists. Thus, concomitant activation of TLR7/8 with TLR4 or TLR 7/8 with T cell receptor (TCR) in PBMC, amongst all possible paired TLR-TLR and TLR-TCR agonist combinations, produced cytokine mix high in IFNgamma, in combination with IFNalpha, IL-6, IL-8, TNFalpha. Such cytokine mix was equal or more effective tumor cell killing and inhibition of tumor cell proliferation than the best rec-cytokine mixture tested. These results suggest that, TLR and/or TCR agonists combinations generate an optimal mixture of cytokines and chemokines competent in regulating in vitro tumor growth, and imply that realizing such "right cytokine induction" in vivo might be more efficacious than that with individual cytokines or TLR agonists induced cytokine mix.
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PMID:Inhibition of in vitro tumor cell proliferation by cytokines induced by combinations of TLR or TLR and TCR agonists. 1776 51


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