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 represent a large family of polypeptide signaling molecules that are notable for their role in chemotaxis, leukocyte homing, directional migration, and G protein coupled receptor activation. Chemo kines have recently been implicated in tumor progression and metastasis. The demonstration of chemokine expression and receptor activation in melanoma tumor cells themselves, and the tumor infiltrating leukocytes, may have important implications in terms of tumor progression and tumor cell homing to metastatic sites. In addition to their chemotactic and cell homing properties, chemokines and their receptors also play a part in other biologic functions relevant to oncogenesis, including cell proliferation, protease induction, tumor growth, and angiogenesis. Melanomas, and the cells derived from them, have been found to express a number of chemokines, including CXCL8 (interleukin-8), CXCL1-3 (MGSA-GROalpha-gamma), CCL5 (RANTES), and CCL2 (monocyte chemotactic protein-1), which have been implicated in tumor growth and progression. Furthermore, recent studies have demonstrated organ-specific patterns of melanoma metastasis that correlate with their expression of specific chemokine receptors, including CXCR4, CCR7, and CCR10. This review will focus on the current biology of chemokines and chemokine receptors in the context of understanding their potential roles in melanoma progression and metastasis, and is not meant to be a comprehensive review of chemokine biology. Continued understanding and progress in the determination of the role of chemokines and their receptors in tumorigenesis and metastasis, including melanoma, may lead to novel approaches in the treatment and management of this disease.
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PMID:The role of chemokines in melanoma tumor growth and metastasis. 1206 Mar 84

The CXC chemokine, CXCL1 (melanoma growth-stimulatory activity/growth-regulated protein alpha), plays a major role in inflammation, angiogenesis, tumorigenesis, and wound healing. Recently, chemokines have been extensively related to cellular transformation, tumor growth, homing, and metastasis. CXCL1 and its mouse homologue MIP-2 have been shown to be involved in the process of tumor formation. When chemokines such as CXCL1 and CXCL8 (IL-8) become disregulated so that they are chronically expressed, tissue damage, angiogenesis, and tumorigenesis can follow. This up-regulation of chemokines has been attributed to constitutive activation of NF-kappaB. The constitutive NF-kappaB activation is an emerging hallmark in various types of tumors including breast, colon, pancreatic, ovarian, as well as melanoma. Previous findings from our laboratory and other laboratories have demonstrated the role of endogenous activation of NF-kappaB in association with enhanced metastatic potential of malignant melanoma cells and suggest that targeting NF-kappaB may have potential therapeutic effects in clinical trials. An important step in this direction would be to delineate the important intracellular pathways and upstream kinases involved in up-regulation of NF-kappaB in melanoma cells. In this review, the signaling pathways involved in the disregulation of NF-kappaB and chemokine expression are discussed.
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PMID:Role of CXCL1 in tumorigenesis of melanoma. 1210 Dec 57

Interleukin-8 (IL-8) is an important cytokine involved in tumor growth and angiogenesis in a variety of malignancies. Furthermore, matrix metalloptoteinases (MMPs) also play important roles in the invasion and metastasis of carcinomas including oral squamous cell carcinoma (OSCC). We studied whether IL-8 and MMPs participate in tumorigenesis and metastasis of OSCC. First, we investigated the gene and protein expressions of IL-8 and IL-8 receptor (IL-8R), and the effect of IL-8 on proliferation, migration and invasion of OSCC. Second, we thus also investigated the effect of IL-8 on MMP release in OSCC cells. OSCC cell lines NA and HSC-4 constitutively expressed IL-8 mRNA and secreted its protein in vitro. The production of IL-8 was significantly enhanced by the addition of tumor necrosis factor (TNF)-alpha and IL-beta, but not interferon (IFN)-gamma, granulocyte-macrophage colony-stimulating factor (GM-CSF) or IL-2. Flow cytometric analysis revealed the constitutive expression of both receptors of IL-8, IL-8RA and IL-8RB, in OSCC cell lines. The expression of IL-8 receptors in HSC-4 cells was stronger than that in NA cells. The intensity of IL-8RA expression was stronger than that of IL-8RB expression in each cell line. The expression of IL-8 receptors was not altered by the addition of cytokines such as TNF-alpha and IL-1beta. The conditioned medium containing IL-8 from OSCC cell lines induced migration and invasion of OSCC cells, but did not change cell proliferation. The differences in migrational and invasive ability between NA cells and HSC-4 cells were correlated with the expression intensity of IL-8 receptors in each cell line. Neutralizing antibodies to IL-8, IL-8RA and IL-8RB partially inhibited the chemotactic activity induced by conditioned medium. The expression of MMP-2, -7 and -9 was detected in culture supernatants from these OSCC cell lines. The expressions of MMP-7 protein and mRNA were enhanced by the addition of rIL-8, but that of other MMPs was not observed in a similar manner. These results suggest that IL-8 secreted from OSCC may contribute to the invasion of OSCC through the regulation of MMP-7 expression.
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PMID:Role of interleukin-8 secreted from human oral squamous cell carcinoma cell lines. 1216 19

Dysregulated activation of Ras or its downstream effectors such as mitogen-activated protein kinase kinase and ERK has been shown to play a critical role in tumorigenesis of many cancer types. However, in melanoma, activating mutations in Ras are rarely observed and are limited to N-Ras in UV-exposed cells. In this study, we identify constitutively activated ERK in almost all melanoma cell lines and in tumor tissues tested, which is in contrast to normal melanocytes and several early stage radial growth phase melanoma lines where ERK can be activated by serum or growth factors. Constitutive activation of ERK is preceded by phosphorylation of mitogen-activated protein kinase kinase and c-RAF. In all of the melanoma cell lines tested, Ras is constitutively activated without underlying mutations. On the contrary, activating mutations in the kinase domain of BRAF are present in the majority of the cell lines tested. Furthermore, ERK activation can be partially inhibited from the cell surface using inhibitors of fibroblast growth factor and hepatocyte growth factor but not interleukin 8 signaling pathways. These data suggest that melanoma growth, invasion, and metastasis are attributable to constitutively activated ERK apparently mediated by excessive growth factors through autocrine mechanisms and BRAF kinase activation.
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PMID:Constitutive mitogen-activated protein kinase activation in melanoma is mediated by both BRAF mutations and autocrine growth factor stimulation. 1259 21

We have demonstrated that nuclear factor-kappa B (NF-kappa B) is constitutively activated in human pancreatic adenocarcinoma and human pancreatic cancer cell lines but not in normal pancreatic tissues or in immortalized, nontumorigenic pancreatic epithelial cells, suggesting that NF-kappa B plays a critical role in the development of pancreatic adenocarcinoma. To elucidate the role of constitutive NF-kappa B activity in human pancreatic cancer cells, we generated pancreatic tumor cell lines that express a phosphorylation defective I kappa B alpha (S32, 36A) (I kappa B alpha M) that blocks NF-kappa B activity. In this study, we showed that inhibiting constitutive NF-kappa B activity by expressing I kappa B alpha M suppressed the tumorigenicity of a nonmetastatic human pancreatic cancer cell line, PANC-1, in an orthotopic nude mouse model. Immunohistochemical analysis showed that PANC-1-derived tumors expressed vascular endothelial growth factor (VEGF) and induced angiogenesis. Inhibiting NF-kappa B signaling by expressing I kappa B alpha M significantly reduced expression of Bcl-x(L) and Bcl-2. The cytokine-induced expression of VEGF and Interleukin-8 in PANC-1 cells is also decreased. Taken together, these results suggest that the inhibition of NF-kappa B signaling can suppress tumorigenesis of pancreatic cancer cells and that the NF-kappa B signaling pathway is a potential target for anticancer agents.
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PMID:Inhibition of constitutive NF-kappa B activity by I kappa B alpha M suppresses tumorigenesis. 1261 62

Progranulin (Pgrn) is a pluripotent secreted growth factor that mediates cell cycle progression and cell motility. It activates the extracellular regulated kinases and phosphatidyl inositol-3 kinase signal cascades, among others, and increases expression of cyclins D and B. Structurally, it belongs to none of the well-established growth factor families. It regulates developmental events as diverse as the onset of cavitation in the preimplantation embryo and male-specific brain differentiation. During wound repair it promotes granulation and neovascularization. It regulates inflammation through a tripartite loop with secretory leukocyte protease inhibitor (SLPI) which protects pgrn from proteolysis, and elastase, which digests it to smaller peptides. Intact pgrn is anti-inflammatory through the inhibition of some of the actions of tumor necrosis factor, while the proteolytic peptides may stimulate the production of proinflammatory cytokines such as interleukin 8. Pgrn is highly expressed in aggressive cancer cell lines and clinical specimens including breast, ovarian, and renal cancers as well as gliomas. In experimental systems it confers an aggressive phenotype on poorly tumorigenic epithelial cancer cells. The malignancy of highly tumorigenic progranulin-expressing cell lines depends on the expression level of the pgrn gene since attenuating pgrn mRNA levels in pgrn-responsive cells greatly inhibits tumor progression. Given its actions in wound repair and tumorigenesis pgrn may prove a useful clinical target, both for prognosis and for therapy.
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PMID:Progranulin (granulin-epithelin precursor, PC-cell-derived growth factor, acrogranin) mediates tissue repair and tumorigenesis. 1292 86

Chemokines are small cytokines that function in immune responses, wound healing, and pathological conditions such as chronic inflammation and tumorigenesis. This multifunctionality has been attributed primarily to ligand interaction with multiple or dimerized receptors. However, multifunctionality could also result from interactions of the receptors with small peptides produced by processing of the chemokines. Chemokine peptides are functional in vivo, but it is not yet known whether they can interact with and activate their receptors. The work presented here examines the interactions between the two forms of human interleukin 8 (hIL-8), and its N- and C-peptides, with the chemokine receptors hCXCR1 and hCXCR2. We used a Tet-on retroviral system to introduce CXCR1 into mouse NIH 3T3 cells (that lack endogenous CXCR1) and monitored activation of this receptor by the ligands by using quantitative Ca2+ imaging and mitogen-activated protein kinase (MAPK) activation. We found that the N and C termini of the chemokine can stimulate the respective CXCR1 to induce intracellular Ca2+ release and MAPK activation independent of the other regions of the molecules. Furthermore, we showed that these peptides can also stimulate chemotaxis of several cell types, including primary human microvascular endothelial cells, and that this function is specific and mediated by hCXCR1 and/or hCXCR2. These findings advance understanding of the multifunctionality exhibited by chemokines, reveal a new mode of functional regulation, and may serve as the basis for therapeutic targeting.
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PMID:The N- and C-terminal peptides of hIL8/CXCL8 are ligands for hCXCR1 and hCXCR2. 1476 5

Elevated tumor cyclooxygenase (COX)-2 activity plays a multifaceted role in non-small cell lung cancer (NSCLC). To elucidate the role of COX-2 in the in vitro and in vivo expression of two known NSCLC angiogenic peptides, CXC ligand (CXCL) 8 and CXCL5, we studied two COX-2 gene-modified NSCLC cell lines, A549 and H157. COX-2 overexpression enhanced the in vitro expression of both CXCL8 and CXCL5. In contrast, specific COX-2 inhibition decreased the production of both peptides as well as nuclear translocation of nuclear factor kappaB. In a severe combined immunodeficient mouse model of human NSCLC, the enhanced tumor growth of COX-2-overexpressing tumors was inhibited by neutralizing anti-CXCL5 and anti-CXCL8 antisera. We conclude that COX-2 contributes to the progression of NSCLC tumorigenesis by enhancing the expression of angiogenic chemokines CXCL8 and CXCL5.
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PMID:Cyclooxygenase-2-dependent expression of angiogenic CXC chemokines ENA-78/CXC Ligand (CXCL) 5 and interleukin-8/CXCL8 in human non-small cell lung cancer. 1499 49

Kaposi sarcoma (KS) is a multifocal angioproliferative neoplasm strictly dependent on angiogenic growth factors and cytokines and invariably associated with infection by the Kaposi sarcoma-associated herpesvirus (KSHV or HHV8). A G protein-coupled receptor encoded by KSHV (vGPCR) is able to initiate KS-like tumors when targeted to the vascular endothelium of mice. Analogous to human KS, vGPCR sarcomagenesis involves the paracrine secretion of angiogenic growth factors and proinflammatory molecules from vGPCR-expressing cells. Here we demonstrate that vGPCR up-regulates expression and secretion of critical KS cytokines by stimulating key transcription factors, including nuclear factor-kappaB (NF-kappaB), activator protein-1 (AP-1), and nuclear factor of activated T cells (NFAT), through the activation of the small G protein Rac1. Inhibition of Rac1 blocked vGPCR-induced transcription and secretion of KS cytokines, including interleukin-6 (IL-6), IL-8, and growth-regulated oncogene alpha (GROalpha), in vitro and reduced vGPCR tumorigenesis in vivo. Moreover, endothelial-specific infection with the constitutively active Rac1QL induced vascular lesions in mice that were remarkably similar to early vGPCR experimental lesions. These results identify Rac1 as a key mediator of vGPCR paracrine neoplasia, suggesting that this small G protein and its downstream effectors may represent suitable therapeutic targets for the treatment of KS.
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PMID:The small GTPase Rac1 links the Kaposi sarcoma-associated herpesvirus vGPCR to cytokine secretion and paracrine neoplasia. 1523 71

Chemokines are chemotactic cytokines that play important roles in immune responses and wound healing, as well as in pathological conditions such as chronic inflammation and tumorigenesis. The chemokines and their receptors are highly conserved and maintain similar functions in different species. One noteworthy exception is the chemokine interleukin (IL)8/CXC ligand 8 and its specific receptor CXCR1, which are found in humans but are not found in the traditional model organisms, mice and rats. As a consequence, we are using model organisms other than mice to study the functions of IL-8 and CXCR1, as well as the mechanisms involved in receptor activation by IL-8. Toward this goal, we have isolated and characterized a new receptor that is highly homologous to human (h)CXCR1, which we named chicken (c)CXCR1. To determine whether this receptor is activated by cIL-8 and its N- and C-terminal peptides and whether it responds to hIL-8, we expressed cCXCR1 in NIH3T3 cells, which naturally lack this receptor, and used single-cell Ca(2)(+) imaging to detect increases in intracellular Ca(2)(+) and immunoblot analysis to detect extracellular signal-regulated kinase 1/2 phosphorylation. We show that cIL-8, its N and C peptides, and hIL-8 activate cCXCR1. We further show that cIL-8 and hIL-8 stimulate chemotaxis of chicken embryonic fibroblasts, cells that express cCXCR1, and that this effect is specific for each chemokine and this receptor. These results strongly suggest that cCXCR1 is the ortholog for hCXCR1 and that chickens can be used as an effective model system to study the functions of IL-8, its terminal peptides, and its specific receptor CXCR1.
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PMID:cCXCR1 is a receptor for cIL-8 (9E3/cCAF) and its N- and C-terminal peptides and is also activated by hIL-8 (CXCL8). 1557 19


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