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)

2B1 is a bispecific murine monoclonal antibody (BsMAb) with specificity for the c-erbB-2 and Fc gamma RIII extracellular domains. This BsMAb promotes the targeted lysis of malignant cells overexpressing the c-erbB-2 gene product of the HER2/neu proto-oncogene by human natural killer cells and mononuclear phagocytes expressing the Fc gamma RIII A isoform. In a Phase I clinical trial of 2B1, 15 patients with c-erbB-2-overexpressing tumors were treated with 1 h i.v. infusions of 2B1 on days 1, 4, 5, 6, 7, and 8 of a single course of treatment. Three patients were treated with daily doses of 1.0 mg/m2, while six patients each were treated with 2.5 mg/m2 and 5.0 mg/m2, respectively. The principal non-dose-limiting transient toxicities were fevers, rigors, nausea, vomiting, and leukopenia. Thrombocytopenia was dose limiting at the 5.0 mg/m2 dose level in two patients who had received extensive prior myelosuppressive chemotherapy. Murine antibody was detectable in serum following 2B1 administration, and its bispecific binding properties were retained. The pharmacokinetics of this murine antibody were variable and best described by nonlinear kinetics with an average t 1/2 of 20 h. Murine antibody bound extensively to all neutrophils and to a proportion of monocytes and lymphocytes. The initial 2B1 treatment induced more than 100-fold increases in circulating levels of tumor necrosis factor-alpha, interleukin 6, and interleukin 8 and lesser rises in granulocyte-monocyte colony-stimulating factor and IFN-gamma. Brisk human anti-mouse antibody responses were induced in 14 of 15 patients. Several minor clinical responses were observed, with reductions in the thickness of chest wall disease in one patient with disseminated breast cancer. Resolution of pleural effusions and ascites, respectively, were noted in two patients with metastatic colon cancer, and one of two liver metastases resolved in a patient with metastatic colon cancer. Treatment with 2B1 BsMAb has potent immunological consequences. The maximum tolerated dose and Phase II daily dose for patients with extensive prior myelosuppressive chemotherapy was 2.5 mg/m2. Continued dose escalation is required to identify the maximally tolerated dose for patients who have been less heavily pretreated.
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PMID:Phase I trial of 2B1, a bispecific monoclonal antibody targeting c-erbB-2 and Fc gamma RIII. 755 34

IL-8 is a chemotactic cytokine with proinflammatory and growth-promoting activities. Recently it has been shown to influence several functions of keratinocytes, including HLA-DR expression, chemotaxis, and proliferation by binding to a specific receptor. Because psoriasis vulgaris is characterized by epidermal hyperproliferation and infiltration of inflammatory cells, we investigated the expression of IL-8 and its receptor in normal and psoriatic epidermis using semiquantitative reverse-transcriptase-polymerase chain reaction. In addition the mRNA levels of the proto-oncogenes c-ras, c-raf, c-myc, and HER-2 were also investigated as potential growth-promoting stimuli in psoriatic epidermis. IL-8 mRNA was only detected in lesional psoriatic epidermis, and IL-8R-specific mRNA was found to be 10 times increased in lesional psoriatic epidermis. There was no significant difference in the protooncogene mRNA levels. In order to test the relevance of the massively increased IL-8R levels in psoriatic epidermis, we investigated the effect of the antipsoriatic drug FK-506 on specific IL-8 and IL-8R mRNA expression. FK-506 dose dependently inhibited IL-8R expression and function. Our data suggest that in psoriatic skin, elevated IL-8 levels and markedly increased IL-8R expression may act in concert to induce the cardinal signs of psoriasis--epidermal hyperproliferation and leukocyte infiltration. IL-8R may prove a molecular target for antipsoriatic drugs such as FK-506.
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PMID:Increased expression of epidermal IL-8 receptor in psoriasis. Down-regulation by FK-506 in vitro. 769 48

Topical steroid treatment is a common therapy for psoriasis. Steroids are known to bind to specific cytoplasmic receptors and to influence gene expression. We investigated the effects of the novel steroid derivative mometasone furoate on the expression of putative target genes in normal human epidermal cells (KC). Gene expression was measured by semiquantitative mRNA-PCR. In addition, cytokine receptor characteristics were assessed by ligand binding studies. We found a dose-dependent downregulation of proinflammatory mediators (IL-8, TNF alpha). Genes involved in growth regulation (HER-2, p53) were also modulated. IL-8 binding to KC was inhibited. We conclude that modulation of the expression of cytokine, cytokine receptor and growth factor genes may contribute to the antipsoriatic action of steroids.
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PMID:Novel steroid derivative modulates gene expression of cytokines and growth regulators. 852 52

In vivo models utilizing orthotopic injection of tumor cells into nude mice have proven valuable for the study of metastasis. However, breast cancers are among the more difficult of human tumors to grow in immunodeficient mice, with a relatively low tumor take. Fewer still develop spontaneous metastases. The injection of GI101A breast cancer cells into the mammary fatpad (mfp) produced lung metastases in 25% of tumor-bearing mice. Selecting cells from the lung metastases and recycling in vivo resulted in the isolation of a series of variant cell lines. These cell lines were tested for tumorigenicity and metastasis in nude mice following mfp injection compared with the original cell line, and in vitro expression of factors associated with the metastatic phenotype measured. The in vivo selected cell lines were more aggressive, with higher tumor take, faster local growth rate and increased incidence (> or = 85%) and extent of lung metastasis. However, the metastasis-selected variants showed no increases in expression of the growth factor receptors EGFR or HER-2, and the pro-angiogenic factors VEGF-A and IL-8. Immunohistochemistry of mfp tumors revealed no differences in microvessel density (counting CD-31 positive structures) and cell proliferation (PCNA-positive cells) comparing the GI101A line with selected variants. No TUNEL-positive cells were detected in the tumors of the metastasis-derived variant, with a small number of cells undergoing apoptosis detected in sections of GI101A tumors. In vitro, the metastasis-derived variants were found to have a more robust expression of phosphorylated PKB/Akt, with or without EGF or serum stimulation, suggesting an association between Akt activation and metastatic ability. This new series of isogenic cell lines may be valuable for identifying molecular mechanisms involved in the metastatic progression of breast cancer.
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PMID:Selection of more aggressive variants of the gI101A human breast cancer cell line: a model for analyzing the metastatic phenotype of breast cancer. 1459 85

Bacterial DNA contains a high frequency of unmethylated CpG motifs that stimulate immune cells via TLR9. NK cells express a low-affinity activating receptor for the Fc portion of IgG (FcgammaRIIIa), but were not thought to express TLR9 protein. The direct response of NK cells to CpG oligodeoxynucleotides (ODN) in the presence of FcR stimulation was investigated. Human NK cells cultured in the presence of CpG ODN plus immobilized IgG or Ab-coated tumor cells secreted large amounts of IFN-gamma (>2000 pg/ml), whereas cells stimulated with Ab alone, CpG ODN alone, or Ab and control ODN produced negligible amounts. Enhanced secretion of IL-8, macrophage-derived chemokine, and MIP-1alpha was also observed after costimulation. NK cell cytokine production was not the result of interactions with APCs or their cytokine products. Flow cytometric analysis revealed that 36 +/- 3.5% of human NK cells expressed basal levels of TLR9. TLR9 expression in human NK cells was confirmed by immunoblot analysis. Only TLR9-expressing NK cells responded to CpG ODN and Ab, because cytokine production was not observed in NK cells from TLR9-deficient mice. Mice receiving CpG ODN and HER2/neu-positive tumor cells treated with an anti-HER2 Ab exhibited enhanced systemic levels of IFN-gamma compared with mice receiving either agent alone. TLR9-/- animals reconstituted with TLR9+/+ NK cells secreted IFN-gamma in response to CpG ODN and Ab-coated tumor cells. These findings indicate that CpG ODN can directly enhance the NK cell cytokine response to Ab-coated targets via activation of TLR9.
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PMID:CpG-containing oligodeoxynucleotides act through TLR9 to enhance the NK cell cytokine response to antibody-coated tumor cells. 1603 1

NK cells express an activating FcR (FcgammaRIIIa) that mediates Ab-dependent cellular cytotoxicity and the production of immune modulatory cytokines in response to Ab-coated targets. IL-21 has antitumor activity in murine models that depends in part on its ability to promote NK cell cytotoxicity and IFN-gamma secretion. We hypothesized that the NK cell response to FcR stimulation would be enhanced by the administration of IL-21. Human NK cells cultured with IL-21 and immobilized IgG or human breast cancer cells coated with a therapeutic mAb (trastuzumab) secreted large amounts of IFN-gamma. Increased secretion of TNF-alpha and the chemokines IL-8, MIP-1alpha, and RANTES was also observed under these conditions. NK cell IFN-gamma production was dependent on distinct signals mediated by the IL-21R and the FcR and was abrogated in STAT1-deficient NK cells. Supernatants derived from NK cells that had been stimulated with IL-21 and mAb-coated breast cancer cells were able to drive the migration of naive and activated T cells in an in vitro chemotaxis assay. IL-21 also enhanced NK cell lytic activity against Ab-coated tumor cells. Coadministration of IL-21 and Ab-coated tumor cells to immunocompetent mice led to synergistic production of IFN-gamma by NK cells. Furthermore, the administration of IL-21 augmented the effects of an anti-HER2/neu mAb in a murine tumor model, an effect that required IFN-gamma. These findings demonstrate that IL-21 significantly enhances the NK cell response to Ab-coated targets and suggest that IL-21 would be an effective adjuvant to administer in combination with therapeutic mAbs.
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PMID:Interleukin-21 enhances NK cell activation in response to antibody-coated targets. 1678 6

Identification of genes/proteins that are differentially expressed in HER2 (erbB-2) oncogene-dependent breast carcinomas is essential in elucidating the mechanistic basis of their increased metastastic potential and resistance to several anti-cancer therapies. We here applied human cytokine antibody arrays with the goal of identifying a unique HER2-induced 'cytokine signature' in breast cancer. Human Cytokine Array III (RayBiotech, Inc.), which simultaneously detects 42 cytokines and growth factors on one membrane, was used to determine the profile of cytokines in conditioned media obtained from MCF-7/Her2-18 cells, a MCF-7-derived clone engineered to stably express the full-length human HER2 cDNA controlled by a SV40 viral promoter, and from the MCF-7/neo control sub-line. We identified two inflammatory and pro-angiogenic CXC chemokines with at least a 10-fold increased expression in HER2-overexpressing MCF-7/Her2-18 transfectants when compared to matched control MCF-7/neo cells: CXCL8 (IL-8; Interleukin-8) and CXCL1 and (GRO; Growth-related oncogene). HER2-induced differential overexpression of IL-8 and GRO was validated by ELISA and further confirmed by switching off the HER2 signalling. Treatment with the tyrosine kinase inhibitor gefitinib (Iressa) returned the expression levels of IL-8 and GRO back to the baseline observed in MCF-7 breast cancer cells, which express physiological levels of HER2. To evaluate the diagnostic utility of these findings, cytokine-specific antibody arrays were incubated with sera retrospectively collected from metastatic breast cancer patients. This approach revealed a high similarity between the 'cytokine signature' observed in serum samples and that obtained in media conditioned by breast cancer-derived cell lines. Thus, IL-8 and GRO circulating levels were significantly higher in HER2-positive breast cancer patients compared with HER2-negative patients. These findings reveal for the first time that: a) Enhanced synthesis and secretion of members of the IL-8/GRO chemokine family, which have recently been linked to oestrogen receptor (ER) inaction, increased cell invasion and angiogenesis, may represent a new pathway involved in the metastatic progression and endocrine resistance of HER2-overexpressing breast carcinomas, and b) Circulating levels of IL-8 and GRO cytokines may represent novel biomarkers monitoring breast cancer responses to endocrine treatments and/or HER2-targeted therapies.
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PMID:Protein array technology to detect HER2 (erbB-2)-induced 'cytokine signature' in breast cancer. 1737 3

S100A7 is a small calcium binding protein, which has been shown to be differentially expressed in psoriatic skin lesions, as well as in squamous cell tumors of the skin, lung and breast. Although its expression has been correlated to HER+ high-grade tumors and to a high risk of progression, the molecular mechanisms of these S100A7-mediated tumorigenic effects are not well known. Here, we showed for the first time that epidermal growth factor (EGF) induces S100A7 expression in both MCF-7 and MDA-MB-468 cell lines. We also observed a decrease in EGF-directed migration in shRNA-downregulated MDA-MB-468 cell lines. Furthermore, our signaling studies revealed that EGF induced simultaneous EGF receptor phosphorylation at Tyr1173 and HER2 phosphorylation at Tyr1248 in S100A7-downregulated cell lines as compared to the vector-transfected controls. In addition, reduced phosphorylation of Src at tyrosine 416 and p-SHP2 at tyrosine 542 was observed in these downregulated cell lines. Further studies revealed that S100A7-downregulated cells had reduced angiogenesis in vivo based on matrigel plug assays. Our results also showed decreased tumor-induced osteoclastic resorption in an intra-tibial bone injection model involving SCID mice. S100A7-downregulated cells had decreased osteoclast number and size as compared to the vector controls, and this decrease was associated with variations in IL-8 expression in in vitro cell cultures. This is a novel report on the role of S100A7 in EGF-induced signaling in breast cancer cells and in osteoclast formation.
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PMID:S100A7-downregulation inhibits epidermal growth factor-induced signaling in breast cancer cells and blocks osteoclast formation. 1832 59

Identification of genes/proteins that are differentially expressed in HER2-overexpressing breast carcinomas (BC) is essential in elucidating the mechanistic basis of their increased metastastic potential. With the goal of identifying a unique HER2-induced "cytokine signature" in BC, Human Cytokine Array III (RayBiotech, Inc.) simultaneously detecting 42 cytokines and growth factors on one membrane was used to determine the profile of cytokines in conditioned media obtained from MCF-7/Her2-18 cells, a MCF-7-derived clone engineered to stably express the full-length human HER2 cDNA, and from the MCF-7/neo control sub-line. We identified two inflammatory and proangiogenic CXC chemokines with at least a 10-fold increased expression in MCF-7/Her2-18 transfectants when compared with matched control MCF-7/neo cells: CXCL8 (IL-8; interleukin-8) and CXCL1 and (GRO; growth-related oncogene). HER2 up-regulation of IL-8 and GRO was validated by ELISA and further confirmed by switching off the HER2 signaling. Treatment with the tyrosine kinase inhibitor gefitinib (Iressa) returned the expression levels of IL-8 and GRO back to the baseline observed in HER2-negative MCF-7 BC cells. Moreover, IL-8 and GRO circulating levels were significantly higher in sera from HER2-positive BC patients. These findings reveal for the first time that (a) Enhanced synthesis and secretion of members of the IL-8/GRO chemokine family, which have recently been linked to estrogen receptor (ER) inaction, increased cell invasion, and angiogenesis, may represent a new pathway involved in the metastatic progression and endocrine resistance of HER2-overexpressing breast carcinomas; and (b) Circulating levels of IL-8 and GRO cytokines may represent novel biomarkers monitoring BC responses to endocrine treatments and/or HER2-targeted therapies.
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PMID:Her-2/neu-induced "cytokine signature" in breast cancer. 1849 54

The ability of human tumor cell lines to produce various cytokines, chemokines, angiogenic and growth factors was investigated using Luminex multiplex technology. Media conditioned by tumor cells protected tumor cells from drug-induced apoptosis and stimulated tumor cell proliferation. Antibodies neutralizing IL-6, CXCL8, CCL2 and CCL5 blocked this stimulation. Treatment of tumor cells with doxorubicin and cisplatin resulted in a substantial increase in the production of IL-6, CXCL8, CCL2, CCL5, BFGF, G-CSF and VEGF. This stimulation was associated with drug-induced activation of NF-kappaB, AP-1, AP-2, CREB, HIF-1, STAT-1, STAT-3, STAT-5 and ATF-2 transcription factors and upregulation of IL-6, CXCL8, FGF-2, CSF-3 and CCL5 gene expression. Treatment of tumor cells with doxorubicin and antibodies neutralizing G-CSF, CCL2 or CCL5 had higher inhibitory effects than each modality used alone. These results indicate that chemokines and growth factors produced by tumor by binding to the cognate receptors on tumor and stroma cells could provide proliferative and antiapoptotic signals helping tumor to escape drug-mediated destruction. Clinical studies showed that antibodies neutralizing VEGF (Avastin/Bevacizumab) or blocking HER2/neu signaling (Herceptin/Trastuzumab) could increase the efficacy of chemotherapy, although these beneficial effects have been limited. It is possible that drug-stimulated production of growth and proangiogenic factors could counterbalance the effects of antibody therapy. In addition, numerous growth factors and chemokines share angiogenic and growth-stimulating properties, and thus reduction of a single factor is insufficient to completely block tumor growth. Thus, a broad disruption of tumor cytokine network is needed to further increase the efficacy of cancer therapy.
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PMID:Chemotherapeutic drugs and human tumor cells cytokine network. 1869 97


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