Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.59 (MIP)
 4,906 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oligonucleotides with a "CpG" motif trigger a proinflammatory response through activation of Toll-like receptor 9 (TLR9) and are being studied to exploit these properties for use as adjuvants and cancer therapies. However, oligonucleotides intended for antisense applications (ASOs) are designed to minimize proinflammatory responses by avoiding CpG motifs and by using chemical modifications [i.e., 2'-methoxyethyl (MOE) sugars and 5-methyl cytosine residues]. Nonetheless, modified ASOs are capable of eliciting a proinflammatory response at high doses, albeit mild compared with CpG oligos. To determine whether this phenomena is TLR-mediated, wild-type, TLR9 knockout, and myeloid differentiation factor 88 (MyD88) knockout mice were treated with a phosphorothioate-modified oligodeoxyribonucleotide CpG optimal oligo (ISIS 12449), and a representative non-CpG 2'-MOE oligonucleotide (ISIS 116847). The non-CpG oligonucleotide had a lower proinflammatory potency relative to ISIS 12449, requiring a >10-fold higher dose in wild-type animals to trigger a proinflammatory response. Furthermore, the inflammatory response to ISIS 12449 at low doses was TLR9 and MyD88-dependent, whereas non-CpG oligonucleotides retained the ability to activate a proinflammatory response in the knockout animals. Animals treated with the non-CpG oligonucleotide exhibited an increased spleen weight, elevated cytokine levels, increased immune cell infiltrates in liver, and an increased level of mRNA for cell surface markers typical of monocyte/macrophage type cells. Bone marrow-derived cells from wild-type and knockout animals treated with non-CpG oligonucleotide responded similarly with the production of MIP-2 and the activation of extracellular signal-regulated kianse1/2. These data implicate a TLR-independent mechanism of activation for non-CpG 2'-MOE oligonucleotides.
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PMID:Non-CpG-containing antisense 2'-methoxyethyl oligonucleotides activate a proinflammatory response independent of Toll-like receptor 9 or myeloid differentiation factor 88. 1591 63

Previously, we observed that liquid form bovine bone (BB) gelatin stimulates murine spleen cells to proliferate in vitro. In this study, activity of BB gelatin to stimulate murine-adherent peritoneal exudate cells (PEC) to secrete cytokines has been examined. Quantitatively, BB gelatin stimulated adherent PEC of C3H/HeN mice to secrete interleukin (IL)-12 (+p40), TNF-alpha, and IL-6 but not IL-1beta, IL-2, IL-10, and IFN-gamma. Qualitatively, BB gelatin-induced secretion of KC, MIP-2, MCP-1, RANTES, and MIP-1a as well as IL-6 but not 6Ckine, CTACK, Eotaxin, G-CSF, GM-CSF, IL-2,-3,-4,-5,-9,-10,-12,-13,-17, Leptin, IFN-gamma, SCF, sTNFri, TARC, TNF-alpha, TIMP-1, Tpo, and VEGF. BB gelatin acted on adherent PEC of C3H/HeN mice but not C3H/HeJ mice, which lack Toll-like receptor 4. Polymyxin B, a LPS antagonist, did not inhibit the activity of BB gelatin. Lipopolysaccharide (LPS) but not BB gelatin induced secretion of an appreciable amount of mIL-1beta. These results suggest that the activity of BB gelatin is not attributed to contamination of LPS but BB gelatin itself. It was also suggested that BB gelatin stimulated adherent PEC to newly produce and secrete cytokines.
Cancer Biother Radiopharm 2005 Aug
PMID:Activity of gelatins to induce secretion of a variety of cytokines from murine peritoneal exudate macrophages. 1611 90

Preclinical studies demonstrated that certain cytokines are potentially useful for the induction of antitumor immune responses. However, their administration in clinical settings was only marginally useful and evoked serious toxicity. In this study, we demonstrate that the combination of autologous inactivated tumor cells expressing IL-12 and IL-10 induced tumor remission in 50-70% of mice harboring large established colon or mammary tumors and spontaneous lung metastases, with the consequent establishment of an antitumor immune memory. Mice treatment with tumor cells expressing IL-12 was only marginally effective, while expression of IL-10 was not effective at all. Administration of the combined immunotherapy stimulated the recruitment of a strong inflammatory infiltrate that correlated with local, increased expression levels of the chemokines MIP-2, MCP-1, IFN-gamma-inducible protein-10, and TCA-3 and the overexpression of IFN-gamma, but not IL-4. The combined immunotherapy was also therapeutically effective on established lung metastases from both colon and mammary tumors. The antitumor effect of the combined immunotherapy was mainly dependent on CD8+ cells although CD4+ T cells also played a role. The production of IFN-gamma and IL-4 by spleen cells and the development of tumor-specific IgG1 and IgG2a Abs indicate that each cytokine stimulated its own Th pathway and that both arms were actively engaged in the antitumor effect. This study provides the first evidence of a synergistic antitumor effect of IL-12 and IL-10 suggesting that a Th1 and a Th2 cytokine can be effectively combined as a novel rational approach for cancer immunotherapy.
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PMID:IL-12 and IL-10 expression synergize to induce the immune-mediated eradication of established colon and mammary tumors and lung metastasis. 1623 81

Dendritic cells (DC), the most potent antigen presenting cells (APC), have been shown able to process apoptotic tumor cells and necrotic tumor cells for antigen presentation. Apoptosis and necrosis are the two common final pathways through which the tumors are killed by chemotherapy or radiation therapy. The tumor cells receiving radiation often produce the "danger signal" cytokines such as TNF-alpha and IL-1. Another cytokine MIP-3alpha that is able to attract DC to the tumor site is normally not secreted. We hypothesize that if artificial introduction of a large number of DC to the necrotic tumor site after radiation therapy by transfecting any cells at the tumor site to secrete DC-tropic MIP-3alpha, an anti-tumor immune response would be initiated. C57BL/6J mice bearing a well-known Lewis lung carcinoma are used to assess efficacy of this modality. The plasmid DNA containing pcDNA3.1/MIP-3alpha was injected into the subcutaneous tumors after radiation treatment. We demonstrate a detectable local expression of MIP-3alpha and local accumulation of DC. Tumor infiltrating lymphocytes after the treatment are predominantly CD8+ T-cells with rare CD4+ T-cells. The anti-tumor immune response was also measurable, which contributes at least in part to the finding that the treated mice have smaller tumor and prolonged survival, comparing to the control groups. This study suggests a potential new means of immune modulation and provides us a new concept of immunotherapy of cancer.
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PMID:Administration of MIP-3alpha gene to the tumor following radiation therapy boosts anti-tumor immunity in a murine model of lung carcinoma. 1625 60

CXCL8, a ligand for the chemokine receptor CXCR2, was recently reported to be a transcriptional target of Ras signaling, but its role in Ras-induced tumorigenesis has not been fully defined. Here, we investigated the role of KC and MIP-2, the murine homologues of CXCL8, in Kras(LA1) mice, which develop lung adenocarcinoma owing to somatic activation of the KRAS oncogene. We first investigated biological evidence of CXCR2 ligands in Kras(LA1) mice. Malignant progression of normal alveolar epithelial cells to adenocarcinoma in Kras(LA1) mice was associated with enhanced intralesional vascularity and neutrophilic inflammation, which are hallmarks of chemoattraction by CXCR2 ligands. In in vitro migration assays, supernatants of bronchoalveolar lavage samples from Kras(LA1) mice chemoattracted murine endothelial cells, alveolar inflammatory cells, and the LKR-13 lung adenocarcinoma cell line derived from Kras(LA1) mice, an effect that was abrogated by pretreatment of the cells with a CXCR2-neutralizing antibody. CXCR2 and its ligands were highly expressed in LKR-13 cells and premalignant alveolar lesions in Kras(LA1) mice. Treatment of Kras(LA1) mice with a CXCR2-neutralizing antibody inhibited the progression of premalignant alveolar lesions and induced apoptosis of vascular endothelial cells within alveolar lesions. Whereas the proliferation of LKR-13 cells in vitro was resistant to treatment with the antibody, LKR-13 cells established as syngeneic tumors were sensitive, supporting a role for the tumor microenvironment in the activity of CXCR2. Thus, high expression of CXCR2 ligands may contribute to the expansion of early alveolar neoplastic lesions induced by oncogenic KRAS.
Cancer Res 2006 Apr 15
PMID:High expression of ligands for chemokine receptor CXCR2 in alveolar epithelial neoplasia induced by oncogenic kras. 1661 42

Harnessing neutrophils for the eradication of cancer cells remains an attractive but still controversial notion. In this study, we provide evidence that neutrophils are required to prevent relapse of skin tumors following topical treatment with a new anticancer agent, ingenol-3-angelate (PEP005). Topical PEP005 treatment induces primary necrosis of tumor cells, potently activates protein kinase C, and was associated with an acute T cell-independent inflammatory response characterized by a pronounced neutrophil infiltrate. In Foxn1(nu) mice depleted of neutrophils and in CD18-deficient mice (in which neutrophil extravasation is severely impaired) PEP005 treatment was associated with a >70% increase in tumor relapse rates. NK cell or monocyte/macrophage deficiency had no effect on relapse rates. Both in vitro and in mice, PEP005 induced MIP-2/IL-8, TNF-alpha, and IL-1beta, all mediators of neutrophil recruitment and activation. In vitro, PEP005 activated human endothelial cells resulting in neutrophil adhesion and also induced human neutrophils to generate tumoricidal-reactive oxygen intermediates. Treatment of tumors with PEP005 significantly elevated the level of anticancer Abs, which were able to promote neutrophil-mediated Ab-dependent cellular cytotoxicity (ADCC) in vitro. PEP005 treatment of tumors grown in SCID mice was also associated with >70% increase in tumor relapse rates. Taken together, these data suggest a central role for neutrophil-mediated ADCC in preventing relapse. PEP005-mediated cure of tumors therefore appears to involve initial chemoablation followed by a neutrophil-dependent ADCC-mediated eradication of residual disease, illustrating that neutrophils can be induced to mediate important anticancer activity with specific chemotherapeutic agents.
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PMID:Neutrophils are a key component of the antitumor efficacy of topical chemotherapy with ingenol-3-angelate. 1711 87

Breast cancer preferentially metastasizes to the skeleton, a hospitable environment that attracts and allows breast cancer cells to thrive. Growth factors released as bone is degraded support tumor cell growth, and establish a cycle favoring continued bone degradation. While the osteoclasts are the direct effectors of bone degradation, we found that osteoblasts also contribute to bone loss. Osteoblasts are more than intermediaries between tumor cells and osteoclasts. We have presented evidence that osteoblasts contribute through loss of function induced by metastatic breast cancer cells. Metastatic breast cancer cells suppress osteoblast differentiation, alter morphology, and increase apoptosis. In this study we show that osteoblasts undergo an inflammatory stress response in the presence of human metastatic breast cancer cells. When conditioned medium from cancer cells was added to human osteoblasts, the osteoblasts were induced to express increased levels of IL-6, IL-8, and MCP-1; cytokines known to attract, differentiate, and activate osteoclasts. Similar findings were seen with murine osteoblasts and primary murine calvarial osteoblasts. Osteoblasts are co-opted into creating a microenvironment that exacerbates bone loss and are prevented from producing matrix proteins for mineralization. This is the first study implicating osteoblast produced IL-6, IL-8 (human; MIP-2 and KC mouse), and MCP-1 as key mediators in the osteoblast response to metastatic breast cancer cells.
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PMID:Metastatic breast cancer induces an osteoblast inflammatory response. 1797 81

Macrophage inflammatory protein 1 alpha (MIP-1 alpha) is detected at high concentrations in patients with multiple myeloma, and it is thought to play an important role in the etiology of multiple myeloma and osteolysis. Thus, we investigated whether or not YM529/ONO-5920, a new bisphosphonate, inhibited MIP-1 alpha mRNA expression in, and MIP-1 alpha secretion from, mouse myeloma cells. When the cells were stimulated by lipopolysaccharide, increased MIP-1 alpha mRNA expression and MIP-1 alpha secretion were observed. YM529/ONO-5920 inhibited MIP-1 alpha mRNA expression and MIP-1 alpha secretion in a concentration-dependent manner. A transient increase in the phosphorylation of extracellular-regulated kinase 1/2 (ERK1/2) and Akt was observed after lipopolysaccharide stimulation. After YM529/ONO-5920 was given, there was no transient increase in the phosphorylation of ERK1/2 or Akt. These results indicated that YM529/ONO-5920 inhibited the expression and secretion of MIP-1 alpha through blocking the signaling pathway of the Ras/mitogen-activated protein kinase kinase/ERK and Ras/phosphatidylinositol-3 kinase/Akt. Accordingly, YM529/ONO-5920 appears to have promise for use in effective future therapy for osteolysis and myeloma cell growth that depends on MIP-1 alpha.
Cancer Sci 2008 Jan
PMID:Nitrogen-containing bisphosphonate, YM529/ONO-5920, inhibits macrophage inflammatory protein 1 alpha expression and secretion in mouse myeloma cells. 1797 96

Adult T-cell /lymphomaleukemia (ATLL) is caused by human T-cell lymphotropic virus type 1 (HTLV-1). Approximately 80% of ATLL patients develop humoral hypercalcemia of malignancy (HHM), a life-threatening complication leading to a poor prognosis. Parathyroid hormone-related protein (PTHrP) and macrophage inflammatory protein-1 alpha (MIP-1 alpha) are important factors in the pathogenesis of HHM in ATLL and the expression of PTHrP can be activated by nuclear factor kappaB (NF-kappaB). NF-kappaB is constitutively activated in ATLL cells and is essential for leukemogenesis including transformation of lymphocytes infected by HTLV-1. Our goal was to evaluate the effects of NF-kappaB disruption by a proteasomal inhibitor (PS-341) and osteoclastic inhibition by zoledronic acid (Zol) on the development of ATLL and HHM using a novel bioluminescent mouse model. We found that PS-341 decreased cell viability, increased apoptosis, and down-regulated PTHrP expression in ATLL cells in vitro. To investigate the in vivo efficacy, nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice were xenografted with ATLL cells and treated with vehicle control, PS-341, Zol, or a combination of PS-341 and Zol. Bioluminescent imaging and tumor cell count showed a significant reduction in tumor burden in mice from all treatment groups. All treatments also significantly reduced the plasma calcium concentrations. Zol treatment increased trabecular bone volume and decreased osteoclast parameters. PS-341 reduced PTHrP and MIP-1 alpha expression in tumor cells in vivo. Our results indicate that both PS-341 and Zol are effective treatments for ATLL and HHM, which are refractory to conventional therapy.
Cancer Res 2007 Dec 15
PMID:A novel bioluminescent mouse model and effective therapy for adult T-cell leukemia/lymphoma. 1808 16

Hypoxia inducible factor-1 (HIF-1) is a master regulatory transcription factor controlling multiple cell-autonomous and non-cell-autonomous processes, such as metabolism, angiogenesis, matrix invasion, and cancer metastasis. Here we used a new line of transgenic mice with constitutive gain of HIF-1 function in basal keratinocytes and demonstrated a signaling pathway from HIF-1 to nuclear factor kappa B (NFkappaB) activation to enhanced epithelial chemokine and cytokine elaboration. This pathway was responsible for a phenotypically silent accumulation of stromal inflammatory cells and a marked inflammatory hypersensitivity to a single 12-O-tetradecanoylphorbol-13-acetate (TPA) challenge. HIF-1-induced NFkappaB activation was composed of 2 elements, IkappaB hyperphosphorylation and phosphorylation of Ser276 on p65, enhancing p65 nuclear localization and transcriptional activity, respectively. NFkappaB transcriptional targets macrophage inflammatory protein-2 (MIP-2/CXCL2/3), keratinocyte chemokine (KC/CXCL1), and tumor necrosis factor [alfa] (TNFalpha) were constitutively up-regulated and further increased after TPA challenge both in cultured keratinocytes and in transgenic mice. Whole animal KC, MIP-2, or TNFalpha immunodepletion each abrogated TPA-induced inflammation, whereas blockade of either VEGF or placenta growth factor (PlGF) signaling did not affect transgenic inflammatory hyper-responsiveness. Thus, epithelial HIF-1 gain of function remodels the local environment by cell-autonomous NFkappaB-mediated chemokine and cytokine secretion, which may be another mechanism by which HIF-1 facilitates either inflammatory diseases or malignant progression.
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PMID:HIF-1alpha regulates epithelial inflammation by cell autonomous NFkappaB activation and paracrine stromal remodeling. 1819 27


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