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  • PLZF regulates CCR6 and is critical for the acquisition and maintenance of the Th17 phenotype in human cells. 25833398

    Th17 cells, which express the chemokine receptor CCR6, are implicated in many immune-mediated disorders, such as psoriasis and multiple sclerosis. We found that expression levels of CCR6 on human effector/memory CD4(+) T cells reflect a continuum of Th17 differentiation. By evaluating the transcriptome in cells with increasing CCR6, we detected progressive upregulation of ZBTB16, which encodes the broad complex, tramtrack, bric-à-brac-zinc finger transcription factor promyelocytic leukemia zinc finger protein (PLZF). Using chromatin immunoprecipitation for modified histones, p300, and PLZF, we identified enhancer-like sites at -9/-10 and -13/-14 kb from the upstream transcription start site of CCR6 that bind PLZF in CCR6(+) cells. For Th cells from adult blood, both in the CCR6(+) memory population and in naive cells activated ex vivo, knockdown of ZBTB16 downregulated CCR6 and other Th17-associated genes. ZBTB16 and RORC (which encodes the "master regulator" RORγt) cross-regulate each other, and PLZF binds at the RORC promoter in CCR6(+) cells. In naive Th cells from cord blood, ZBTB16 expression was confined to CD161(+) cells, which are Th17 cell precursors. ZBTB16 was not expressed in mouse Th17 cells, and Th17 cells could be made from luxoid mice, which harbor an inactivating mutation in Zbtb16. These studies demonstrate a role for PLZF as an activator of transcription important both for Th17 differentiation and the maintenance of the Th17 phenotype in human cells, expand the role of PLZF as a critical regulator in the human adaptive immune system, and identify a novel, essential element in a regulatory network that is of significant therapeutic interest.
    Tipo de documento:
    Referencia
    Referencia del producto:
    17-10085
    Nombre del producto:
    Magna ChIP™ A/G Chromatin Immunoprecipitation Kit

  • Inhibition of human immunodeficiency virus fusion by a monoclonal antibody to a coreceptor (CXCR4) is both cell type and virus strain dependent. 8995702

    CXCR4 (also termed fusin, LESTR, or HUMSTR) is a member of the G-protein-coupled chemokine receptor family with seven membrane-spanning domains. CXCR4 acts as a coreceptor for syncytium-inducing human immunodeficiency virus type 1 (HIV-1) strains, conferring entry into CD4+ cells. We show here that a novel mouse monoclonal antibody (12G5) that recognizes CXCR4 blocked cell-to-cell fusion and cell free-virus infection of CXCR4+ CD4+ RD rhabdomyosarcoma cells by seven HIV-1 and HIV-2 strains that had various cell tropisms for different CD4+ human cell types. Yet the majority of the members of the same virus panel resisted 12G5 inhibition on T-cell lines. When inhibition was observed on these cell types, it was both cell type and virus strain dependent. In at least one situation, 12G5 failed to block LAI infection of cells expressing CXCR4 as the only available coreceptor. Our observations suggest that CXCR4 could be processed or presented differently depending on the cell type, allowing some strains to evade 12G5 inhibition. Alternatively, since several of the viruses could infect certain CXCR4- CD4+ cell lines, it is conceivable that alternative coreceptors are active, enabling individual HIV strains to choose between compatible coreceptors during entry into cells. Moreover, the strain dependency of 12G5 inhibition implies that the interaction of different HIVs with CXCR4 varies.
    Tipo de documento:
    Referencia
    Referencia del producto:
    MABF981
    Nombre del producto:
    Anti-CXCR4 Antibody, clone 12G5

  • Nitric oxide donor upregulation of stromal cell-derived factor-1/chemokine (CXC motif) receptor 4 enhances bone marrow stromal cell migration into ischemic brain after st ... 17641243

    Stromal cell-derived factor-1 (SDF1) and its chemokine (CXC motif) receptor 4 (CXCR4), along with matrix metalloproteinases (MMPs), regulate bone marrow stromal cell (BMSC) migration. We tested the hypothesis that a nitric oxide donor, DETA-NONOate, increases endogenous ischemic brain SDF1 and BMSC CXCR4 and MMP9 expression, which promotes BMSC migration into ischemic brain and thereby enhances functional outcome after stroke. C57BL/6J mice were subjected to middle cerebral artery occlusion (MCAo), and 24 hours later, the following were intravenously administered (n = 9 mice per group): (a) phosphate-buffered saline; (b) BMSCs (5 x 10(5)); (c) 0.4 mg/kg DETA-NONOate; (d) combination of CXCR4-inhibition BMSCs with DETA-NONOate; and (e) combination of BMSCs with DETA-NONOate. To elucidate the mechanisms underlying combination-enhanced BMSC migration, transwell cocultures of BMSC with mouse brain endothelial cells (MBECs) or astrocytes were performed. Combination treatment significantly improved functional outcome after stroke compared with BMSC monotherapy and MCAo control, and it increased SDF1 expression in the ischemic brain compared with DETA-NONOate monotherapy and MCAo control. The number of BMSCs in the ischemic brain was significantly increased after combination BMSC with DETA-NONOate treatment compared with monotherapy with BMSCs. The number of engrafted BMSCs was significantly correlated with functional outcome after stroke. DETA-NONOate significantly increased BMSC CXCR4 and MMP9 expression and promoted BMSC adhesion and migration to MBECs and astrocytes compared with nontreatment BMSCs. Inhibition of CXCR4 or MMPs in BMSCs significantly decreased DETA-NONOate-induced BMSC adhesion and migration. Our data demonstrate that DETA-NONOate enhanced the therapeutic potency of BMSCs, possibly via upregulation of SDF1/CXCR4 and MMP pathways, and increased BMSC engraftment into the ischemic brain.
    Tipo de documento:
    Referencia
    Referencia del producto:
    AB1846
    Nombre del producto:
    Anti-C-X-C Chemokine Receptor 4 Antibody, NT

  • CCL2/CCR2 chemokine signaling coordinates survival and motility of breast cancer cells through Smad3 protein- and p42/44 mitogen-activated protein kinase (MAPK)-dependent ... 22927430

    Increased cell motility and survival are important hallmarks of metastatic tumor cells. However, the mechanisms that regulate the interplay between these cellular processes remain poorly understood. In these studies, we demonstrate that CCL2, a chemokine well known for regulating immune cell migration, plays an important role in signaling to breast cancer cells. We report that in a panel of mouse and human breast cancer cell lines CCL2 enhanced cell migration and survival associated with increased phosphorylation of Smad3 and p42/44MAPK proteins. The G protein-coupled receptor CCR2 was found to be elevated in breast cancers, correlating with CCL2 expression. RNA interference of CCR2 expression in breast cancer cells significantly inhibited CCL2-induced migration, survival, and phosphorylation of Smad3 and p42/44MAPK proteins. Disruption of Smad3 expression in mammary carcinoma cells blocked CCL2-induced cell survival and migration and partially reduced p42/44MAPK phosphorylation. Ablation of MAPK phosphorylation in Smad3-deficient cells with the MEK inhibitor U0126 further reduced cell survival but not migration. These data indicate that Smad3 signaling through MEK-p42/44MAPK regulates CCL2-induced cell motility and survival, whereas CCL2 induction of MEK-p42/44MAPK signaling independent of Smad3 functions as an alternative mechanism for cell survival. Furthermore, we show that CCL2-induced Smad3 signaling through MEK-p42/44MAPK regulates expression and activity of Rho GTPase to mediate CCL2-induced breast cancer cell motility and survival. With these studies, we characterize an important role for CCL2/CCR2 chemokine signaling in regulating the intrinsic relationships between breast cancer cell motility and survival with implications on the metastatic process.
    Tipo de documento:
    Referencia
    Referencia del producto:
    06-1086

  • CD4-independent infection by HIV-2 is mediated by fusin/CXCR4. 8929542

    Several members of the chemokine receptor family have been shown to function in association with CD4 to permit HIV-1 entry and infection. However, the mechanism by which these molecules serve as CD4-associated cofactors is unclear. In the present report, we show that one member of this family, termed Fusin/ CXCR4, is able to function as an alternative receptor for some isolates of HIV-2 in the absence of CD4. This conclusion is supported by the finding that (1) CD4-independent infection by these viruses is inhibited by an anti-Fusin monoclonal antibody, (2) Fusin expression renders human and nonhuman CD4-negative cell lines sensitive to HIV-2-induced syncytium induction and/or infection, and (3) Fusin is selectively down-regulated from the cell surface following HIV-2 infection. The finding that one chemokine receptor can function as a primary viral receptor strongly suggests that the HIV envelope glycoprotein contains a binding site for these proteins and that differences in the affinity and/or the availability of this site can extend the host range of these viruses to include a number of CD4-negative cell types.
    Tipo de documento:
    Referencia
    Referencia del producto:
    Múltiplo
    Nombre del producto:
    Múltiplo

  • TCR activation inhibits chemotaxis toward stromal cell-derived factor-1: evidence for reciprocal regulation between CXCR4 and the TCR. 9886389

    Stromal cell-derived factor-1 (SDF-1), a C-X-C family chemokine, is a potent T lymphocyte chemoattractant. We investigated the effects of T cell activation on the chemotactic response to SDF-1. Anti-CD3 Ab stimulation of either Jurkat T cells or murine peripheral CD4+ T lymphocytes produced a dramatic inhibition of SDF-1-induced chemotaxis. In contrast, the SDF-1 responses of Jurkat clones with deficiencies in key TCR signaling components (Lck, CD45, and TCR-beta), were only marginally reduced by anti-CD3 stimulation. Similar to PMA treatment, which abolished both CXCR4 receptor expression and the chemotactic response of Jurkat cells to SDF-1, anti-CD3 Ab treatment reduced cell surface expression of CXCR4 to 65% of the control value, an effect that was blocked by protein kinase C inhibitors. Our data suggest that initial T cell activation events inhibit the response of Jurkat T cells to CXCR4 stimulation. In contrast, SDF-1 treatment resulted in a reduction of tyrosine phosphorylation of the TCR downstream effectors, ZAP-70, SLP-76, and LAT (linker for activation of T cells), suggesting that this chemokine potentially regulates the threshold for T cell activation.
    Tipo de documento:
    Referencia
    Referencia del producto:
    06-807
    Nombre del producto:
    Anti-LAT Antibody

  • CXCR4 chemokine receptor signaling induces apoptosis in acute myeloid leukemia cells via regulation of the Bcl-2 family members Bcl-XL, Noxa, and Bak. 23798675

    The CXCR4 chemokine receptor promotes survival of many different cell types. Here, we describe a previously unsuspected role for CXCR4 as a potent inducer of apoptosis in acute myeloid leukemia (AML) cell lines and a subset of clinical AML samples. We show that SDF-1, the sole ligand for CXCR4, induces the expected migration and ERK activation in the KG1a AML cell line transiently overexpressing CXCR4, but ERK activation did not lead to survival. Instead, SDF-1 treatment led via a CXCR4-dependent mechanism to apoptosis, as evidenced by increased annexin V staining, condensation of chromatin, and cleavage of both procaspase-3 and PARP. This SDF-1-induced death pathway was partially inhibited by hypoxia, which is often found in the bone marrow of AML patients. SDF-1-induced apoptosis was inhibited by dominant negative procaspase-9 but not by inhibition of caspase-8 activation, implicating the intrinsic apoptotic pathway. Further analysis showed that this pathway was activated by multiple mechanisms, including up-regulation of Bak at the level of mRNA and protein, stabilization of the Bak activator Noxa, and down-regulation of antiapoptotic Bcl-XL. Furthermore, adjusting expression levels of Bak, Bcl-XL, or Noxa individually altered the level of apoptosis in AML cells, suggesting that the combined modulation of these family members by SDF-1 coordinates their interplay to produce apoptosis. Thus, rather than mediating survival, SDF-1 may be a means to induce apoptosis of CXCR4-expressing AML cells directly in the SDF-1-rich bone marrow microenvironment if the survival cues of the bone marrow are disrupted.
    Tipo de documento:
    Referencia
    Referencia del producto:
    06-536
    Nombre del producto:
    Anti-Bak Antibody, NT

  • CXCL12 in astrocytes contributes to bone cancer pain through CXCR4-mediated neuronal sensitization and glial activation in rat spinal cord. 24735601

    Previous studies have demonstrated that chemokine CXCL12 and its receptor CXCR4 are critical for pain sensitization, but the mechanisms involved are not clear. In this study, we investigated the specific cellular mechanisms of CXCL12/CXCR4 chemokine signaling in the development and maintenance of bone cancer pain after tumor cell implantation (TCI).TCI in the tibial cavity of rats was used to establish a bone cancer pain model. Mechanical allodynia and thermal hyperalgesia were determined by measuring the paw withdrawal threshold and latency, respectively. The protein expression and cellular localization of CXCL12 and CXCR4 were detected by western blot and immunofluorescence staining. The sensitization of neurons, activation of astrocytes and microglia were examined by observing the immunofluorescence intensity of c-Fos, GFAP and IBA1.Our results demonstrated that CXCL12 was upregulated in a time-related manner, both in the dorsal root ganglia and spinal cord after TCI. Spinal CXCL12 was predominately expressed in astrocytes, and an intrathecal injection of astrocyte metabolic inhibitor fluorocitrate or selective JNK inhibitor SP600125 abolished TCI-induced CXCL12 production. A single intrathecal injection of a CXCL12 neutralizing antibody (10 μg/10 μl) at day 10 after TCI transiently reversed bone cancer pain in a dose-dependent manner. Whereas repetitive intrathecal administration of a CXCL12 neutralizing antibody (10 μg/10 μl, once a day from day 3 to 5 after TCI) significantly delayed the onset of TCI-induced pain behaviors for nearly five days. Spinal CXCR4 was also upregulated after TCI and colocalized with neurons, astrocytes and microglia. Blocking CXCR4 suppressed TCI-induced activation of neurons, astrocytes and microglia in the spinal cord at day 14. Repeated intrathecal administration of AMD3100 (5 μg/10 μl, once a day for three days) significantly delayed and suppressed the initiation and persistence of bone cancer pain in the early phase (at day 5, 6 and 7 after TCI) and in the late phase (at day 12, 13 and 14 after TCI) of bone cancer, respectively.Taken together, these results demonstrate that CXCL12/CXCR4 signaling contributed to the development and maintenance of bone cancer pain via sensitizing neurons and activating astrocytes and microglia. Additionally, this chemokine signaling may be a potential target for treating bone cancer pain.
    Tipo de documento:
    Referencia
    Referencia del producto:
    MAB377X
    Nombre del producto:
    Anti-NeuN Antibody, clone A60, Alexa Fluor®488 conjugated

  • Stromal-cell derived factor is expressed by dendritic cells and endothelium in human skin. 10550315

    Stromal-cell derived factor or SDF-1 is a CXC chemokine constitutively expressed by stromal bone marrow cell cultures that binds to the G-protein-coupled receptor CXCR4. SDF-1/CXCR4 represents a unique, nonpromiscuous ligand/receptor pair that plays an essential role in prenatal myelo- and lymphopoiesis as well as in cardiovascular and neural development. SDF-1 prevents entry of CXCR4-dependent (X4) HIV viruses in T lymphocytes, by binding and internalizing CXCR4. The expression pattern of SDF-1 protein in normal tissues is not known. Here we describe an analysis of SDF-1 mRNA and protein in normal and inflamed skin by in situ hybridization and immunohistochemistry, using a novel anti-SDF-1 monoclonal antibody. We also describe the expression pattern of CXCR4 receptor by immunohistochemistry. Our results show that SDF-1 protein and mRNA are normally expressed by endothelial cells, pericytes, and either resident or explanted CD1a+ dendritic cells. Epithelial cells of sweat glands but not keratinocytes also express SDF-1. In various inflammatory skin diseases, a large number of mononuclear cells and fibroblasts in close contact with CXCR4-positive lymphocytic infiltrates also express SDF-1. CXCR4 was also detected in many different normal cell types, including endothelial and epithelial cells, which points to a role for SDF-1/CXCR4 cell signaling in vascular and epithelial homeostasis. The demonstration of SDF-1 expression in dendritic and endothelial cells provides new insights into the mechanisms of normal and pathological lymphocyte circulation and makes it possible to envisage a role for locally secreted SDF-1 in the selective incapacity of mucosal dendritic cells to support and propagate infection by X4 HIV isolates.
    Tipo de documento:
    Referencia
    Referencia del producto:
    MABC184
    Nombre del producto:
    Anti-SDF-1 Antibody, clone K15C, Azide free

  • The chemokine CXCL12 promotes survival of postmitotic neurons by regulating Rb protein. 18583990

    Postmitotic neurons need to keep their cell cycle under control to survive and maintain a differentiated state. This study aims to test the hypothesis that the chemokine CXCL12 regulates neuronal survival and differentiation by promoting Rb function, as suggested by previous studies showing that CXCL12 protects neurons from apoptosis induced by Rb loss. To this end, the effect of CXCL12 on Rb expression and transcriptional activity and the role of Rb in CXCL12-induced neuronal survival were studied. CXCL12 increases Rb protein and RNA levels in rat cortical neurons. The chemokine also stimulates an exogenous Rb promoter expressed in these neurons and counteracts the inhibition of the Rb promoter induced by E2F1 overexpression. Furthermore CXCL12 stimulates Rb activity as a transcription repressor. The effects of CXCL12 are mediated by its specific receptor CXCR4, and do not require the presence of glia. Finally, shRNA studies show that Rb expression is crucial to the neuroprotective activity of CXCL12 as indicated by NMDA-neurotoxicity assays. These findings suggest that proper CXCR4 stimulation in the mature CNS can prevent impairment of the Rb-E2F pathway and support neuronal survival. This is important to maintain CNS integrity in physiological conditions and prevent neuronal injury and loss typical of many neurodegenerative and neuroinflammatory conditions.
    Tipo de documento:
    Referencia
    Referencia del producto:
    MAB377
    Nombre del producto:
    Anti-NeuN Antibody, clone A60