Publications (32)155.56 Total impact
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Article: Rat mir-155 generated from the lncRNA Bic is 'hidden' in the alternate genomic assembly and reveals the existence of novel mammalian miRNAs and clusters.
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ABSTRACT: MicroRNAs (miRNAs) are a class of small noncoding RNAs acting as post-transcriptional gene expression regulators in many physiological and pathological conditions. During the last few years, many novel mammalian miRNAs have been predicted experimentally with bioinformatics approaches and validated by next-generation sequencing. Although these strategies have prompted the discovery of several miRNAs, the total number of these genes still seems larger. Here, by exploiting the species conservation of human, mouse, and rat hairpin miRNAs, we discovered a novel rat microRNA, mir-155. We found that mature miR-155 is overexpressed in rat spleen myeloid cells treated with LPS, similarly to humans and mice. Rat mir-155 is annotated only on the alternate genome, suggesting the presence of other "hidden" miRNAs on this assembly. Therefore, we comprehensively extended the homology search also to mice and humans, finally validating 34 novel mammalian miRNAs (two in humans, five in mice, and up to 27 in rats). Surprisingly, 15 of these novel miRNAs (one for mice and 14 for rats) were found only on the alternate and not on the reference genomic assembly. To date, our findings indicate that the choice of genomic assembly, when mapping small RNA reads, is an important option that should be carefully considered, at least for these animal models. Finally, the discovery of these novel mammalian miRNA genes may contribute to a better understanding of already acquired experimental data, thereby paving the way to still unexplored investigations and to unraveling the function of miRNAs in disease models.RNA 01/2013; · 5.09 Impact Factor -
Article: Nuclear Phosphoinositide-Specific Phospholipase C β1 Controls Cytoplasmic CCL2 mRNA Levels in HIV-1 gp120-Stimulated Primary Human Macrophages.
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ABSTRACT: HIV-1 envelope glycoprotein gp120 induces, independently of infection, the release of CCL2 from macrophages. In turn, this chemokine acts as an autocrine factor enhancing viral replication. In this study, we show for the first time that phosphoinositide-specific phospholipase C (PI-PLC) is required for the production of CCL2 triggered by gp120 in macrophages. Using a combination of confocal laser-scanner microscopy, pharmacologic inhibition, western blotting and fluorescence-activated cell sorter analysis, we demonstrate that gp120 interaction with CCR5 leads to nuclear localization of the PI-PLC β1 isozyme mediated by mitogen-activated protein kinase ERK-1/2. Notably, phosphatidylcholine-specific phospholipase C (PC-PLC), previously reported to be required for NF-kB-mediated CCL2 production induced by gp120 in macrophages, drives both ERK1/2 activation and PI-PLC β1 nuclear localization induced by gp120. PI-PLC β1 activation through CCR5 is also triggered by the natural chemokine ligand CCL4, but independently of ERK1/2. Finally, PI-PLC inhibition neither blocks gp120-mediated NF-kB activation nor overall accumulation of CCL2 mRNA, whereas it decreases CCL2 transcript level in the cytoplasm. These results identify nuclear PI-PLC β1 as a new intermediate in the gp120-triggered PC-PLC-driven signal transduction pathway leading to CCL2 secretion in macrophages. The finding that a concerted gp120-mediated signaling involving both PC- and PI-specific PLCs is required for the expression of CCL2 in macrophages suggests that this signal transduction pathway may also be relevant for the modulation of viral replication in these cells. Thus, this study may contribute to identify novel targets for therapeutic intervention in HIV-1 infection.PLoS ONE 01/2013; 8(3):e59705. · 4.09 Impact Factor -
Article: Revisiting the specificity of small molecule inhibitors: the example of stattic in dendritic cells.
Chemistry & biology 10/2012; 19(10):1213-4. · 6.52 Impact Factor -
Article: LF immunomodulatory strategies: mastering bacterial endotoxin.
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ABSTRACT: Lactoferrin (LF), an iron-binding glycoprotein expressed in most biological fluids, represents a major component of mammalian innate immune system. The multiple activities of LF rely not only on its capacity to bind iron but also to interact with molecular and cellular components of both the host and pathogens. LF can bind and sequester lipopolysaccharide thus preventing proinflammatory pathway activation, sepsis, and tissue damage. However, the interplay between LF and lipopolysaccharide is complex and may lead to different outcomes including both the suppression of inflammatory response and immune activation. Understanding the molecular basis and the functional consequences of this complex interaction is critically relevant in the development of LF-based therapeutic interventions in humans.Biochemistry and Cell Biology 02/2012; 90(3):269-78. · 2.67 Impact Factor -
Article: Toll-like receptor cross-talk in human monocytes regulates CC-chemokine production, antigen uptake and immune cell recruitment.
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ABSTRACT: Chemokines production in monocytes/macrophages is crucial in modulating immune responses generated through Toll-like receptor (TLR)-mediated recognition of microbes. During microbial onset, multiple pathogen-associated structures can be present at infection sites, and simultaneously trigger different TLRs. We report here that TLR3, TLR4 and TLR8 engagement induce CCL1, CCL2 and CCL4 production in freshly isolated monocytes. While differentiating cells maintain the capacity to secrete CCL2 and CCL4, CCL1 is no longer induced at later differentiation stages. Although different pairs of TLR agonists have been described to synergistically induce cytokine production in different cell types, agonist combinations cooperate in reducing CCL1 and CCL2, but not CCL4 secretion in freshly isolated monocytes, and fail to rescue CCL1 production at later differentiation stages. The effects of single, but not combined, TLR engagement on chemokine expression mostly occur at transcriptional level, and are IL-10 independent. Conversely, inhibition of CCL1 secretion upon combined TLR engagement is partially rescued by blocking IL-23. A different chemotactic activity of monocyte-conditioned medium on blood mononuclear cells as well as antigen uptake capacity of TLR agonist activated monocytes parallel the regulated production of chemokines. Overall, these findings indicate that simultaneous engagement of TLRs may lead to different patterns of chemokine expression depending on cellular differentiation state, chemokine, and TLR agonist combination. These different responses may be relevant for the distinct but complementary functions of monocytes and macrophages in the immune response, and may have important implications for the therapeutic manipulation of the innate immune system.Immunobiology 04/2011; 216(10):1135-42. · 3.20 Impact Factor -
Article: Bovine lactoferrin counteracts Toll-like receptor mediated activation signals in antigen presenting cells.
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ABSTRACT: Lactoferrin (LF), a key element in mammalian immune system, plays pivotal roles in host defence against infection and excessive inflammation. Its protective effects range from direct antimicrobial activities against a large panel of microbes, including bacteria, viruses, fungi and parasites, to antinflammatory and anticancer activities. In this study, we show that monocyte-derived dendritic cells (MD-DCs) generated in the presence of bovine LF (bLF) fail to undergo activation by up-modulating CD83, co-stimulatory and major histocompatibility complex molecules, and cytokine/chemokine secretion. Moreover, these cells are weak activators of T cell proliferation and retain antigen uptake activity. Consistent with an impaired maturation, bLF-MD-DC primed T lymphocytes exhibit a functional unresponsiveness characterized by reduced expression of CD154 and impaired expression of IFN-γ and IL-2. The observed imunosuppressive effects correlate with an increased expression of molecules with negative regulatory functions (i.e. immunoglobulin-like transcript 3 and programmed death ligand 1), indoleamine 2,3-dioxygenase, and suppressor of cytokine signaling-3. Interestingly, bLF-MD-DCs produce IL-6 and exhibit constitutive signal transducer and activator of transcription 3 activation. Conversely, bLF exposure of already differentiated MD-DCs completely fails to induce IL-6, and partially inhibits Toll-like receptor (TLR) agonist-induced activation. Cell-specific differences in bLF internalization likely account for the distinct response elicited by bLF in monocytes versus immature DCs, providing a mechanistic base for its multiple effects. These results indicate that bLF exerts a potent anti-inflammatory activity by skewing monocyte differentiation into DCs with impaired capacity to undergo activation and to promote Th1 responses. Overall, these bLF-mediated effects may represent a strategy to block excessive DC activation upon TLR-induced inflammation, adding further evidence for a critical role of bLF in directing host immune function.PLoS ONE 01/2011; 6(7):e22504. · 4.09 Impact Factor -
Article: Immunoregulatory role of lactoferrin-lipopolysaccharide interactions.
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ABSTRACT: Lactoferrin (Lf) is a mammalian exclusive protein widely distributed in milk and exocrine secretions exhibiting multifunctional properties. Many of the proven or proposed functions of Lf, apart from its iron binding activity, depend on its capacity to bind to other macromolecules. Lf can bind and sequester lipopolysaccharide (LPS), thus preventing pro-inflammatory pathway activation, sepsis and tissue damage. However, the interplay between Lf and LPS is complex, and may result in different outcomes, including both suppression of the inflammatory response and immune activation. These findings are critically relevant in the development of Lf-based therapeutic interventions in humans. Understanding the molecular basis and functional consequences of Lf-LPS interaction will provide insights for determining its role in health and disease.Biology of Metals 02/2010; 23(3):387-97. · 3.17 Impact Factor -
Article: Reciprocal Interactions between Lactoferrin and Bacterial Endotoxins and Their Role in the Regulation of the Immune Response.
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ABSTRACT: Lactoferrin (Lf), an iron-binding glycoprotein expressed in most biological fluids, represents a major component of the mammalian innate immune system. Lf's multiple activities rely not only on its capacity to bind iron, but also to interact with molecular and cellular components of both host and pathogens. Lf can bind and sequester lipopolysaccharide (LPS), thus preventing pro-inflammatory pathway activation, sepsis and tissue damage. However, Lf-bound LPS may retain the capacity to induce cell activation via Toll-like receptor 4-dependent and -independent mechanisms. This review discusses the complex interplay between Lf and LPS and its relevance in the regulation of the immune response.Toxins. 01/2010; 2(1):54-68. -
Article: gp120 modulates the biology of human hepatic stellate cells: a link between HIV infection and liver fibrogenesis.
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ABSTRACT: In patients with hepatitis C virus (HCV)/HIV co-infection, a faster progression of liver fibrosis to cirrhosis has been reported. In this study, an investigation was carried out to determine whether gp120, an HIV envelope protein, modulates the biology of human hepatic stellate cells (HSCs), key cell types in the pathogenesis of fibrosis. Myofibroblastic HSCs were isolated from normal human liver tissue. Gene expression was measured by real-time PCR. Cell migration was assessed in Boyden chambers. Intracellular signalling pathways were evaluated using phosphorylation-specific antibodies or by transfection of a reporter plasmid. Transcripts for the chemokine receptors CCR5 and CXCR4, which bind gp120, were detectable in human HSCs. Upon exposure to M-tropic recombinant gp120, which binds CCR5, a significant increase in HSC chemotaxis was observed (1.6+/-0.3-fold, p=0.03). The effects of gp120 were prevented by protein inactivation. gp120 also resulted in a significant increase in secretion (1.5+/-0.3-fold, p=0.03) and gene expression (1.47+/-0.13-fold, p=0.02) of the proinflammatory chemokine monocyte chemoattractant protein-1, and in increased gene expression of tissue inhibitor of metalloprotease-1 and interleukin-6 (2.03+/-0.57-fold, p=0.02). gp120-induced migration required Akt activation. gp120 also induced activation of nuclear factor-kappaB (NF-kappaB) and p38(MAPK). Preincubation of HSCs with TAK779, a CCR5 receptor antagonist, prevented gp120-mediated chemotaxis and monocyte chemoattractant protein-1 secretion. Expression of CCR5 was detectable in areas of inflammation and fibrogenesis in liver biopsies of patients with HCV/HIV co-infection. This study shows that HIV gp120 modulates different aspects of HSC biology, including directional cell movement and expression of proinflammatory cytokines. These results identify a direct pathway possibly linking HIV infection with liver fibrogenesis via envelope proteins.Gut 10/2009; 59(4):513-20. · 10.11 Impact Factor -
Article: CC chemokine ligand 2 down-modulation by selected Toll-like receptor agonist combinations contributes to T helper 1 polarization in human dendritic cells.
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ABSTRACT: Toll-like receptor (TLR) signaling activation by pathogens is critical to the induction of immune responses, and demands tight regulation. We describe in this study that CC chemokine ligand 2 (CCL2) secretion triggered by TLR4 or TLR8 engagement is strongly inhibited upon simultaneous activation of both TLRs in human monocyte-derived dendritic cells (DCs). Impaired CCL2 secretion occurs concomitantly to interleukin-12 up-regulation, being part of a complex regulatory circuit ensuring optimal T helper type 1 polarization. Interestingly, triggering selected TLRs or their combinations differently affects nuclear factor-kappaB p65 activation and microRNA expression. Overall, these results indicate that CCL2 supplies an important immunomodulatory role to DCs, and may contribute to dictate the cytokine profile in T helper type 1 responses induced by DCs.Blood 06/2009; 114(4):796-806. · 9.90 Impact Factor -
Article: Phosphatidylcholine-specific phospholipase C activation is required for CCR5-dependent, NF-kB-driven CCL2 secretion elicited in response to HIV-1 gp120 in human primary macrophages.
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ABSTRACT: CCL2 (MCP-1) has been shown to enhance HIV-1 replication. The expression of this chemokine by macrophages is up-modulated as a consequence of viral infection or gp120 exposure. In this study, we show for the first time that the phosphatidylcholine-specific phospholipase C (PC-PLC) is required for the production of CCL2 triggered by gp120 in human monocyte-derived macrophages (MDMs). Using a combination of pharmacologic inhibition, confocal laser-scanner microscopy, and enzymatic activity assay, we demonstrate that R5 gp120 interaction with CCR5 activates PC-PLC, as assessed by a time-dependent modification of its subcellular distribution and a concentration-dependent increase of its enzymatic activity. Furthermore, PC-PLC is required for NF-kB-mediated CCL2 production triggered by R5 gp120. Notably, PC-PLC activation through CCR5 is specifically induced by gp120, since triggering CCR5 through its natural ligand CCL4 (MIP-1beta) does not affect PC-PLC cellular distribution and enzymatic activity, as well as CCL2 secretion, thus suggesting that different signaling pathways can be activated through CCR5 interaction with HIV-1 or chemokine ligands. The identification of PC-PLC as a critical mediator of well-defined gp120-mediated effects in MDMs unravels a novel mechanism involved in bystander activation and may contribute to define potential therapeutic targets to block Env-triggered pathologic responses.Blood 05/2008; 111(7):3355-63. · 9.90 Impact Factor -
Article: Role of the cytokine environment and cytokine receptor expression on the generation of functionally distinct dendritic cells from human monocytes.
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ABSTRACT: Myeloid dendritic cells (DC) and macrophages evolve from a common precursor. However, factors controlling monocyte differentiation toward DC or macrophages are poorly defined. We report that the surface density of the GM-CSF receptor (GM-CSFR) alpha subunit in human peripheral blood monocytes varies among donors. Although no correlation was found between the extent of GM-CSFR and monocyte differentiation into DC driven by GM-CSF and IL-4, GM-CSFR expression strongly influenced the generation of CD1a(+) dendritic-like cells in the absence of IL-4. CD1a(+) cells generated in the presence of GM-CSF express CD40, CD80, MHC class I and II, DC-SIGN, MR, CCR5, and partially retain CD14 expression. Interestingly, they spontaneously induce the expansion of CD4(+) and CD8(+) allogeneic T lymphocytes producing IFN-gamma, and migrate toward CCL4 and CCL19. Upon stimulation with TLR ligands, they acquire the phenotypic features of mature DC. In contrast, the allostimulatory capacity is not further increased upon LPS activation. However, by blocking LPS-induced IL-10, a higher T cell proliferative response and IL-12 production were observed. Interestingly, IL-23 secretion was not affected by endogenous IL-10. These results highlight the importance of GM-CSFR expression in monocytes for cytokine-induced DC generation and point to GM-CSF as a direct player in the generation of functionally distinct DC.European Journal of Immunology 04/2008; 38(3):750-62. · 5.10 Impact Factor -
Article: GM-CSF in the generation of dendritic cells from human blood monocyte precursors: recent advances.
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ABSTRACT: Dendritic cells (DCs) play a key role in the orchestration of the immune system by virtue of their capacity to control both immunity and tolerance induction. The functions of DCs depend on the subset as well as their location and activation state. A number of in vitro protocols, developed to recapitulate DC generation from hematopoietic precursors, have suggested the importance of microenvironment and cytokine milieu in driving the generation of DCs endowed with peculiar phenotypic and functional features. Recently, some important concepts on the development of DCs from human blood monocytes have been challenged. The finding that human DCs can be generated from monocytes in the presence of granulocyte/macrophage colony-stimulating factor (GM-CSF) alone points to this cytokine as a direct player, rather than a survival-promoting factor, in the development of DCs with distinct properties. This review summarizes the role of different cytokine cocktails in the in vitro generation of human DCs from blood monocyte precursors, focusing on GM-CSF as a direct player in the generation of functionally distinct DCs.Immunobiology 02/2008; 213(9-10):859-70. · 3.20 Impact Factor -
Article: Role of endogenous interferon and LPS in the immunomodulatory effects of bovine lactoferrin in murine peritoneal macrophages.
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ABSTRACT: Lactoferrin (Lf) plays an important role in host defense against infection and excessive inflammation. Although the mechanisms underlying its immunomodulatory properties have not been fully elucidated yet, recent evidence suggests that some of these effects may be related to its capacity to form complexes with LPS. We report that the culture of resting mouse peritoneal macrophages (PM) with bovine Lf (bLf), prior to infection with the vesicular stomatitis virus (VSV), resulted in a significant reduction of virus yield with respect to control cultures. The antiviral activity of bLF was related to its capacity of inducing IFN-alpha/beta expression, which in turn inhibited VSV replication. Indeed, the accumulation of IFN-beta but not of IFNalpha(1-2) transcripts was up-modulated markedly early after bLf addition. Furthermore, bLf did not exert any antiviral activity in the presence of neutralizing antibodies to IFN-alpha/beta in PM from wild-type mice, as well as in PM from mice genetically defective for the response to IFN. The antiviral activity of bLf relied on its intrinsic capacity to bind LPS, as this protein did not induce IFN expression in PM from LPS-hyporesponsive mice. It is interesting that this LPS-binding property was dispensable for the production of TNF-alpha, which also occurred in LPS-hyporesponsive mice. Overall, these results indicate that some of the immunomodulatory effects ascribed to Lf may be related to its capacity to favor Type I IFN expression and argue in favor of an important role of the LPS-binding feature and TLR4 in some of the effects ascribed to this molecule.Journal of Leukocyte Biology 09/2007; 82(2):347-53. · 4.99 Impact Factor -
Article: Role of gp120 in dendritic cell dysfunction in HIV infection.
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ABSTRACT: Only a limited fraction of circulating virions are demonstrably infectious; therefore, exposure to inactivated viruses may mimic the most frequent type of CD4-HIV interactions that occur in vivo. Several studies have recently underscored the crucial role that those noninfectious viruses could play in defective immune function in HIV-infected individuals and in particular, in the dysregulation of dendritic cell (DC) function. In this review, we discuss how interactions between DC and HIV gp120 or inactivated virus, which harbor intact surface gp120, lead to impaired DC function through direct (direct contact) or indirect mechanisms (as a consequence of primary CD4+ T cell dysregulation, followed by defective CD4-DC interactions). It is important that these functionally impaired DCs fail to give optimal signal to T cells but appear to favor the emergence of regulatory T cells. gp120-mediated impairment of DC function could therefore play an important role in the pathogenesis of HIV disease.Journal of Leukocyte Biology 12/2006; 80(5):994-1000. · 4.99 Impact Factor -
Article: Human immunodeficiency virus type 1 gp120 and other activation stimuli are highly effective in triggering alpha interferon and CC chemokine production in circulating plasmacytoid but not myeloid dendritic cells.
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ABSTRACT: Exposure to aldrithiol-2-inactivated human immunodeficiency virus type 1 or gp120, but not gp41, triggered alpha interferon (IFN-alpha), CC chemokine ligand 2 (CCL2), CCL3, and CCL4 production in human plasmacytoid dendritic cells (DCs) but not in myeloid DCs (M-DCs) or monocyte-derived DCs from the same donors. The nonresponsiveness of M-DCs for IFN-alpha/beta production was a general feature specific to these cells, as they also failed to produce it in response to inactivated influenza virus, poly(I-C), lipopolysaccharide, Staphylococcus aureus Cowans I, or CD40L. The different capacities of circulating DC subsets to produce immune mediators in response to most stimuli argue for a different role for these cells in the regulation of innate immunity to pathogens.Journal of Virology 11/2005; 79(19):12597-601. · 5.40 Impact Factor -
Article: IL-2 induces expression and secretion of IFN-gamma in murine peritoneal macrophages.
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ABSTRACT: We investigated the effect of interleukin (IL)-2, a T cell growth factor capable of activating certain macrophage functions, on interferon (IFN)-gamma expression in resting mouse peritoneal macrophages (PM). IL-2 addition to PM from different mouse strains up-modulated IFN-gamma mRNA and protein secretion. It is notable that endogenous type I and II IFNs did not play any role in the IL-2-mediated effect, as comparable levels of secreted IFN-gamma were observed upon IL-2 stimulation of PM from deficient mice. In contrast, endogenous IFN-gamma was requested for the IL-12-induced IFN-gamma production. It is interesting that blocking of each component of the IL-2 receptor (IL-2R) by neutralizing antibodies almost completely abolished IL-2-induced IFN-gamma production, suggesting that all IL-2R chains contribute to the PM biological response to IL-2. The simultaneous treatment of PM with IL-2 and IL-12 resulted in a higher IFN-gamma secretion with respect to that obtained upon treatment with IL-2 or IL-12 alone. It is notable that IFN-gamma protein was expressed intracellularly in the majority of cells exhibiting a macrophage phenotype (i.e., F4/80+) and was secreted upon IL-2 stimulation. Overall, these findings demonstrate that IL-2 regulates at different levels IFN-gamma expression in macrophages, highlighting the crucial role of these cells and their regulated responsiveness to key cytokines in the cross-talk between innate and adaptive immunity.Journal of Leukocyte Biology 10/2005; 78(3):686-95. · 4.99 Impact Factor -
Article: IRF-4 expression in the human myeloid lineage: up-regulation during dendritic cell differentiation and inhibition by 1alpha,25-dihydroxyvitamin D3.
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ABSTRACT: Interferon (IFN) regulatory factor (IRF)-4 is a lymphoid- and myeloid-restricted transcription factor of the IRF family. We analyzed its expression during differentiation of human monocytes along the macrophage or the dendritic cell (DC) pathway and in blood myeloid and plasmacytoid DC (M-DC and P-DC, respectively) subsets. Monocyte differentiation into DC, driven by granulocyte macrophage-colony stimulating factor (GM-CSF)/interleukin-4 or GM-CSF/IFN-beta, resulted in a strong up-regulation of IRF-4 mRNA and protein, which was further increased by lipopolysaccharide. It is interesting that 1alpha,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], a potent inhibitor of DC differentiation, completely abolished IRF-4 up-regulation. IRF-4 was also detected in blood P-DC and M-DC. However, up-regulation upon in vitro culture and down-regulation by 1,25(OH)(2)D(3) was observed in M-DC but not in P-DC. These results point to IRF-4 as a potential player in human myeloid DC differentiation and as a novel target for the immunomodulatory activity of 1,25(OH)(2)D(3).Journal of Leukocyte Biology 07/2005; 77(6):944-7. · 4.99 Impact Factor -
Article: Reciprocal activating interaction between dendritic cells and pamidronate-stimulated gammadelta T cells: role of CD86 and inflammatory cytokines.
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ABSTRACT: We investigated the interactions between human monocyte-derived dendritic cells (DCs) and Ag-activated circulating TCR-gammadelta-expressing lymphocytes (Vdelta2). Coculture of immature DCs (iDCs) with peripheral blood Vdelta2 T cells activated with either pyrophosphomonoesters (isopentenyl pyrophosphate; IPP) or aminobiphosphonates (pamidronate; PAM) led to a significant up-modulation of CD86 and MHC class I molecules and to the acquisition of functional features typical of activated DCs. DC activation induced by both IPP- and PAM-stimulated gammadelta T cells was mostly mediated by TNF-alpha and IFN-gamma secreted by activated lymphocytes. However, the effect of PAM-activated gammadelta T cells, but not that of IPP-activated cells, required cell-to-cell contact. Reciprocally, activation of Vdelta2 T cells by PAM, but not by IPP, was dependent on cell contact with iDCs. In fact, when PAM-stimulated DC-gammadelta T cell cocultures were separated by a semipermeable membrane or treated with blocking anti-CD86 Abs, induction of CD25 and CD69 as well as IFN-gamma and TNF-alpha secretion by Vdelta2 cells were strongly reduced. These results demonstrate for the first time a bidirectional activating interaction between iDCs and PAM-stimulated gammadelta T lymphocytes, thus suggesting a potential adjuvant role of this early cross-talk in the therapeutic activity of aminobiphosphonate drugs.The Journal of Immunology 02/2005; 174(1):252-60. · 5.79 Impact Factor -
Article: Suppressive effect of 1alpha,25-dihydroxyvitamin D3 on type I IFN-mediated monocyte differentiation into dendritic cells: impairment of functional activities and chemotaxis.
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ABSTRACT: Dendritic cells (DCs) generated by a single-step exposure of human monocytes to type I IFN and GM-CSF (IFN-DCs) are endowed with potent immunostimulatory activities and a distinctive migratory response to specific chemokines. In this study, we evaluated the effects of 1alpha,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), the biologically active metabolite of vitamin D(3), on the DC differentiation/activation induced by type I IFN. We found that 1,25(OH)(2)D(3) prevented the generation of IFN-DCs when added to freshly isolated monocytes, and was capable of redirecting already differentiated IFN-DCs toward a more immature stage, as revealed by their immunophenotype, reduced allostimulatory activity, and impaired LPS-induced production of Th1-polarizing cytokines. Control and 1,25(OH)(2)D(3)-treated IFN-DCs exhibited a similar expression of vitamin D receptor, as well as comparable cell death rates. Furthermore, the chemotactic response of IFN-DCs to CCL4 and CCL19 was markedly reduced or completely abrogated by 1,25(OH)(2)D(3). Despite these changes in the IFN-DC migratory behavior, the expression of CCR5 and CCR7 and the calcium fluxes triggered by CCL4 and CCL19 were not affected. These findings indicate that, in this innovative single-step DC generation model from monocytes, the suppressive effect of 1,25(OH)(2)D(3) is associated with a potent impairment of DC migration in response to inflammatory and lymph node-homing chemokines, thus unraveling a novel mechanism involved in 1,25(OH)(2)D(3)-mediated immunomodulation.The Journal of Immunology 02/2005; 174(1):270-6. · 5.79 Impact Factor
Top co-authors
Top Journals
- Journal of Leukocyte Biology (5)
- Blood (3)
- The Journal of Immunology (3)
- Journal of Virology (2)
- Immunobiology (2)
Institutions
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1997–2011
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Istituto Superiore di Sanità
- • Department of Cell Biology and Neuroscience
- • Laboratory of Virology
Roma, Latium, Italy
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2006
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Cincinnati Children's Hospital Medical Center
- Department of Pediatrics
Cincinnati, OH, USA
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