Showing papers by "Silvano Sozzani published in 2003"
TL;DR: Chemerin appears as a potent chemoattractant protein of a novel class, which requires proteolytic activation and is specific for APCs, and was shown to promote calcium mobilization and chemotaxis of immature DCs and macrophages in a ChemR23-dependent manner.
Abstract: Dendritic cells (DCs) and macrophages are professional antigen-presenting cells (APCs) that play key roles in both innate and adaptive immunity. ChemR23 is an orphan G protein-coupled receptor related to chemokine receptors, which is expressed specifically in these cell types. Here we present the characterization of chemerin, a novel chemoattractant protein, which acts through ChemR23 and is abundant in a diverse set of human inflammatory fluids. Chemerin is secreted as a precursor of low biological activity, which upon proteolytic cleavage of its COOH-terminal domain, is converted into a potent and highly specific agonist of ChemR23, the chemerin receptor. Activation of chemerin receptor results in intracellular calcium release, inhibition of cAMP accumulation, and phosphorylation of p42-p44 MAP kinases, through the Gi class of heterotrimeric G proteins. Chemerin is structurally and evolutionary related to the cathelicidin precursors (antibacterial peptides), cystatins (cysteine protease inhibitors), and kininogens. Chemerin was shown to promote calcium mobilization and chemotaxis of immature DCs and macrophages in a ChemR23-dependent manner. Therefore, chemerin appears as a potent chemoattractant protein of a novel class, which requires proteolytic activation and is specific for APCs.
833 citations
TL;DR: The paucity of intratumoural DCs and the predominant immature phenotype of peritumoural dermal DCs indicate defective maturation of primary cutaneous melanoma‐associated DCs, resulting in lack of T‐cell priming, which may explain why melanoma cells grow despite the presence of infiltrating immune cells.
Abstract: The present study has analysed the distribution and phenotype of dendritic cells (DCs) in primary cutaneous melanomas and sentinel lymph nodes by immunohistochemistry. In primary melanomas, an increase of DCs was found in the epidermis and the peritumoural area. Intraepidermal DCs were mostly CD1a+/Langerin+ Langerhans cells. Peritumoural DCs included a large population of DC-SIGN+/mannose-receptor+/CD1a− DCs, a small subset of CD1a+ DCs, and, remarkably, plasmacytoid monocytes/plasmacytoid DCs (PM/PDCs). The PM/PDCs, most likely recruited by SDF-1 secreted by melanoma cells, produced type I interferon (IFN-I), but the expression of the IFN-α inducible protein MxA was extremely variable and very limited in the majority of cases. All DC subsets were predominantly immature. The peritumoural area also contained a minor subset of mature CD1a+ DCs. However, the small amount of local interleukin (IL)-12 p40 mRNA and the naive phenotype of 20–50% of peritumoural T-lymphocytes are consistent with poor T-cell stimulation or erroneous recruitment. In sentinel lymph nodes, notable expansion of mature CD1a+/Langerin+ DCs was observed. The paucity of intratumoural DCs and the predominant immature phenotype of peritumoural dermal DCs indicate defective maturation of primary cutaneous melanoma-associated DCs, resulting in lack of T-cell priming. These results may explain why melanoma cells grow despite the presence of infiltrating immune cells. Copyright © 2003 John Wiley & Sons, Ltd.
293 citations
TL;DR: The results indicate that D6 acts as an inflammatory chemokine scavenging nonactivatory decoy receptors and suggest that in lymphatic vessels D6 may function as a gatekeeper for inflammatory CC chemokines, by clearing them and preventing excessive diffusion via afferent lymphatics to lymph nodes.
Abstract: In an effort to define the actual function of the promiscuous putatively silent chemokine receptor D6, transfectants were generated in different cell types. Engagement of D6 by inflammatory CC chemokines elicited no calcium response nor chemotaxis, but resulted in efficient agonist internalization and degradation. Also in lymphatic endothelium, where this receptor is expressed in vivo, D6 did not elicit cellular responses other than ligand internalization and degradation. In particular, no evidence was obtained for D6-mediated transcytosis of chemokines in the apical-to-basal or basal-to-apical directions. These results indicate that D6 acts as an inflammatory chemokine scavenging nonactivatory decoy receptors and suggest that in lymphatic vessels D6 may function as a gatekeeper for inflammatory CC chemokines, by clearing them and preventing excessive diffusion via afferent lymphatics to lymph nodes.
194 citations
TL;DR: CCL18 may act as a chemotactic signal that promotes the colocalization of immature DC with naive T lymphocytes in an IL-10-dominated environment with the consequent generation of T regulatory cells, suggesting that CCL18 is part of an inhibitory pathway devoted to limiting the generation of specific immune responses at peripheral sites.
Abstract: Dendritic cells (DC) orchestrate the trafficking of lymphocytes by secreting chemokines with different specificity and function. Chemokines are produced at higher levels by mature DC. This study shows that CCL18 is one of the most abundant chemokines produced by immature DC. In contrast to all other chemokines investigated to date, CCL18 was selectively down-regulated during the maturation process induced by LPS, TNF, CD40 ligand, Staphylococcus aureus Cowan I, Candida albicans , and influenza virus. IL-10 and vitamin D 3 , two known inhibitors of DC differentiation and function, strongly promoted CCL18 secretion, whereas IFN-γ, a costimulator of DC function, inhibited its production. IL-10 also induced CCL18 secretion in blood myeloid DC. No CCL18 secretion was observed in blood plasmacytoid DC. The opposite pattern of regulation was observed for CCL20, a prototypic inflammatory chemokine. CCL18 was found to be a chemotactic factor for immature DC. Therefore, CCL18 may act as a chemotactic signal that promotes the colocalization of immature DC with naive T lymphocytes in an IL-10-dominated environment with the consequent generation of T regulatory cells. These characteristics suggest that CCL18 may be part of an inhibitory pathway devoted to limiting the generation of specific immune responses at peripheral sites.
151 citations
TL;DR: OPN-mediated recruitment of proangiogenic monocytes may represent a mechanism of amplification of FGF2-induced neovascularization during inflammation, wound healing, and tumor growth.
Abstract: The cytokine/extracellular matrix protein osteopontin (OPN/Eta-1) is an important component of cellular immunity and inflammation. It also acts as a survival, cell-adhesive, and chemotactic factor for endothelial cells. Here, subtractive suppression hybridization showed that serum-deprived murine aortic endothelial (MAE) cells transfected with the angiogenic fibroblast growth factor-2 (FGF2) overexpress OPN compared with parental cells. This was confirmed by Northern blotting and Western blot analysis of the conditioned media in different clones of endothelial cells overexpressing FGF2 and in endothelial cells treated with the recombinant growth factor. In vivo, FGF2 caused OPN expression in newly formed endothelium of the chick embryo chorioallantoic membrane (CAM) and of murine s.c. Matrigel plug implants. Recombinant OPN (rOPN), the fusion protein GST-OPN, and the deletion mutant GST-ΔRGD-OPN were angiogenic in the CAM assay. Angiogenesis was also triggered by OPN-transfected MAE cells grafted onto the CAM. OPN-driven neovascularization was independent from endothelial αvβ3 integrin engagement and was always paralleled by the appearance of a massive mononuclear cell infiltrate. Accordingly, rOPN, GST-OPN, GST-ΔRGD-OPN, and the conditioned medium of OPN-overexpressing MAE cells were chemotactic for isolated human monocytes. Also, rOPN triggered a proangiogenic phenotype in human monocytes by inducing the expression of the angiogenic cytokines TNF-α and IL-8. OPN-mediated recruitment of proangiogenic monocytes may represent a mechanism of amplification of FGF2-induced neovascularization during inflammation, wound healing, and tumor growth.
130 citations
TL;DR: The results indicate that the anti‐inflammatory activity of benzydamine is exerted at multiple levels, including monocyte migration to chemotactic factors associated to a blockage of ERK and p38 MAPK pathways.
Abstract: 1. The present study was aimed to investigate the effect of benzydamine, an anti-inflammatory drug devoid of activity on arachidonic acid metabolism, on monocyte chemotaxis and to define the possible biochemical correlates of activity. 2. Benzydamine inhibited monocyte chemotaxis in response to three classes of chemoattractants: the prototypic CC-chemokine CCL2 (MCP-1), the microbial product fMLP and the complement cascade component C5a. The effect was dose-dependent with IC50's of 100, 50 and 45 microm for MCP-1/CCL2, fMLP and C5a, respectively. At the dose of 100 microm, the effect resulted in a 50+/-10% inhibition of MCP-1/CCL2-induced chemotaxis and 53+/-6 and 54+/-5% inhibitions of chemotaxis in response of fMLP and C5a, respectively (n=3). 3. Receptor expression as well as calcium fluxes in response to chemoattractants were not affected by benzydamine. 4. Benzydamine strongly inhibited chemoattractant-induced activation of the mitogen-activated protein kinase (MAPK) ERK1/2, and of its upstream activator kinase MEK1/2. ERK1/12 activation in response to chemoattractants was 89-98% inhibited by a 100 microm concentration of benzydamine with an IC50 of 30 microm. 5. Under the same experimental conditions, pretreatment with 100 microm benzydamine caused a 75-89% inhibition of p38 activation (IC50 25 microm). 6. These results indicate that the anti-inflammatory activity of benzydamine is exerted at multiple levels, including monocyte migration to chemotactic factors associated to a blockage of ERK and p38 MAPK pathways.
19 citations
01 Jan 2003
TL;DR: This chapter focuses on CC chemokines, which are a complex system of molecules that affect a variety of hematopoietic and non-hematopoetic cell types and role in the transition from innate to acquired immunity, and in amplification of polarized responses on selected molecules, and pathologies are used as a paradigm.
Abstract: This chapter focuses on CC chemokines, which are a complex system of molecules that affect a variety of hematopoietic and non-hematopoietic cell types. Validation as pharmacological targets includes gene targeting, usage of antibodies or antagonists, whose expression in human pathology is discussed in the chapter. CC chemokine receptor antagonists have been developed, and are at various stages of preclinical or clinical development. CC chemokines are the most numerous, and diversified family of the four subgroups defined, based on the Cys motif (CC, CXC, C, CX3C). In humans, it includes at least 25 members interacting with at least 11 signaling receptors. CC chemokines have been discovered following different pathways, ranging from biological, and biochemical identification to direct cDNA cloning to, more recently, in silico cloning by gene bank mining. The development of efficacious CC chemokine antagonists remains a “holy grail” for the general field of cytokine pharmacology. The chemokines role in the transition from innate to acquired immunity, and in amplification of polarized responses on selected molecules, and pathologies are used as a paradigm.
7 citations
Patent•
25 Jun 2003
TL;DR: In this article, a G-protein coupled receptor and a novel ligand were proposed for the diagnosis and treatment of a disease or disorder related to the dysregulation of Gprotein-coupled receptor signaling.
Abstract: The present invention relates to a G-protein coupled receptor and a novel ligand therefor. The invention provides screeing assays for the identification of candidate compounds which modulate the activity of the G-protein coupled receptor, as well as assays useful for the diagnosis and treatment of a disease or disorder related to the dysregulation of G-protein coupled receptor signaling.