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Mariagrazia Uguccioni

Publications and source records attributed to Mariagrazia Uguccioni.

18 recordsLinked to original sources
PubMed2005

CD molecules 2005: human cell differentiation molecules.

The immune system works through leukocytes interacting with each other, with other cells, with tissue matrices, with infectious agents, and with other antigens. These interactions are mediated by cell-surface glycoproteins and glycolipids. Antibodies against these leukocyte molecules have provided powerful tools for analysis of their structure, function, and distribution. Antibodies have been used widely in hematology, immunology, and pathology, and in research, diagnosis, and therapy. The associated CD nomenclature is commonly used when referring to leukocyte surface molecules and antibodies against them. It provides an essential classification for diagnostic and therapeutic purposes. The most recent (8th) Workshop and Conference on Human Leukocyte Differentiation Antigens (HLDA), held in Adelaide, Australia, in December 2004, allocated 95 new CD designations and made radical changes to its aims and future operational strategy in order to maintain its relevance to modern human biology and clinical practice.

Antigens, CD↗
PubMed2005

Systematic microanatomical analysis of CXCL13 and CCL21 in situ production and progressive lymphoid organization in rheumatoid synovitis.

CXCL13 and CCL21 have been functionally implicated in lymphoid tissue organization both in the upstream phases of lymphoid tissue embryogenesis and in ectopic lymphoid neogenesis in transgenic mice. Here, we analyzed the relationship between CXCL13 and CCL21 production and lymphoid tissue organization in rheumatoid synovitis as a model of a naturally occurring ectopic lymphoneogenesis. Through systematic analysis of mRNA and protein expression, we defined the microanatomical relationship between CXCL13 and CCL21 in progressive aggregational and structural phases of synovial inflammatory infiltrate. We provide the first direct in situ evidence that production of CXCL13 and CCL21 (rather than simply protein binding) is associated with inflammatory lymphoid tissue formation and development with the demonstration, in organized aggregates, of a secondary lymphoid organ-like compartmentalization and vascular association. Notably, the presence of CXCL13 and CCL21 (protein and mRNA) was also demonstrated in non-organized clusters and minor aggregational stages, providing evidence that their induction can take place independently and possibly upstream of T-B compartmentalization, CD21(+) follicular dendritic cell network differentiation and germinal center formation. Our data support the concept that, under inflammatory conditions, CXCL13 and CCL21 participate in lymphoid tissue microanatomical organization, attempting to recapitulate, in an aberrant lymphoid neogenetic process, their homeostatic and morphogenetic physiologic functions.

Arthritis, Rheumatoid↗
PubMed2005

CCL22-induced responses are powerfully enhanced by synergy inducing chemokines via CCR4: evidence for the involvement of first beta-strand of chemokine.

In an attempt to clarify how cells integrate the signals provided by multiple chemokines expressed during inflammation, we have uncovered a novel mechanism regulating leukocyte trafficking. Our data indicate that the concomitant exposure to CCR4 agonists and CXCL10/IP-10 strongly enhances the chemotactic response of human T lymphocytes. This enhancement is synergistic rather than additive and occurs via CCR4 since it persists after CXCR3 blockade. Besides chemotaxis, other cellular responses are enhanced upon stimulation of CCR4-transfected cells with CCL22/MDC plus CXCL10. Several other chemokines in addition to CXCL10 were able to increase CCL22-mediated chemotaxis. The first beta-strand of the chemokine structure is highly and specifically implicated in this phenomenon, as established using synergy-inducing and non-synergy-inducing chimeric chemokines. As shown in situ for skin from atopic and allergic contact dermatitis patients, this organ becomes the ideal environment in which skin-homing CCR4(+) T lymphocytes can accumulate under the stimulus offered by CCR4 agonists, together with the synergistic chemokines that are concomitantly expressed. Overall, our results indicate that chemokine-induced synergism strengthens leukocyte recruitment towards tissues co-expressing several chemokines.

Amino Acid Sequence↗
PubMed2004

A rich chemokine environment strongly enhances leukocyte migration and activities.

The migration of leukocytes in immune surveillance and inflammation is largely determined by their response to chemokines. While the chemokine specificities and expression patterns of chemokine receptors are well defined, it is still a matter of debate how leukocytes integrate the messages provided by different chemokines that are concomitantly produced in physiologic or pathologic situations in vivo. We present evidence for a novel regulatory mechanism of leukocyte trafficking. Our data are consistent with a mode of action where CC-chemokine receptor 7 (CCR7) agonists and unrelated, nonagonist chemokines first form a heteromeric complex, in the presence of which the triggering of CCR7 can occur at a much lower agonist concentration. The increase is synergistic and can be evoked by many but not all chemokines. Chemokine-induced synergism might provide an amplification system in "chemokine-rich" tissues, rendering leukocytes more competent to respond to migratory cues.

Animals↗
PubMed2004

I-TAC/CXCL11 is a natural antagonist for CCR5.

The selective CXC chemokine receptor 3 (CXCR3) agonists, monokine induced by interferon-gamma (IFN- gamma)/CXC chemokine ligand 9 (CXCL9), IFN-inducible protein 10/CXCL10, and IFN-inducible T cell alpha chemoattractant (I-TAC)/CXCL11, attract CXCR3+ cells such as CD45RO+ T lymphocytes, B cells, and natural killer cells. Further, all three chemokines are potent, natural antagonists for chemokine receptor 3 (CCR3) and feature defensin-like, antimicrobial activities. In this study, we show that I-TAC, in addition to these effects, acts as an antagonist for CCR5. I-TAC inhibited the binding of macrophage-inflammatory protein-1alpha (MIP-1alpha)/CC chemokine ligand 3 (CCL3) to cells transfected with CCR5 and to monocytes. Furthermore, cell migration evoked by regulated on activation, normal T expressed and secreted (RANTES)/CCL5 and MIP-1beta/CCL4, the selective agonist of CCR5, was inhibited in transfected cells and monocytes, respectively. In two other functional assays, namely the release of free intracellular calcium and actin polymerization, I-TAC reduced CCR5 activities to minimal levels. Sequence and structure analyses indicate a potential role for K17, K49, and Q51 of I-TAC in CCR5 binding. Our results expand on the potential role of I-TAC as a negative modulator in leukocyte migration and activation, as I-TAC would specifically counteract the responses mediated by many "classical," inflammatory chemokines that act not only via CCR3 but via CCR5 as well.

Actins↗
PubMed2004

Eotaxin-3/CCL26 is a natural antagonist for CC chemokine receptors 1 and 5. A human chemokine with a regulatory role.

Eotaxin-3 (CCL26), like eotaxin (CCL11) and eotaxin-2 (CCL24), has long been considered a specific agonist for CC chemokine receptor 3 (CCR3), attracting and activating eosinophils, basophils, and Th2 type T lymphocytes. Although not characterized extensively yet, its expression profile coincides with a potential role in allergic inflammation. We recently reported that eotaxin-3 is an antagonist for CCR2 (Ogilvie, P., Paoletti, S., Clark-Lewis, I., and Uguccioni, M. (2003) Blood 102, 789-784). In the present report, we provide evidence that eotaxin-3 acts as a natural antagonist on CCR1 and -5 as well. Eotaxin-3 bound to cells transfected with either CCR1 or -5 as well as to monocytes expressing both receptors. Further, it inhibited chemotaxis, the release of free intracellular calcium, and actin polymerization when cells were stimulated with known agonists of CCR1 and -5. An analysis of its three-dimensional structure indicated the presence of two distinct epitopes that may be involved in specific binding to CCR1, -2, -3, and -5. Taken together, our data thus indicate eotaxin-3 to be the first human chemokine that features broadband antagonistic activities, suggesting that it may have a modulatory rather than an inflammatory function. Further, eotaxin-3 may play an unrecognized role in the polarization of cellular recruitment by attracting Th2 lymphocytes as well as eosinophils and basophils via CCR3, while concomitantly blocking the recruitment of Th1 lymphocytes and monocytes via CCR1, -2, and -5.

Amino Acid Sequence↗
PubMed2004

Secondary lymphoid tissue chemokine (CCL21) is upregulated in allergic contact dermatitis.

Chemokines are important players in the development of allergic contact dermatitis (ACD). The participation of secondary lymphoid tissue chemokine (CCL21) is essential in the induction of the disease due to its expression in lymphatic vessels and in secondary lymphoid organs. Since there is no information about its participation during the effector phase of ACD, we studied this chemokine in patients already diagnosed with ACD, who were challenged with the relevant positive and negative (control) antigens. All patients showed a specific antigen-induced immune response characterized by early expression of inflammatory markers in blood endothelial cells followed by dermal accumulation of mononuclear cells with an important increase in infiltration of CXCR3+ but not of CCR7+ cells. In situ hybridization and immunohistochemistry showed low levels of CCL21 in lymphatic vessels at 2 h, whereas they were significantly increased at 10 and 48 h in all positive patch tests. In contrast, very low expression of this chemokine was observed in skin biopsies from the control site at 48 h. In addition, Langerin+ cells, which were present in dermis from positive patch tests at 2 h, were diminished in number at 10 and 48 h, but a significant number of those cells was still present in dermal areas of the control site at 48 h. We demonstrate for the first time that CCL21, a constitutively expressed chemokine, is strongly upregulated in human lymphatic vessels during a Th1/Tc1 allergic inflammatory response. This can provide the signal required for CCR7+ cells to leave the skin through CCL21-positive lymphatic vessels.

Adult↗
PubMed2004

A role for chemokines in the induction of chondrocyte phenotype modulation.

OBJECTIVE: To extend the study of the chemokine receptor repertoire on human chondrocytes to receptors with reported housekeeping functions (CXCR3, CXCR4, CXCR5, and CCR6) and to evaluate whether ligands of these receptors play a role in chondrocyte phenotype modulation and proliferation. METHODS: Chemokine receptor expression was determined by flow cytometry. Subcultures of chondrocytes were collected and fixed at confluence or during the exponential phase of growth and analyzed for chemokine receptor modulation. The effects of chemokines on isolated cells as well as chondrocytes cultured within an intact extracellular matrix were investigated. Isolated human chondrocytes were stimulated with 100 nM chemokines (monokine induced by interferon-gamma, stromal cell-derived factor 1alpha [SDF-1alpha], B cell-attracting chemokine 1 [BCA-1], or macrophage inflammatory protein 3alpha), and conditioned media were assessed for matrix-degrading enzyme contents (matrix metalloproteinases [MMPs] 1, 3, and 13, and N-acetyl-beta-D-glucosaminidase [NAG]). Cell proliferation and phenotype modulation were evaluated by bromodeoxyuridine incorporation and cathepsin B production. Induction of cell proliferation was assessed in cartilage explants by immunodetection of the proliferation-associated antigen S100A4. RESULTS: CXCR3, CXCR4, CXCR5, and CCR6 were detected on human chondrocytes. CXCR3 and CXCR4 expression was increased in exponentially growing chondrocyte subcultures. Ligands of all receptors enhanced the release of MMPs 1, 3, and 13. Release of NAG and cathepsin B was significantly higher in chemokine-stimulated cultures than in unstimulated cultures. SDF-1alpha and BCA-1 also induced DNA synthesis and chondrocyte proliferation, as was shown by the up-regulation of S100A4 in cartilage explants as well. CONCLUSION: Our findings extend the repertoire of functional responses elicited by the activity of chemokines on chondrocytes and open new avenues in our understanding of the control of chondrocyte differentiation status by chemokines and their receptors.

Acetylglucosaminidase↗
PubMed2004

Prostaglandin E2 modulates the functional responsiveness of human monocytes to chemokines.

Prostaglandin E(2) (PGE(2)) plays an important role in the immune response by modulating the complex interactions between leukocytes and tissue cells under inflammatory conditions. PGE(2) may possibly influence pro-inflammatory effects of chemokines and chemokine receptors that are among the main regulators of directional leukocyte migration. We analyzed whether PGE(2) affects chemokine receptor expression on human monocytes and their functional responsiveness to inflammatory chemokines. Expression of CCR5 on monocytes was significantly reduced, whereas CCR2 and CXCR4 expression were not affected by PGE(2). However, PGE(2 )treatment significantly increased the chemotactic response of monocytes to monocyte-chemoattractant protein-1 (MCP-1), RANTES and stromal cell-derived factor-1 (SDF-1). In addition, PGE(2) induced a higher calcium mobilization and actin polymerization upon chemokine stimulation. To better characterize PGE(2) effects, we used specific agonists for the PGE(2) receptors (EP(1) - EP(4)) characterized so far. The 11-deoxy PGE(1), an EP(2) /EP(4 )ligand, could mimic the effects observed using PGE(2). In contrast, the EP(1 )agonist, sulprostone, had not effects on monocytes, indicating that the effects of PGE(2) are mediated by EP(2)/EP(4 )receptors. Monocytes acquire a higher functional responsiveness to MCP-1, RANTES and SDF-1 after exposure to PGE(2), independently of the level of chemokine receptor expression. This mechanism might enhance the local monocyte recruitment under inflammatory conditions, and suggests specific PGE(2) receptor EP(2)/EP(4) antagonists as novel agents for the treatment of inflammatory diseases.

Actins↗
PubMed2003

Regulation of dendritic cell migration to the draining lymph node: impact on T lymphocyte traffic and priming.

Antigen-pulsed dendritic cells (DCs) are used as natural adjuvants for vaccination, but the factors that influence the efficacy of this treatment are poorly understood. We investigated the parameters that affect the migration of subcutaneously injected mouse-mature DCs to the draining lymph node. We found that the efficiency of DC migration varied with the number of injected DCs and that CCR7+/+ DCs migrating to the draining lymph node, but not CCR7-/- DCs that failed to do so, efficiently induced a rapid increase in lymph node cellularity, which was observed before the onset of T cell proliferation. We also report that DC migration could be increased up to 10-fold by preinjection of inflammatory cytokines that increased the expression of the CCR7 ligand CCL21 in lymphatic endothelial cells. The magnitude and quality of CD4+ T cell response was proportional to the number of antigen-carrying DCs that reached the lymph node and could be boosted up to 40-fold by preinjection of tumor necrosis factor that conditioned the tissue for increased DC migration. These results indicate that DC number and tissue inflammation are critical parameters for DC-based vaccination.

Animals↗
PubMed2003

CXC and CC chemokine expression in inflamed and noninflamed pelvic ileal pouch tissue.

BACKGROUND AND AIMS: Pouchitis is the major long-term complication after ileal pouch-anal anastomosis (IPAA) in patients operated on for ulcerative colitis. The cause is unknown, but both the history of ulcerative colitis and increased bacterial concentration are important factors. Chemokines are mediators for the recruitment of inflammatory cells to the site of inflammation. This study examined the tissue expression of a panel of specific chemokines and the corresponding recruitment of inflammatory cells in IPAA tissue with and without inflammation and after antibiotic treatment. PATIENTS AND METHODS: Biopsy specimens postoperatively from ulcerative colitis patients with IPAA were obtained by endoscopy. Biopsies were taken from 8 patients with noninflamed IPAA and from 14 patients with an episode of acute pouchitis, before and after antibiotic treatment. Biopsies were stained for CD68, CD3, elastase, eotaxin, IP-10, MCP-1, MCP-3, and IL-8 and analyzed by NIH Image analyzer. RESULTS: Expression of IL-8, MCP-1, MCP-3, and IP-10 was significantly higher in pouchitis than normal pouch. The expression of MCP-1, MCP-3 and IP-10 were significantly lower after antibiotic treatment. CONCLUSION: These data support the importance of chemokines for the leukocyte recruitment in pouch tissue during acute pouchitis.

Adult↗
PubMed2003

Eotaxin-3 is a natural antagonist for CCR2 and exerts a repulsive effect on human monocytes.

Eotaxin-3 (CCL26) belongs to the group of CC chemokines that attract eosinophils, basophils, and Th2 lymphocytes. Like eotaxin (CCL11) and eotaxin-2 (CCL24), eotaxin-3 mediates its activity through CCR3. Here we show that eotaxin-3 also binds to CCR2 on monocytes and CCR2-transfected cells. In contrast to monocyte chemotactic protein 1 (MCP-1; CCL2), eotaxin-3 does not trigger intracellular calcium mobilization, enzyme release, or phosphorylation of the mitogen-activated protein (MAP) kinase ERK and induces a weak chemotaxis in monocytes. Instead, eotaxin-3 inhibits MCP-1-mediated responses, thus acting as a natural antagonist for CCR2. This study also demonstrates that eotaxin-3 promotes active movement of monocytes away from a gradient of eotaxin-3 in vitro. This repellent effect is amplified when an additional gradient of MCP-1 is applied, demonstrating that the 2 mechanisms are synergistic. Eotaxin-3 effects on monocytes are largely abolished when cells are pretreated with MCP-1 or CCR2 antagonists. Like MCP-1-mediated migration, repulsion is sensitive to Bordetella pertussis toxin, indicating the involvement of Gi protein-coupled receptors. However, using transfected cells expressing CCR2 we could not detect F-actin formation or an active movement away induced by eotaxin-3, suggesting that either expression of a single receptor type is not sufficient to mediate cell repulsion or that the used transfected cell lines lack additional interaction molecules that are required for reverse migration. Eotaxin-3 was expressed by vascular endothelial cells and was essential for endothelial transmigration of eosinophils. Our data provide a mechanism by which 2 chemokine gradients that are oriented in opposite directions could cooperate in efficiently driving out monocytes from blood vessels into tissue.

Calcium↗
PubMed2003

Macrophages exposed to Mycobacterium tuberculosis release chemokines able to recruit selected leucocyte subpopulations: focus on gammadelta cells.

Granuloma is a typical feature of tuberculosis. We evaluated the chemotaxis of selected human leucocyte subsets induced by macrophages incubated with Mycobacterium tuberculosis (MT)-derived products in vitro. The release of monocyte chemotactic protein 1 (MCP-1) and interleukin-8 (IL-8) correlated with the specific induction of strong chemotaxis towards monocytes and polymorphonuclear leucocytes (PMNs). gammadelta and T helper type 1 (Th1) alphabeta lymphocytes were chemoattracted, while T-resting, IL-2-activated and Th2 lymphocytes were unaffected. Activation with mycobacterium-derived, phosphate-containing components, modulated the chemokine receptor profile of gammadelta T lymphocytes as well as their pattern of cyto-chemokine production, disclosing a potential for their active participation in granuloma formation. In particular, CXCR3 and IP-10, which we found to be released by MT-pulsed alveolar macrophages, seem to represent the receptor-counter-receptor pair implicated in the chemotaxis of gammadelta lymphocytes. Immunohistochemical analysis and in situ hybridization revealed the in vivo presence of IL-8, MCP-1 and IL-10 in lymph node and lung tuberculous granulomas. Our results underscore the role of MT extracts in the induction of macrophage-derived chemokines responsible for the orchestrated recruitment of PMNs, monocytes, and Th1 and gammadelta T cells, as well as in the regulation of gammadelta function.

Antigens, Bacterial↗
PubMed2002

Expression of B-cell-attracting chemokine 1 (CXCL13) by malignant lymphocytes and vascular endothelium in primary central nervous system lymphoma.

Primary central nervous system lymphoma (PCNSL) is a rare but often rapidly fatal form of non-Hodgkin B-cell lymphoma that arises within the central nervous system (CNS) and has a low propensity to metastasize. We performed immunohistochemistry on formalin-fixed, paraffin-embedded brain biopsy specimens from 24 patients with PCNSL to investigate the expression of B cell-attracting chemokine 1 (BCA-1, CXCL13), a lymphoid chemokine involved in B-cell compartmental homing within secondary lymphoid organs and recently implicated in the pathogenesis of inflammatory and malignant lymphocyte-mediated diseases. Whereas BCA-1 was not detected in normal human brain, all 24 brain biopsy specimens containing PCNSL were positive for BCA-1. Double immunostaining on selected specimens localized BCA-1 to malignant B lymphocytes and vascular endothelium. In contrast, 2 chemokines implicated particularly in T-cell movement, secondary lymphoid tissue chemokine (SLC, CCL21) and Epstein-Barr virus-induced molecule 1 ligand chemokine (ELC, CCL19), were expressed only by occasional stromal cells in 2 and 4 of the 24 specimens, respectively. Tumor cells stained positively for CXCR5, the primary receptor for BCA-1. In situ hybridization verified the expression of BCA-1 mRNA by malignant B cells, but not vascular endothelium, within the tumor mass, suggesting that vascular endothelial BCA-1 expression may be consequent to transcytosis. In PCNSL, expression of BCA-1 by malignant lymphocytes and vascular endothelium may influence tumor development and localization to CNS.

Adult↗
PubMed2002

CD antigens 2002.

Explore the source record for details and available documents.

Antibodies, Monoclonal↗
PubMed2002

Growth-related oncogene alpha induction of apoptosis in osteoarthritis chondrocytes.

OBJECTIVE: To evaluate the apoptotic effect of the chemokine growth-related oncogene alpha (GROalpha), which we recently reported to be up-regulated in osteoarthritis (OA) chondrocytes. Chondrocyte apoptosis is considered to be a major determinant of cartilage damage in OA, a disease resulting from the aberrant production of inflammatory mediators (cytokines and chemokines) and effectors (matrix metalloproteinases and reactive oxygen and nitrogen species) by chondrocytes. METHODS: We investigated the apoptotic effect of GROalpha on isolated human cells and on in vitro-cultured cartilage explants by conventional methods (morphology, detection of DNA fragmentation in situ and in solution, exposure of phosphatidylserine) and by analysis of "early" biochemical events (plasma membrane depolarization, activation of caspase 3, and phosphorylation of c-Jun N-terminal kinase/stress-activated protein kinase). RESULTS: We clearly demonstrated that GROalpha was able to initiate a series of morphologic, biochemical, and molecular changes that led to chondrocyte apoptosis. Moreover, we found that additional signals delivered from the extracellular matrix (ECM) were essential in the control of chondrocyte susceptibility to GROalpha-induced apoptosis, since cell death was detected only when cells were stimulated after reestablishment of their proper interactions with the ECM, or in cartilage explant samples with reduced ECM, as indicated by decreased Safranin O staining. CONCLUSION: GROalpha can induce apoptosis in articular chondrocytes, and the induction is dependent upon additional signals from the ECM. These findings are relevant to understanding the pathogenesis of OA, in view of the availability of the GROalpha chemokine in the joint space in the course of this rheumatic disease.

Annexin A5↗