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M Uguccioni

Publications and source records attributed to M Uguccioni.

At least 37 records · Page 2Linked to original sources
PubMed2000

Macrophages infiltrating the tissue in chronic pancreatitis express the chemokine receptor CCR5.

BACKGROUND: The immunologic mechanisms involved in the development of chronic pancreatitis (CP) are poorly understood. Chronically inflamed tissues contain increased numbers of mononuclear cells expressing the CC chemokine receptor 5 (CCR5), which is also a coreceptor for HIV entry of macrophagetropic strains. However, whether this receptor is involved in the inflammatory process in CP is not known. In the current study, we analyzed the expression of CCR5 in CP. The detection of chemokine receptors on inflammatory cells would strongly suggest their involvement in the pathogenesis of CP (i.e., attraction and activation of these cells). To further evaluate this, we consecutively analyzed the expression of 2 ligands of CCR5: RANTES and MIP-alpha. METHODS: Pancreatic tissue samples of 22 patients with CP and of 7 healthy pancreas were evaluated. CCR5, RANTES, and MIP-1alpha were analyzed by Northern blot analysis. Consecutive tissue sections were stained for CCR5, CD3, and CD68 to define the leukocyte subtype expressing CCR5 in CP. RESULTS: By Northern blot analysis, CCR5, RANTES, and MIP-1alpha messenger RNA (mRNA) levels were 12.9-fold, 13.3-fold and 9.2-fold higher in CP specimens compared with healthy controls, respectively (P<.01). Immunostaining for CCR5 revealed a 30-fold increase of CCR5-positive cells in CP tissue compared with the healthy pancreas. Staining of consecutive tissue sections revealed that the majority of CCR5-positive cells were also CD68-positive (macrophages). CONCLUSIONS: Our data indicate that a remarkable portion of CCR5-positive cells in CP are macrophages. CCR5 is most likely involved in the attraction and activation of these macrophages, since the CCR5 ligands RANTES and MIP-1alpha are concomitantly upregulated.

Adult↗
PubMed2000

[The role of chemokines in nasal polyps].

Nasal polyposis is an inflammatory condition of the nose and the sinuses characterised by a marked infiltration of eosinophils in addition to lymphocytes, mast cells and macrophages. The selective recruitment of eosinophils to inflammatory sites is mediated by CC chemokines such as Eotaxin and Eotaxin-2. In the present study histology, immunohistochemistry and ELISA were performed. The levels of Eotaxin and Eotaxin-2 and for comparison other chemokines RANTES and IL-8 were measured in nasal polyp tissue and in control nasal tissue. On histological examination 6 polyps showed an oedematous structure, one was glandular and one had a fibromatous pattern, while all showed a marked eosinophil infiltration. Immunohistochemistry of the polyps showed that epithelial cells were strongly positive for Eotaxin and IL-8, whereas endothelial cells stained positive for Eotaxin-2. Significantly higher amounts of Eotaxin, Eotaxin-2 and IL-8 were detected in polyp tissue when compared with control middle turbinates. The increased levels of eosinophil-stimulating chemokines, such as Eotaxin and Eotaxin-2 in nasal polyps suggest that they may be important regulators of eosinophil recruitment in this inflammatory disease.

Chemokine CCL11↗
PubMed1999

Increased expression of IP-10, IL-8, MCP-1, and MCP-3 in ulcerative colitis.

Chemokines are thought to be important for the recruitment of granulocytes and mononuclear cells and thus for the maintenance of inflammation in ulcerative colitis (UC). We have studied the expression of interferon-gamma inducible protein-10 (IP-10), interleukin-8 (IL-8), monocyte chemoattractant protein (MCP)-1, MCP-3, and macrophage inflammatory protein (MIP)-1alpha in UC patients and control individuals to assess the role of these chemokines in disease progression. Colonic biopsies were taken endoscopically from patients and controls, frozen immediately and subsequently stained for IP-10, IL-8, MCP-1, MCP-3, and MIP-1alpha in serial sections. Cells infiltrating the lamina propria but not epithelial cells express the analyzed chemokines. They were differentiated and counted, and chemokine-expressing cells were quantified by image analysis. The percentage of cells expressing IP-10, IL-8, MCP-1, and MCP-3 was significantly enhanced in all UC samples as compared to controls. Expression in the controls was borderline, except for IP-10. No expression of MIP-1alpha was found in controls and UC. IP-10 was also markedly expressed in the mucosa of control biopsies and therefore could have a role in activated T lymphocytes' recruitment into the healthy mucosa.

Adult↗
PubMed1999

Enhanced expression of eotaxin and CCR3 in atopic dermatitis.

Chemokines are thought to play an important part in the development of inflammation in atopic dermatitis. Eotaxin, a CC chemokine, is a potent chemoattractant and activator of human eosinophils, basophils and Th2 lymphocytes which acts via the chemokine receptor CCR3. We studied the expression of eotaxin and CCR3, as well as MCP-3, MIP-1alpha and interleukin-8, in atopic dermatitis and normal skin by immunohistochemistry and nested reverse transcriptase-polymerase chain reaction. Skin biopsy specimens were obtained from nonlesional and lesional skin of patients with atopic dermatitis and of nonatopic controls. Immunoreactivity and transcripts of eotaxin and CCR3 were significantly increased in lesional skin from atopic dermatitis, but not in nonatopic controls. In nonlesional atopic dermatitis samples CCR3 expression was also significantly increased at the mRNA and protein level, whereas eotaxin was increased at the mRNA level only. No significant difference in the expression of MCP-3, MIP-1alpha, and interleukin-8 was observed between skin samples from atopic dermatitis and nonatopic controls. The enhanced local production of eotaxin may lead to the recruitment of eosinophils and T lymphocytes, which both express CCR3 and contribute to the initiation and maintenance of inflammation.

Adolescent↗
PubMed1999

BCA-1 is highly expressed in Helicobacter pylori-induced mucosa-associated lymphoid tissue and gastric lymphoma.

Infection with Helicobacter pylori (Hp) induces the formation of lymphoid tissue in the stomach and the occasional development of primary gastric B-cell lymphomas. We have studied the expression of 2 chemokines that attract B lymphocytes, BCA-1 and SLC, in gastric tissue samples obtained from patients with chronic gastritis induced by Hp infection or nonsteroidal anti-inflammatory drugs, as well as from patients with Hp-associated low-grade and high-grade gastric lymphomas. High-level expression of BCA-1 and its receptor, CXCR5, was observed in all mucosal lymphoid aggregates and in the mantle zone of all secondary lymphoid follicles in Hp-induced gastric mucosa-associated lymphoid tissue (MALT). Follicular dendritic cells and B lymphocytes are possible sources of BCA-1, which is not expressed by T lymphocytes, macrophages, or CD1a(+) dendritic cells. Strong expression of BCA-1 and CXCR5 was also detected in the transformed B cells of gastric MALT lymphomas. By contrast, SLC was confined almost exclusively to endothelial cells in and outside the lymphoid tissue. Only scant, occasional SLC expression was observed in the marginal zone of MALT follicles. Our findings indicate that BCA-1, which functions as a homing chemokine in normal lymphoid tissue, is induced in chronic Hp gastritis and is involved in the formation of lymphoid follicles and gastric lymphomas of the MALT type.

Aged↗
PubMed1999

[The management of syncope in the hospital: the OESIL Study (Osservatorio Epidemiologico della Sincope nel Lazio)].

BACKGROUND: While syncope is generally considered a frequent finding in clinical practice, no clear epidemiological evidence is available about the relevance of such an event in the general population of Italy. METHODS: The OESIL Study was designed and undertaken in 15 hospitals of the Italian region of Latium in order to assess the percentage of emergency-room visits and admissions due to syncope, as well as to analyze the in-hospital diagnostic work-up performed for this condition. RESULTS: During a two-month observation period, 781 (372 males and 409 females, mean age 55.2 (22.8 years) consecutive patients came to the emergency rooms of the 15 hospitals included in the investigation due to a syncope spell (0.9% of emergency room visits); 450/781 patients (57.6%) were subsequently hospitalized (1.3% of all admissions): 48.0% of the admissions were admitted to a general medical ward, 29.3% to an observation ward, 13.3% to a cardiology section, 1.6% to a neurology section and 7.8% to other clinical sections (neurosurgery, general surgery). The mean duration of in-hospital stay was 6.9 (5.8 days; range 1-40 days). During the hospitalization period, 93.1% of patients underwent an ECG, 51.0% an EEG, 44.3% a CT scan of the central nervous system, 40.2% an echocardiogram and 19.5% a tilt-test. The syncope spell was considered to have a cardiovascular origin in 33.8% of the cases and a non-cardiovascular in 11.6% of the cases, while the origin was unknown in 54.4% of the cases. CONCLUSIONS: Collected data support the idea that syncope represents a frequent event in the general population and is responsible for a significant percentage of emergency-room visits and hospital admissions. However, the performance of conventional diagnostic work-ups is far from being satisfactory.

Adult↗
PubMed1998

Enhanced and coordinated in vivo expression of inflammatory cytokines and nitric oxide synthase by chondrocytes from patients with osteoarthritis.

OBJECTIVE: To evaluate the sites of expression of interleukin-1beta (IL-1beta), tumor necrosis factor alpha (TNFalpha), and inducible nitric oxide synthase (iNOS) in patients with inflammatory and degenerative joint diseases. METHODS: Cytokines and iNOS were detected by immunohistochemistry analysis of synovial and cartilage biopsy specimens obtained at knee arthroscopy in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), osteoarthritis (OA), and traumatic knee arthritis. Cytokine and iNOS expression was quantified using computerized image analysis. RESULTS: IL-1beta, TNFalpha, and iNOS were highly expressed by synovial cells (lining layer cells, infiltrating leukocytes, endothelial cells) from patients with inflammatory arthritides and significantly less by synovial cells from patients with OA and traumatic arthritis. In contrast, the latter patients showed high chondrocyte expression of cytokines and iNOS while RA and PsA patients had only minor chondrocyte positivity. In both joint compartments, IL-1beta expression, TNFalpha expression, and iNOS expression were strongly correlated. CONCLUSION: The enhanced and coordinated expression of IL-1beta, TNFalpha, and iNOS by chondrocytes strongly supports the hypothesis that chondrocytes are the major site of production of mediators of inflammation in human OA, thus playing a primary role in the pathogenesis of this disease.

Adult↗
PubMed1997

Functional expression of the eotaxin receptor CCR3 in T lymphocytes co-localizing with eosinophils.

BACKGROUND: The chemokine eotaxin is produced at sites of allergic inflammation, binds selectively to the chemokine receptor CCR3 and attracts eosinophil and basophil leukocytes, which express high numbers of this receptor. Responses of T lymphocytes to eotaxin have not been reported so far. We have investigated the expression of CCR3 in T lymphocytes and analysed the properties and in vivo distribution of T lymphocytes expressing this receptor. RESULTS: In search of chemokine receptors with selective expression in T lymphocytes, we have isolated multiple complementary DNAs (cDNAs) encoding CCR3 from a human CD4+ T-cell cDNA library. T-lymphocyte clones with selectivities for protein and non-protein antigens were analysed for expression of CCR3 and production of Th1- and Th2-type cytokines. Of 13 clones with surface CCR3, nine secreted enhanced levels of interleukin-4 and/or interleukin-5, indicating that CCR3 predominates in Th2-type lymphocytes. CCR3+ T lymphocytes readily migrated in response to eotaxin, and showed the characteristic changes in cytosolic free calcium. Immunostaining of contact dermatitis, nasal polyp and ulcerative colitis tissue showed that CCR3+ T lymphocytes are recruited together with eosinophils and, as assessed by flow cytometry, a large proportion of CD3+ cells extracted from the inflamed skin tissue were CCR3+. By contrast, CCR3+ T lymphocytes were absent from tissues that lack eosinophils, as demonstrated for normal skin and rheumatoid arthritis synovium. CONCLUSIONS: We show that T lymphocytes co-localizing with eosinophils at sites of allergic inflammation express CCR3, suggesting that eotaxin/CCR3 represents a novel mechanism of T-lymphocyte recruitment. These cells are essential in allergic inflammation, as mice lacking mature T lymphocytes were insensitive to allergen challenge. Surface CCR3 may mark a subset of T lymphocytes that induce eosinophil mobilization and activation through local production of Th2-type cytokines.

Cell Movement↗
PubMed1997

High expression of the chemokine receptor CCR3 in human blood basophils. Role in activation by eotaxin, MCP-4, and other chemokines.

Eosinophil leukocytes express high numbers of the chemokine receptor CCR3 which binds eotaxin, monocyte chemotactic protein (MCP)-4, and some other CC chemokines. In this paper we show that CCR3 is also highly expressed on human blood basophils, as indicated by Northern blotting and flow cytometry, and mediates mainly chemotaxis. Eotaxin and MCP-4 elicited basophil migration in vitro with similar efficacy as regulated upon activation normal T cells expressed and secreted (RANTES) and MCP-3. They also induced the release of histamine and leukotrienes in IL-3-primed basophils, but their efficacy was lower than that of MCP-1 and MCP-3, which were the most potent stimuli of exocytosis. Pretreatment of the basophils with a CCR3-blocking antibody abrogated the migration induced by eotaxin, RANTES, and by low to optimal concentrations of MCP-4, but decreased only minimally the response to MCP-3. The CCR3-blocking antibody also affected exocytosis: it abrogated histamine and leukotriene release induced by eotaxin, and partially inhibited the response to RANTES and MCP-4. In contrast, the antibody did not affect the responses induced by MCP-1, MCP-3, and macrophage inflammatory protein-1alpha, which may depend on CCR1 and CCR2, two additional receptors detected by Northern blotting with basophil RNA. This study demonstrates that CCR3 is the major receptor for eotaxin, RANTES, and MCP-4 in human basophils, and suggests that basophils and eosinophils, which are the characteristic effector cells of allergic inflammation, depend largely on CCR3 for migration towards different chemokines into inflamed tissues.

Basophils↗
PubMed1997

Eotaxin-2, a novel CC chemokine that is selective for the chemokine receptor CCR3, and acts like eotaxin on human eosinophil and basophil leukocytes.

A novel human CC chemokine consisting of 78 amino acids and having a molecular mass of 8,778.3 daltons (VVIPSPCCMF FVSKRIPENR VVSYQLSSRS TCLKAGVIFT TKKGQQ SCGD PKQEWVQRYM KNLDAKQKKA SPRARAVA) was isolated together with three minor COOH-terminally truncated variants with 73, 75, and 76 residues. The new chemokine was termed eotaxin-2 because it is functionally very similar to eotaxin. In terms of structure, however, eotaxin and eotaxin-2 are rather distant, they share only 39% identical amino acids and differ almost completely in the NH2-terminal region. Eotaxin-2 induced chemotaxis of eosinophils as well as basophils, with a typically bimodal concentration dependence, and the release of histamine and leukotriene C4 from basophils that had been primed with IL-3. In all assays, eotaxin-2 had the same efficacy as eotaxin, but was somewhat less potent. The migration and the release responses were abrogated in the presence of a monoclonal antibody that selectively blocks the eotaxin receptor, CCR3, indicating that eotaxin-2, like eotaxin, acts exclusively via CCR3. Receptor usage was also studied in desensitization experiments by measuring [Ca2+]i changes in eosinophils. Complete cross-desensitization was observed between eotaxin-2, eotaxin and MCP-4 confirming activation via CCR3. No Ca2+ mobilization was obtained in neutrophils, monocytes and lymphocytes, in agreement with the lack of chemotactic responsiveness. Intradermal injection of eotaxin-2 in a rhesus monkey (100 or 1,000 pmol per site) induced a marked local infiltration of eosinophils, which was most pronounced in the vicinity of postcapillary venules and was comparable to the effect of eotaxin.

Amino Acid Sequence↗
PubMed1997

CKbeta8, a novel CC chemokine that predominantly acts on monocytes.

We have studied the biological properties of a new human CC chemokine, CKbeta8, consisting of 99 amino acids including six cysteines. CKbeta8 mRNA transcripts were induced in monocytes by IL-1beta and, to a lesser extent, by IFNgamma, and were detected in RNA extracted from normal human liver and gastrointestinal tract. CKbeta8 is chemotactic for monocytes, but is inactive on IL-2 conditioned T lymphocytes, eosinophils and neutrophils. Desensitization experiments indicate that CKbeta8 and MIP-1beta completely share receptors on monocytes and that the CKbeta8 receptor, which appears to differ from the known ones, is also recognized by MCP-1, MCP-2, MCP-3, MCP-4, MIP-1alpha and RANTES.

Acetylglucosaminidase↗
PubMed1997

Synovial expression of cell adhesion molecules in polymyalgia rheumatica.

Polymyalgia rheumatica (PMR) is a common disorder of the elderly: the pathogenesis of the syndrome is still debated, though active synovitis of the shoulder has recently been confirmed. To investigate the pathogenesis of this synovitis we evaluated cell adhesion molecule (CAM) expression in shoulder synovial tissue from patients with PMR, correlated synovial expression with the serum levels of soluble forms, and assessed the changes associated with corticosteroid treatment. Arthroscopic synovial biopsies were obtained from 12 untreated and seven corticosteroid (CS)-treated cases. CAM expression was evaluated by MoAb staining on frozen sections and computerized image analysis. Soluble CAM were quantified by ELISA. Endothelial cells expressed intercellular adhesion molecule-1 (ICAM-1), E- and P-selectins. Infiltrating cells were ICAM-1 and beta1-integrin-positive, while L-selectin expression was limited to intravascular leucocytes. Synovial lining cells strongly expressed vascular cell adhesion molecule-1 (VCAM-1), and less intensely ICAM-1. Only the soluble form of ICAM-1 (sICAM-1) was elevated in untreated patients. CS treatment was associated with a decrease in ICAM-1, VCAM-1 and E- and P-selectin expression. sICAM-1 levels were in the normal range in treated patients. VLA-5 and 6 expression was widely distributed among cell types, and was not CS-sensitive. Active shoulder synovitis is associated with different CAM expression in PMR. ICAM-1 expression is widely distributed and correlates with elevated levels of the soluble form; it is significantly lower in CS-treated asymptomatic cases.

Aged↗
PubMed1996

RANTES and MCP-3 antagonists bind multiple chemokine receptors.

Antagonists of multiple chemokines could be more effective than inhibitors of specific chemokines for controlling cell migration and inflammation. To attempt to identify such antagonists we characterized a number of truncated analogs of regulated on activation normal T cell expressed protein (RANTES), monocyte chemoattractant protein (MCP)-3, and MCP-1. On the basis of their ability to compete for binding of their parent chemokines, three analogs were selected for cross-reactivity studies: RANTES (9-68), MCP-3 (10-76), and MCP-1 (9-76). These analogs bound to THP-1 monocytic cells with dissociation constants that were within 4-6-fold of their native counterparts, but they did not promote detectable chemotaxis of THP-1 cells or enzyme release from purified human monocytes. The RANTES (9-68) analog competed for the binding and inhibited the activities of all three chemokines. In contrast, native RANTES was specific for RANTES binding sites. However, truncation of either MCP-1 or MCP-3 did not change their respective binding specificity. MCP-3 and MCP-3 (10-76) competed for binding of all three labeled chemokines. MCP-1 (9-76) competed strongly for binding of labeled MCP-1, but only weakly for the other two labeled ligands and inhibited the activities induced by MCP-1 and MCP-3 but not RANTES. Although RANTES (9-68) and MCP-3 (10-76) inhibited all three chemokines, the RANTES analog was significantly more potent for RANTES-induced activity. The results indicate that NH2-terminal residues partly determine the receptor specificity of RANTES, and deletions within this region permit binding to multiple chemokine receptors. The findings suggest the feasibility of design of high affinity multi-specific CC chemokine antagonists.

Amino Acid Sequence↗
PubMed1996

Monocyte chemotactic protein 4 (MCP-4), a novel structural and functional analogue of MCP-3 and eotaxin.

A novel human CC chemokine complementary DNA was identified in a library constructed from human fetal RNA, cloned into a baculovirus vector, and expressed in Sf9 insect cells. The mature recombinant protein that was released had the NH2-terminal sequence pyro-QPDALNVPSTC...and consisted of 75 amino acids. Minor amounts of two variants of 77 and 82 residues (NH2 termini: LAQPDA...and FNPQGLAQPDA...) were released as well. The novel chemokine was designated monocyte chemotactic protein 4 (MCP-4) and the variants were designated (LA)MCP-4 and (FNPQGLA)MCP-4. MCP-4 shares the pyroglutamic acidproline NH2-terminal motif and 56-61% sequence identity with the three known monocyte chemotactic proteins and is 60% identical to eotaxin. It has marked functional similarities to MCP-3 and eotaxin. Like MCP-3, MCP-4 is a chemoattractant of high efficacy for monocytes and T lymphocytes. On these cells, it binds to receptors that recognize MCP-1, MCP-3, and RANTES. On eosinophils, MCP-4 has similar efficacy and potency as MCP-3, RANTES, and cotaxin. It shares receptors with eotaxin and shows full cross-desensitization with this cosinophil-selective chemokine. Of the two variants, only (LA)MCP-4 could be purified in sufficient quantities for testing and was found to be at least 30-fold less potent than MCP-4 itself. This suggests that the 75-residue form with the characteristic NH2 terminus of an MCP is the biologically relevant species.

Acetylglucosaminidase↗
PubMed1996

Deletion of the NH2-terminal residue converts monocyte chemotactic protein 1 from an activator of basophil mediator release to an eosinophil chemoattractant.

Chemotactic cytokines of the CC subfamily (CC chemokines) are considered as major mediators of allergic inflammation owing their actions on basophil and eosinophil leukocytes. The monocyte chemotactic protein (MCP) 1 is a potent inducer of mediator release from basophils but is inactive on eosinophils. To obtain information on the structural determinants of the activities of MCP-1, we have synthesized several NH2-terminally truncated analogues and tested their effects on basophils and eosinophils. Through deletion of the NH2-terminal residue, MCP-1(2-76) was obtained, which was a potent activator of eosinophils, as assessed by chemotaxis, cytosolic free Ca2+ changes, actin polymerization, and that induction of the respiratory burst. In contrast, the activity of MCP-1(2-76) on basophil leukocytes was dramatically decreased (50-fold) compared with that of full-length MCP-1. Deletion of the next residue led to total loss of activity on eosinophil and basophil leukocytes. Analogues with three or four residue deletions, MCP-1(4-76) and MCP-1(5-76), were again active on both cells, whereas all further truncation analogues, MCP-1(6-76) through MCP-1(10-76), were inactive. Thus, a minimal structural modification can change receptor and target cell selectivity of MCP-1. Our observations indicate that the recognition sites of CC chemokine receptors on eosinophils and basophils are similar, although they discriminate between MCP-1 and MCP-1(2-76) and suggest NH2-terminal processing as a potential mechanism for the regulation of CC chemokine activities.

Actins↗