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Biomedical subjects

A Vecchi

Publications and source records attributed to A Vecchi.

At least 19 recordsLinked to original sources
PubMed2006

Hepatic portal venous gas in a patient with enterovascular fistula.

Hepatic portal venous gas is an uncommon clinical condition that is often characterized by acute onset of abdominal pain and is associated with a high rate of mortality despite clinical and/or surgical treatment. Radiologic diagnosis is important and usually includes abdominal radiography, ultrasound, and computed tomography. We describe the clinical, computed tomographic, and angiographic data of a patient with sigmoid diverticulitis who developed a massive embolism of the intra- and extrahepatic portal systems due to an enterovascular fistula and was treated with fistula embolization and subsequent sigmoidectomy.

Adult↗
PubMed2006

The chemoattractant decoy receptor D6 as a negative regulator of inflammatory responses.

Other than signalling receptors sustaining leucocyte recruitment during inflammatory reactions, the chemokine system includes 'silent' receptors with distinct specificity and tissue distribution. The best-characterized molecule of this subgroup is the CC chemokine receptor D6, which binds most inflammatory CC chemokines and targets them to degradation via constitutive ligand-independent internalization. Structure-function analysis and recent results with gene-targeted animals indicate that D6 has unique functional and structural features, which make it ideally adapted to act as a chemokine decoy and scavenger receptor, strategically located on lymphatic endothelium and placenta to dampen inflammation in tissues and draining lymph nodes.

Humans↗
PubMed2001

Decoy receptors: a strategy to regulate inflammatory cytokines and chemokines.

The canonical concept of a receptor includes specific ligand recognition, usually with high affinity and specificity, and signaling. Decoy receptors recognize certain inflammatory cytokines with high affinity and specificity, but are structurally incapable of signaling or presenting the agonist to signaling receptor complexes. They act as a molecular trap for the agonist and for signaling receptor components. The interleukin-1 type II receptor (IL-1RII) was the first pure decoy to be identified. Decoy receptors have subsequently been identified for members of the tumor necrosis factor receptor and IL-1R families. Moreover, silent nonsignaling receptors could act as decoys for chemokines. Therefore, the use of decoy receptors is a general strategy to regulate the action of primary pro-inflammatory cytokines and chemokines.

Amino Acid Sequence↗
PubMed2001

Fractalkine (CX3CL1) as an amplification circuit of polarized Th1 responses.

Fractalkine (FKN, CX3CL1) is a membrane-bound CX3C chemokine induced by primary proinflammatory signals in vascular endothelial cells (ECs). Here we examined the role of FKN in polarized Th1 or Th2 responses. Proinflammatory signals, including LPS, IL-1, TNF, and CD40 ligand, induced FKN, as did IFN-gamma, which had synergistic activity with TNF. IL-4 and IL-13 did not stimulate the expression of FKN and markedly reduced induction by TNF and IFN-gamma. TNF alone or combined with IFN-gamma also induced release of soluble FKN, which was inhibited by IL-4 and IL-13. In light of this differential regulation of FKN by the master cytokines that control polarized responses, we analyzed the interaction of FKN with natural killer (NK) cells and polarized T-cell populations. NK cells expressed high levels of the FKN receptor CX3CR1 and responded to FKN. CX3CR1 was preferentially expressed in Th1 compared with Th2 cells. Th1 but not Th2 cells responded to FKN. By immunohistochemistry, FKN was expressed on ECs in psoriasis, a Th1-dominated skin disorder, but not in Th2-driven atopic dermatitis. Similarly, ECs in Mycobacterium tuberculosis granulomatous lymphadenitis, but not those in reactive lymph node hyperplasia or in Castelman's disease, showed immunoreactive FKN. These results indicate that regulated expression of FKN in ECs participates in an amplification circuit of polarized type I responses.

Adult↗
PubMed2000

Autocrine production of IL-10 mediates defective IL-12 production and NF-kappa B activation in tumor-associated macrophages.

IL-12 is a central cytokine in the activation of inflammation and immunity and in the generation of Th1-type responses. Tumor-associated macrophages (TAM) from mouse and human tumors showed defective production of IL-12. Defective IL-12 production was associated with lack of p50/p65 NF-kappa B activation. TAM produced increased amounts of the immunosuppressive cytokine IL-10. Abs against IL-10 restored the defective capacity of TAM to produce IL-12. Our data suggest that during tumor growth an IL-10-dependent pathway of diversion of macrophage function can be activated into the tumor microenvironment and results in the promotion of the IL-10+ IL-12- phenotype of TAM. Blocking IL-10, as well as other immunosuppressive cytokines present in the tumor microenvironment, such as TGF-beta, may complement therapeutic strategies aimed at activating type I antitumor immune responses.

Animals↗
PubMed2000

The type II decoy receptor of IL-1 inhibits murine collagen-induced arthritis.

IL-1 is a key cytokine involved in the inflammatory response. The type II receptor of IL-1 (IL-1RII) acts as a decoy receptor, binding and inhibiting the effect of IL-1. This study was undertaken to establish whether IL-1RII can ameliorate collagen-induced arthritis, a model of inflammatory arthritis in mice. We used human keratinocytes transfected with the human (h)IL-1 RII gene as a source of hIL-1 RII protein. We showed that these cells expressed both the membrane and soluble form of receptor. In vitro, IL-1-stimulated murine macrophage cells showed a decreased expression of TNF-alpha in the presence of hIL-1 RII. We engrafted the hIL-1RII-transfected cells in the back of mice developing collagen-induced arthritis. We found that clinical and histological parameters of arthritis were significantly decreased in mice treated with cells producing hIL-1RII. In addition, hIL-1RII administration was able to reduce the expression of mRNA for IL-6 and myeloperoxidase in the joints of treated animals. These data show that hIL-1 RII anti-inflammatory properties in the model of collagen-induced arthritis in mice and could have a regulatory role in rheumatoid arthritis.

Animals↗
PubMed2000

Differential effect of benzydamine on pro- versus anti-inflammatory cytokine production: lack of inhibition of interleukin-10 and interleukin-1 receptor antagonist.

The production and action of primary proinflammatory cytokines are strictly controlled by a series of circuits to avoid damage that they can cause if produced in excess. Interleukin-10 and interleukin-1 receptor antagonist contribute to the control of the magnitude of the inflammatory responses in vivo. Benzydamine, a non-steroidal anti-inflammatory drug that has been shown to have suppressive activity for the proinflammatory cytokines, tumor necrosis factor-alpha and interleukin-1beta, was investigated for its effects on interleukin-10 and interleukin-1ra production. The drug did not modify the production of interleukin-10 and interleukin-1ra by peripheral blood mononuclear cells stimulated with lipopolysaccharide, under conditions where tumor necrosis factor-alpha and interleukin-1beta were decreased. The antiinflammatory capacity of benzydamine might thus result from its ability to reduce the production of proinflammatory cytokines, without affecting antiinflammatory factors.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2000

Chemokine receptors: interaction with HIV-1 and viral-encoded chemokines.

Chemokines are a superfamily of proteins that play a central role in immune and inflammatory reactions and in viral infections. About 50 different chemokines divided in four subfamilies are known, CXC, CC, C, and CX3C. Chemokine receptors can function as entry/fusion co-receptors for human immunodeficiency virus (HIV)-1 infection, and regulation of receptor expression by cytokines may be relevant for viral infection. Posttranslational processing of chemokines can profoundly affect their interaction with receptors. The serine protease CD26/dipeptidyl-peptidase IV (CD26/DPP IV) removes NH2-terminal dipeptides from several chemokines and profoundly affect their biological activity. Kaposi's sarcoma (KS)-associated herpes virus 8 encodes for three chemokine-like proteins that show homology with MIP cluster of CC chemokines. These viral chemokines possess a partial agonist activity for certain chemokine receptors and may function as receptor antagonists. This biological activity could represent a strategy developed by the virus to subvert immunity impairing the generation of an effective anti-viral immune response.

Animals↗
PubMed2000

Chemokines and dendritic cell traffic.

Localization in tissues and migration to lymphoid organs are essential steps in the immunobiology of dendritic cells (DC). Chemokines play an important role in guiding the traffic of DC. Receptor expression and responsiveness to constitutively made chemokines account for the presence of DC in normal tissues. Inflammatory chemokines and nonchemokine attractants promote recruitment and localization of DC at sites of inflammation and infection. Upon exposure to maturation signals, DC undergo a chemokine receptor switch, with down-regulation of inflammatory chemokine receptors followed by induction of CCR7. These temporally coordinated events allow DC to leave tissues and to localize in lymphoid organs by responding to CCR7 agonists. DC are also present in tumors that produce chemokines, but their significance remains to be defined. In addition to responding to chemokines, DC are a major source of certain chemokines such as macrophage-derived chemokine. The interaction of DC with chemokines is essential to the function of these cells in normal and pathological conditions and may provide tools for novel therapeutic strategies.

Animals↗
PubMed2000

The chemokine receptor switch paradigm and dendritic cell migration: its significance in tumor tissues.

Localization in tissues and migration to lymphoid organs are essential steps in the immunobiology of dendritic cells (DC). Chemokines play an important role in guiding the traffic of DC. Receptor expression and responsiveness to constitutively made chemokines account for the presence of DC in normal tissues. Inflammatory chemokines and non-chemokine attractants promote recruitment and localization of DC at sites of inflammation and infection. During maturation, DC undergo a profound and orderly rearrangement of their chemokine receptor repertoire. The chemokine receptor switch paradigm provides a conceptual framework for the complex migration of DC in vivo, including their recruitment and positioning in tumor tissues.

Cell Movement↗
PubMed2000

Uncoupling of inflammatory chemokine receptors by IL-10: generation of functional decoys.

As originally demonstrated for the interleukin 1 (IL-1) type II receptor, some primary proinflammatory cytokines from the IL-1 and tumor necrosis factor families are regulated by decoy receptors that are structurally incapable of signaling. Here we report that concomitant exposure to proinflammatory signals and IL-10 generates functional decoy receptors in the chemokine system. Inflammatory signals, which cause dendritic cell (DC) maturation and migration to lymphoid organs, induce a chemokine receptor switch, with down-regulation of inflammatory receptors (such as CCR1, CCR2, CCR5) and induction of CCR7. Concomitant exposure to lipopolysaccharide (LPS) and IL-10 blocks the chemokine receptor switch associated with DC maturation. LPS + IL-10-treated DCs showed low expression of CCR7 and high expression of CCR1, CCR2 and CCR5. These receptors were unable to elicit migration. We provide evidence that uncoupled receptors, expressed on LPS + IL-10-treated cells, sequester and scavenge inflammatory chemokines. Similar results were obtained for monocytes exposed to activating signals and IL-10. Thus, in an inflammatory environment, IL-10 generates functional decoy receptors on DC and monocytes, which act as molecular sinks and scavengers for inflammatory chemokines.

Animals↗
PubMed2000

Inhibition of monocyte chemotactic protein-1 synthesis by statins.

The beneficial effects of statins on the reduction of cardiovascular events has been partly attributed to their anti-inflammatory properties. In the complex of the different pathogenetic events leading to atherosclerosis, recent data suggest a central role of monocyte chemotactic protein-1 (MCP-1), because mice knock-out for MCP-1 or its receptor CC-chemokine receptor 2 were considerably resistant to plaque formation. In this study we investigated the effect of different statins on in vitro and in vivo production of MCP-1. Lovastatin and simvastatin caused a dose-dependent inhibition of MCP-1 production in peripheral blood mononuclear cells exposed to lipopolysaccharide or inactivated Streptococcus hemoliticus and in human endothelial cells exposed to interleukin-1beta. The addition of mevalonate overrode the inhibitory effect of statins indicating that mevalonate-derived products are important for chemokine production. The in vivo anti-inflammatory effect of statins was investigated using the mouse air-pouch model of local inflammation. Lovastatin and pravastatin were orally administered to mice according to a treatment schedule that significantly inhibited the hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase activity without affecting total blood cholesterol. At the dose of 10 mg/kg, lovastatin and pravastatin reduced by approximately 50% the lipopolysaccharide-induced leukocytes recruitment and the exudate MCP-1 production. In conclusion, statins, by inhibiting mevalonate-derived products, reduced both in vitro and in vivo the production of chemokines involved in leukocyte migration, and this effect is unrelated to their cholesterol-lowering action.

Cells, Cultured↗
PubMed1999

The role of chemokines in the regulation of dendritic cell trafficking.

The immunobiology of dendritic cells (DC) involves localization in tissues and trafficking via the lymph or blood to lymphoid organs. Appropriate assays representative of different steps of DC trafficking (e.g., reverse transmigration) provide the tools to dissect the migratory properties of these cells. Chemokines have emerged as important regulators of DC migration. DC are both the target and the source of chemokines. DC express receptors for and respond to a set of chemoattractants that overlap with, but are distinct from, those active on other leukocytes. Differential expression of the CCR6 receptor reveals heterogeneity among DC populations. Functional maturation is associated with loss of responsiveness to chemokines present at sites of inflammation and acquisition of a receptor repertoire that renders these cells responsive to signals that guide their localization in lymphoid organs. A better understanding of the molecular basis of DC trafficking may provide molecular and conceptual tools to direct and modulate DC traffic as a strategy to up-regulate and orient specific immunity.

Animals↗
PubMed1999

Differential responsiveness to constitutive vs. inducible chemokines of immature and mature mouse dendritic cells.

Upon exposure to immune or inflammatory stimuli, dendritic cells (DC) migrate from peripheral tissues to lymphoid organs, where they present antigen. The molecular basis for the peculiar trafficking properties of DC is largely unknown. In this study, mouse DC were generated from CD34+ bone marrow precursors and cultured with granulocyte-macrophage-CSF and Flt3 ligand for 9 days. Chemokines active on immature DC include MIP1alpha, RANTES, MIP1beta, MCP-1, MCP-3, and the constitutively expressed SDF1, MDC, and ELC. TNF-alpha-induced DC maturation caused reduction of migration to inducible chemokines (MIP1alpha, RANTES, MIP1beta, MCP-1, and MCP-3) and increased migration to SDF1, MDC, and ELC. Similar results were obtained by CD40 ligation or culture in the presence of bacterial lipopolysaccharide. TNF-alpha down-regulated CC chemokine receptor (CCR)1, CCR2, and CCR5 and up-regulated CCR7 mRNA levels, in agreement with functional data. This study shows that selective responsiveness of mature and immature DC to inducible vs. constitutively produced chemokines can contribute to the regulated trafficking of DC.

Animals↗
PubMed1999

A small synthetic molecule capable of preferentially inhibiting the production of the CC chemokine monocyte chemotactic protein-1.

Blocking chemokine production or action is a major target for pharmacological intervention in different human diseases. Bindarit (2-methyl-2-[[1-(phenylmethyl)-1H-indazol-3yl]methoxy]propan oic acid) dose-dependently inhibited MCP-1 and TNF-alpha production induced in vitro in monocytes by LPS and Candida albicans. It did not affect the production of the cytokines IL-1, IL-6, or the chemokines IL-8, MIP-1alpha and RANTES. In the air pouch model in mice, oral treatment reduced monocyte recruitment and local MCP-1 production, induced by carrageenan or IL-1 injection. In NZB/W mice, a model of lupus nephritis, oral treatment prolonged survival and delayed the onset of proteinuria. The results presented here show that bindarit is a preferential inhibitor of the production of MCP-1 in vitro and in vivo and suggest that its beneficial effects in models of joint and kidney inflammation are related to its anti-MCP-1 action. It is therefore possible to selectively and differentially regulate chemokines by targeting their production with small synthetic molecules.

Animals↗
PubMed1998

The viral chemokine macrophage inflammatory protein-II is a selective Th2 chemoattractant.

Kaposi's sarcoma (KS) lesions are characterized by a prominent leukocyte infiltrate composed of mononuclear phagocytes and T cells. KS-associated CD4(+) and CD8(+) cells showed predominantly a type II cytokine profile. The CC chemokine viral macrophage inflammatory protein-II (vMIP-II) encoded by the KS-associated herpes virus 8 was a selective chemoattractant for T helper 2 (Th2 cells) and for monocytes, whereas it was inactive on other leukocytes, including Th1 cells, dendritic cells, and natural killer (NK) cells. vMIP-II was an agonist for CCR8, a chemokine receptor selectively expressed on CD4(+) and CD8(+) cells with a type II cytokine profile. Hence, vMIP-II has agonist activity for a chemokine receptor (CCR8), which is preferentially expressed on polarized Th2 cells. The capacity of vMIP-II to attract type II T cells selectively is likely to be a component of the virus strategy to subvert the host immune response.

Cell Movement↗