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      Modulation of PECAM-1 (CD31) Expression in Human Endothelial Cells: Effect of IFNγ and IL-10

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          Intercellular contacts formed between endothelial cells (EC) permit the formation of a confluent monolayer and play a major role in the recruitment and the migration of leukocytes in the inflammatory response. It is currently accepted that cytokines are responsible for the signals involved in the induction of such endothelial alterations. The platelet EC adhesion molecule (PECAM-1), a specific component of EC junctions, is one of many molecules which participate in the regulation of EC interaction with blood components. Given that the regulatory mechanisms which affect the expression of this adhesion molecule are only partially understood, the aim of the present study was to compare the effects of two antagonistic inflammatory cytokines, interferon (IFN)-γ and interleukin (IL)-10, on the expression of PECAM-1. Human umbilical vein EC grown to subconfluence were stimulated with IL-10 (10 ng/ml) and/or IFNγ (100 U/ml) for 24 h. PECAM-1 expression was determined by FACScan and immunofluorescence. Morphological analysis of the cell cultures was performed by optical and scanning electron microscopy. In the presence of IL-10, no changes in cell growth and morphology or in the intensity of PECAM-1 expression were observed. However, when the cultures were treated with IFNγ, the EC acquired a fibroblast-like appearance, growth was disorganized and PECAM-1 disappeared from cell junctions. The mean intensity expression and the percentage of EC expression of this antigen were analyzed by flow cytometry and significantly decreased after culture in the presence of IFNγ. The simultaneous addition of IFNγ and IL-10 to the EC cultures induced modifications similar to those observed in the presence of IFNγ alone. Regulation of the expression of PECAM-1 with the subsequent functional implications seems to be dependent upon the IFNγ signal and it is unaffected by IL-10. The different effects shown by IL-10 and IFNγ on the expression of PECAM-1 in EC could reflect opposite regulatory actions of the inflammatory response induced by these cytokines.

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          Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes

           B Bennett,  R Malefyt,  la De (1991)
          In the present study we demonstrate that human monocytes activated by lipopolysaccharides (LPS) were able to produce high levels of interleukin 10 (IL-10), previously designated cytokine synthesis inhibitory factor (CSIF), in a dose dependent fashion. IL-10 was detectable 7 h after activation of the monocytes and maximal levels of IL-10 production were observed after 24-48 h. These kinetics indicated that the production of IL-10 by human monocytes was relatively late as compared to the production of IL-1 alpha, IL-1 beta, IL-6, IL-8, tumor necrosis factor alpha (TNF alpha), and granulocyte colony-stimulating factor (G-CSF), which were all secreted at high levels 4-8 h after activation. The production of IL-10 by LPS activated monocytes was, similar to that of IL-1 alpha, IL-1 beta, IL-6, IL-8, TNF alpha, granulocyte-macrophage colony-stimulating factor (GM-CSF), and G-CSF, inhibited by IL-4. Furthermore we demonstrate here that IL-10, added to monocytes, activated by interferon gamma (IFN-gamma), LPS, or combinations of LPS and IFN-gamma at the onset of the cultures, strongly inhibited the production of IL-1 alpha, IL-1 beta, IL-6, IL-8, TNF alpha, GM-CSF, and G-CSF at the transcriptional level. Viral-IL-10, which has similar biological activities on human cells, also inhibited the production of TNF alpha and GM-CSF by monocytes following LPS activation. Activation of monocytes by LPS in the presence of neutralizing anti-IL-10 monoclonal antibodies resulted in the production of higher amounts of cytokines relative to LPS treatment alone, indicating that endogenously produced IL-10 inhibited the production of IL-1 alpha, IL-1 beta, IL-6, IL-8, TNF alpha, GM-CSF, and G-CSF. In addition, IL-10 had autoregulatory effects since it strongly inhibited IL-10 mRNA synthesis in LPS activated monocytes. Furthermore, endogenously produced IL-10 was found to be responsible for the reduction in class II major histocompatibility complex (MHC) expression following activation of monocytes with LPS. Taken together our results indicate that IL-10 has important regulatory effects on immunological and inflammatory responses because of its capacity to downregulate class II MHC expression and to inhibit the production of proinflammatory cytokines by monocytes.
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            Mapping the homotypic binding sites in CD31 and the role of CD31 adhesion in the formation of interendothelial cell contacts

            CD31 is a member of the immunoglobulin superfamily consisting of six Ig- related domains. It is constitutively expressed by platelets, monocytes, and some lymphocytes, but at tenfold higher levels on vascular endothelial cells. CD31 has both homotypic and heterotypic adhesive properties. We have mapped the homotypic binding sites using a deletion series of CD31-Fc chimeras and a panel of anti-CD31 monoclonal antibodies. An extensive surface of CD31 is involved in homotypic binding with domains 2 and 3 and domains 5 and 6 playing key roles. A model consistent with the experimental data is that CD31 on one cell binds to CD31 on an apposing cell in an antiparallel interdigitating mode requiring full alignment of the six domains of each molecule. In addition to establishing intercellular homotypic contacts. CD31 binding leads to augmented adhesion via beta 1 integrins. The positive cooperation between CD31 and beta 1 integrins can occur in heterologous primate cells (COS cells). The interaction is specific to both CD31 and beta 1 integrins. Neither intercellular adhesion molecule-1 (ICAM- 1)/leukocyte function-associated antigen-1 (LCAM-1) nor neural cell adhesion molecule (NCAM)/NCAM adhesion leads to recruitment of beta 1 integrin adhesion pathways. Establishment of CD31 contacts have effects on the growth and morphology of endothelial cells. CD31(D1-D6)Fc inhibits the growth of endothelial cells in culture. In addition, papain fragments of anti-CD31 antibodies (Fab fragments) disrupt interendothelial contact formation and monolayer integrity when intercellular contacts are being formed. The same reagents are without effect once these contacts have been established, suggesting that CD31- CD31 interactions are critically important only in the initial phases of intercellular adhesion.
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              Interferon-γ: Mechanism of action and therapeutic potential


                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                April 1999
                22 April 1999
                : 36
                : 2
                : 106-113
                Departments of aMorphological Sciences and Surgery, and bMedicine, Faculty of Medicine, University of Alcalá, and cDivision of Clinical Immunology and Oncology, University Hospital Principe de Asturias, Alcalá de Henares, Madrid, Spain
                25632 J Vasc Res 1999;36:106–113
                © 1999 S. Karger AG, Basel

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                Page count
                Figures: 5, References: 25, Pages: 8
                Research Paper


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