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Biomedical subjects

J Martín-Serrano

Publications and source records attributed to J Martín-Serrano.

4 recordsLinked to original sources
PubMed2001

Hypoxia induces expression of the chemokines monocyte chemoattractant protein-1 (MCP-1) and IL-8 in human dermal fibroblasts.

Hypoxia is an important factor in the pathophysiology of vascular and inflammatory diseases. Leucocyte infiltration, as a consequence of adhesion molecule up-regulation and chemokine release, is a prominent feature of these diseases. The objective of our study was to investigate the potential role of resident fibroblasts in hypoxia-induced chemotactic responses. We show that MCP-1 and IL-8 mRNA are specifically induced by hypoxia in dermal fibroblasts. This response is paralleled by increased NF-kappaB p65/p50 binding activity, and it is inhibited by pretreatment with N-acetyl-L-cysteine. MCP-1 secreted by fibroblasts is chemotactic for monocytic cells and this activity is significantly increased by hypoxia. Chemotactic index correlates with MCP-1 protein levels and is significantly decreased by neutralizing anti-MCP-1 MoAb. These findings demonstrate the ability of resident fibroblasts to mediate chemotaxis of leucocytes through the release of chemokines in response to hypoxia. Our data point to MCP-1 as an important component in this response, and therefore it may be a potential target in inflammatory responses associated with hypoxia.

Cell Hypoxia↗
PubMed1998

In vitro selective elimination of HIV-infected cells from peripheral blood in AIDS patients by the immunotoxin DAB389CD4.

OBJECTIVES: To study the antiviral efficacy of the recombinant immunotoxin DAB389CD4 against wild-type strains of HIV and to analyse its potential toxicity in non-infected peripheral blood mononuclear cells (PBMC). DESIGN AND METHODS: PBMC from HIV-seropositive patients were cultured in the presence of DAB389CD4. After 30 days in culture, viral load was assessed by quantification of RNA levels in supernatants and HIV-specific polymerase chain reaction (PCR) was performed for measuring proviral DNA as an indicator of remaining virus in cells. To study the toxicity of DAB389CD4, PBMC from healthy donors were isolated and cell viability and lymphocyte proliferation were assessed after immunotoxin treatment. RESULTS: DAB389CD4 presented a strong antiviral activity in five of the six primary isolates decreasing p24 production in cultures to undetectable levels and eliminating selectively HIV-infected cells as measured by HIV DNA-specific PCR. One viral isolate was resistant to DAB389CD4 treatment. The immunotoxin was active against both syncytial and non-syncytial HIV strains. DAB389CD4 was not toxic in non-infected PBMC as measured by different techniques: trypan blue exclusion, methyl thiazol tetrazolium oxidation, lymphocyte proliferation, and CD4 cell count. CONCLUSIONS: DAB389CD4 showed a strong antiviral and specific activity against primary HIV isolates by killing selectively HIV-infected cells without affecting non-infected cells. This antiviral effect produced the eradication of HIV in cultures and indicated the potential use of this drug as a new therapeutic tool in combination with antiretroviral drugs. This immunotoxin would be especially interesting in the context of the marginal populations of HIV-infected cells remaining after successful antiviral treatment.

Anti-HIV Agents↗
PubMed1998

Activation of blood T lymphocytes down-regulates CXCR4 expression and interferes with propagation of X4 HIV strains.

The chemokine receptor CXCR4 serves as a coreceptor for HIV-1 entry into CD4+ cells, in particular for strains emerging late in the infection. Cell surface expression of CXCR4 has, therefore, important implications for HIV-1 pathogenesis. Using blood lymphocytes cultured under various conditions, we studied the expression and regulation of CXCR4. Flow cytometry showed that only about 20% of freshly isolated lymphocytes expressed CXCR4 on the cell surface whereas in 80% of resting blood lymphocytes CXCR4 was located intracellularly. Within a few hours in culture, the intracellular CXCR4 was translocated to the surface and was expressed in the large majority of both naive and memory lymphocytes. A decrease in surface expression of CXCR4 was found when lymphocytes cultured overnight for maximal receptor expression were stimulated with phytohemagglutinin, anti-CD3 antibodies, phorbol 12-myristate 13-acetate and stromal cell-derived factor-1. The superantigen staphylococcal enterotoxin A, a more selective stimulus, induced a marked decrease in CXCR4 expression preferentially in cells positive for the CD25 activation marker. Confocal laser scanning microscopy demonstrated the presence of CXCR4 in the cytosol and on the surface of resting lymphocytes and also showed CXCR4 redistribution after activation. The number of cells infected by the X4 HIV strain NL4.3 paralleled the expression of CXCR4 in CD4+ T lymphocytes. Sustained reduction of CXCR4 cell surface expression upon activation with phytohemagglutinin correlated with a low number of CD4+ T lymphocytes expressing HIV p24 gag antigen. Our results indicate that activation of CD4+ T lymphocytes reduces surface expression of CXCR4 in part by receptor internalization and that cell activation-dependent CXCR4 down-regulation limits spread of infection by X4 viruses.

Cells, Cultured↗