Regulation of Gene Expression by Pegylated IFN-α2b and IFN-α2b in Human Peripheral Blood Mononuclear Cells
| Autor: | Jeffrey Spond, Sean Gavor, Grace Michael, Brassard Diana L, Federico M Goodsaid, Yaping Sun, Wei Ding, Marc DeLorenzo, Ronald Bordens, Douglas W. Leaman, Stuart Cox |
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| Rok vydání: | 2004 |
| Předmět: |
Immunology
Enzyme-Linked Immunosorbent Assay Interferon alpha-2 Biology Antiviral Agents Peripheral blood mononuclear cell Polyethylene Glycols Downregulation and upregulation Interferon Virology Leukocytes medicine Humans RNA Messenger Cells Cultured Oligonucleotide Array Sequence Analysis Regulation of gene expression Messenger RNA Gene Expression Profiling Interferon-alpha Cell Biology ISG15 Protein kinase R Molecular biology Recombinant Proteins Gene expression profiling Kinetics Gene Expression Regulation Chemokines medicine.drug |
| Zdroj: | Journal of Interferon & Cytokine Research. 24:455-469 |
| ISSN: | 1557-7465 1079-9907 |
| Popis: | The pleiotropic biologic effects of interferon (IFN) are mediated through regulation of the expression of numerous IFN-sensitive genes. Peripheral blood mononuclear cells (PBMCs) obtained from healthy donors were analyzed to study the immunoregulatory and antiviral messenger RNAs (mRNAs) and proteins regulated by pegylated IFN-alpha2b (PEG-IFN-alpha2b) and IFN-alpha2b. A dose-dependent and time-dependent response for multiple IFN-regulated genes was observed. IFN-dependent protein production and secretion were correlated with IFN-regulated mRNA induction. Overall regulation of gene expression patterns for PEG-IFN-alpha2b and IFN-alpha2b was comparable, even though the antiviral activity of PEG-IFN-alpha2b demonstrated a longer biologic halflife in vitro compared with IFN-alpha2b. To study the heterogeneity of responses, PBMCs obtained from over 25 healthy donors were analyzed. Within a particular donor dataset, gene-specific and dose-dependent responses to PEG-IFN-alpha2b treatment, demonstrated in both the amplitude of transcriptional upregulation and the duration of sustained mRNA upregulation, were observed. However because of donor heterogeneity, the amplitude of a given transcriptional response could not be predicted for a specific dose of PEG-IFN-alpha2b. Notably, mRNA levels of oligoadenylate synthetase (OAS), double-stranded RNA (dsRNA)-activated protein kinase (PKR), IP-10, IFN-stimulated gene 54 (ISG54), and ISG15 were upregulated after 120 h of continuous PEG-IFN-alpha2b treatment. These results suggest that the use of antiviral and immunoregulatory protein mRNA levels as markers to assess the therapeutic efficacy of IFN-alpha2b and PEG-IFN-alpha2b against viral and neoplastic diseases in clinical trials is promising but will require further analysis using clinical patient samples. |
| Databáze: | OpenAIRE |
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