Regulation of gene expression by pegylated IFN-alpha2b and IFN-alpha2b in human peripheral blood mononuclear cells.
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.
Department of Biotechnology, Schering-Plough Research Institute, Union, NJ 07083, USA.
Diana L
DL
Brassard
Marc M
MM
Delorenzo
Stuart
S
Cox
Douglas W
DW
Leaman
Yaping
Y
Sun
Wei
W
Ding
Sean
S
Gavor
Jeffrey
J
Spond
Federico
F
Goodsaid
Ronald
R
Bordens
Michael J
MJ
Grace
D000998:Antiviral Agents / Q000494:pharmacology; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000378:metabolism / Q000494:pharmacology*; D007700:Kinetics; D007962:Leukocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D020411:Oligonucleotide Array Sequence Analysis; D011092:Polyethylene Glycols; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins
D000998:Antiviral Agents; D018925:Chemokines; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D012333:RNA, Messenger; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; C417083:peginterferon alfa-2b