Comparison of gene expression patterns induced by treatment of human umbilical vein endothelial cells with IFN-alpha 2b vs. IFN-beta 1a: understanding the functional relationship between distinct type I interferons that act through a common receptor.
We analyzed whether interferon-alpha 2b (IFN-alpha 2b) and IFN-beta 1a engage their common receptor to generate activated receptor complexes possessing distinct signaling properties. Human vascular endothelial cells (HUVEC) are 100-1000-fold more sensitive to IFN-beta 1a than to IFN-alpha 2b in in vitro assays. An nonarray-based expression profiling (GeneCalling) technology was employed to compare the patterns and levels of gene expression induced by these IFN as the broadest means by which signaling events could be measured. To distinguish subtype-related differences from dose-related effects, RNA was prepared from HUVEC treated with 50-5000 pg/ml of each IFN. The results showed that at 50 pg/ml IFN, only a subset of the genes induced by IFN-beta 1a were also induced by IFN-alpha 2b and that individual genes were induced to higher levels by IFN-beta 1a. In contrast, at 5000 pg/ml, both subtypes induced essentially identical sets of genes to similar levels of expression. No genes were seen to be induced uniquely by IFN-alpha 2b but not by IFN-beta 1a. The results show that the two IFN are intrinsically capable of inducing similar gene induction responses and do not provide evidence that they generate activated receptor complexes possessing distinct signaling properties. In contrast, the two IFN generate gene induction patterns that are both qualitatively and quantitatively distinct at subsaturating and potentially physiologically more relevant concentrations.
da Silva
Antonio J
AJ
Biogen, Inc., Cambridge, MA 02142, USA. antonio_dasilva@biogen.com
Brickelmaier
Margot
M
Majeau
Gerard R
GR
Lukashin
Alexander V
AV
Peyman
John
J
Whitty
Adrian
A
Hochman
Paula S
PS
D000970:Antineoplastic Agents / Q000494:pharmacology; D002478:Cells, Cultured; D016000:Cluster Analysis; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling / Q000379:methods* / Q000706:statistics & numerical data; D005796:Genes / Q000187:drug effects; D006801:Humans; D007370:Interferon Type I / Q000502:physiology*; D000077190:Interferon alpha-2; D000068556:Interferon beta-1a; D016898:Interferon-alpha / Q000494:pharmacology*; D016899:Interferon-beta / Q000494:pharmacology*; D008565:Membrane Proteins; D053633:Receptor, Interferon alpha-beta; D017471:Receptors, Interferon / Q000502:physiology*; D011994:Recombinant Proteins; D015398:Signal Transduction / Q000187:drug effects; D014471:Umbilical Veins
D000970:Antineoplastic Agents; D018076:DNA, Complementary; D007370:Interferon Type I; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D008565:Membrane Proteins; D017471:Receptors, Interferon; D011994:Recombinant Proteins; D053633:Receptor, Interferon alpha-beta; D016899:Interferon-beta; D000068556:Interferon beta-1a