In vitro and in vivo inhibition of interleukin (IL)-5-mediated eosinopoiesis by murine IL-5Ralpha antisense oligonucleotide.
The unique role of interleukin (IL)-5 in eosinophil production, activation, and localization makes this cytokine a prime target for therapeutic intervention in diseases characterized by a selective blood and tissue eosinophilia. In an attempt to block the effects of IL-5 on eosinophils, a strategy was developed to suppress the expression of the IL-5 receptor alpha chain (IL-5Ralpha) by antisense oligonucleotides (ASOs). IL-5Ralpha ASOs were identified which selectively and specifically suppress the expression of messenger RNA and proteins of both the membrane and the soluble form of the receptor in constitutively IL-5R-expressing murine BCL-1 cells in vitro. Moreover, these IL-5Ralpha-specific ASOs were able to selectively inhibit the IL-5-induced eosinopoesis from murine fetal liver and bone marrow cells in vitro, suggesting that these molecules may affect the development of IL-5-mediated eosinophilia in vivo. Indeed, intravenous administration of IL-5Ralpha-specific ASOs not only suppressed the bone-marrow and blood eosinophilia in mice after short-term treatment with recombinant murine IL-5 but also inhibited the development of blood and tissue eosinophilia in a ragweed-induced allergic peritonitis model. Thus, blocking the expression of IL-5Ralpha on eosinophil using ASOs may have therapeutic benefits in eosinophilic diseases such as asthma.
Lach-Trifilieff
E
E
Novartis Horsham Research Centre, Wimblehurst Road, Horsham RH12 5AB, UK.
McKay
R A
RA
Monia
B P
BP
Karras
J G
JG
Walker
C
C
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D004802:Eosinophilia / Q000378:metabolism / Q000517:prevention & control*; D004804:Eosinophils / Q000378:metabolism*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D015848:Interleukin-5 / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D010538:Peritonitis / Q000235:genetics / Q000473:pathology; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D018123:Receptors, Interleukin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053649:Receptors, Interleukin-5; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D014407:Tumor Cells, Cultured
D017931:DNA Primers; D015848:Interleukin-5; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053649:Receptors, Interleukin-5