Antisense inhibition of membrane-bound human interleukin-5 receptor-alpha chain does not affect soluble receptor expression and induces apoptosis in TF-1 cells

Binding of human interleukin-5 (HuIL-5) to its membrane-anchored receptor ( IL-5R) triggers multiple signaling pathways, cellular proliferation, and ma turational responses, as well as protection from apoptosis. In contrast, so luble forms of the HuIL-5R have been shown to inhibit IL-5 signaling and, t herefore, may represent naturally occurring negative regulators of IL-5 fun ction. Because of the central role of IL-5 in promoting eosinophilia and ai rway hyperresponsiveness in animal models of asthma, antisense oligonucleot ides specific either for the membrane form alone or for sequences shared be tween both the membrane and soluble forms of the HuIL-5R alpha ligand bindi ng chain were designed. The activities of these oligonucleotides were chara cterized in IL-5R-expressing erythroleukemic TF-1 cells. Herein we report t hat an antisense oligonucleotide targeted to a sequence unique to the alter natively spliced membrane-bound form of the HuIL-5R alpha chain has been de veloped that selectively inhibits membrane, but not soluble, mRNA isoform e xpression. Both this membrane-specific oligonucleotide and an antisense oli gonucleotide targeted to sequence common to both membrane and soluble isofo rms were found to potently suppress cell surface IL-5R alpha levels and IL- 5-mediated cell survival by inducing apoptosis similar to IL-5 withdrawal. Thus, these oligonucleotides represent unique genetic agents with therapeut ic potential for diseases with an eosinophilic component.