Antisense oligonucleotides to interleukin-4 regulate IgE and IgG2a production by spleen cells from Nippostrongylus brasiliensis-infected rats.

Interleukin-4 (IL-4) plays a key role in the regulation of immunoglobulin production. In the present study, we examined the role of IL-4 in the production of IgE and IgG2a by spleen cells from Nippostrongylus brasiliensis-infected rats using the antisense oligonucleotide strategy. Three antisense oligonucleotides (15 and 20 nucleotides) were selected near the ATG initiation codon of the murine IL-4 gene. Significant and reproducible inhibitions of IgE and IgG2a production were observed with the addition of two different oligonucleotides, the most inhibitory being specific for 15 nucleotides corresponding to the downstream AUG sequence oligodeoxynucleotide (ODN-1), while the corresponding sense sequence had no effect. The inhibition was directly related to the ODN-1 concentration on IgE response, and IgG2a production was more sensitive to the inhibitory effect of ODN-1 than the IgE response. Our results suggest that the ODN-1 effect is rather specific for the IL-4 gene since the production of other cytokines was not modified and the exogenous addition of IL-4 reversed the ODN-1 effect. In contrast to IgE and IgG2a, ODN-1 induced a significant enhancement of IgM synthesis. The use of a phosphorothioate ODN of the same sequence as ODN-1 resulted in a greater inhibitory effect on IgE and IgG2a production. These data indicate that IL-4 contributes to the spontaneous production of IgE and IgG2a, and argue that antisense strategy constitutes a useful tool for the regulation of antibody response.