The Regulatory Effects of All-trans-Retinoic Acid on Isotype Switching: Retinoic Acid Induces IgA Switch Rearrangement in Cooperation with IL-5 and Inhibits IgG1 Switching

All-trans-retinoic acid (RA) can induce germline Cα transcription in LPS-stimulated murine μ(+)B-cells by a TGF-β-independent mechanism. In the present study, we examined whether RA can further drive the IgA switching process to Sμ-Sα switch rearrangement by DC-PCR. RA alone could not induce switch rearrangement but required the cooperation of IL-5. RA has another effect on isotype switching; RA strongly inhibits IL-4-dependent IgG1 and IgE production. To analyze the mechanism of IgG1 inhibition, we tested whether RA can inhibit IL-4-dependent Sμ-Sγ1 switch rearrangement. IL-4 by itself could induce Sμ-Sγ1 switch rearrangement in LPS-stimulated μ(+)B-cells. Addition of RA inhibited this reaction. RA also showed an inhibitory effect on the preceding step, i.e., Iγ1Cγ1 transcription. Therefore, RA inhibition of Sμ-Sγ1 switch rearrangement was regulated at the level of germline Cγ1 transcription. We further analyzed the amounts of both Iγ1Cγ1 and IαCα expressed in LPS-stimulated B-cells exposed to mixtures of the two switch inducers, RA and IL-4, at various concentrations and found that the two transcripts were regulated antagonistically. These results indicated that RA can regulate isotype switching at the level of germline transcription and directs switching to IgA with the help of IL-5 and inhibits IgG1 switching.