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 Calpha transcription in LPS-stimulated murine mu(+)B-cells by a TGF-beta-independent mechanism. In the present study, we examined whether RA can further drive the IgA switching process to Smu-Salpha 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 Smu-Sgamma1 switch rearrangement. IL-4 by itself could induce Smu-Sgamma1 switch rearrangement in LPS-stimulated mu(+)B-cells. Addition of RA inhibited this reaction. RA also showed an inhibitory effect on the preceding step, i.e., Igamma1Cgamma1 transcription. Therefore, RA inhibition of Smu-Sgamma1 switch rearrangement was regulated at the level of germline Cgamma1 transcription. We further analyzed the amounts of both Igamma1Cgamma1 and IalphaCalpha 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. Copyright 1999 Academic Press.