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 C alpha transcription in L PS-stimulated murine mu(+)B-cells by a TGF-beta-independent mechanism, In t he present study, we examined whether RA can further drive the IgA switchin g process to S mu-S alpha switch rearrangement by DC-PCR, RA alone could no t induce switch rearrangement but required the cooperation of IL-5, RA has another effect on isotype switching; RA strongly inhibits IL-4-dependent Ig G1 and IgE production. To analyze the mechanism of IgG1 inhibition, we test ed whether RA can inhibit IL-4-dependent S mu-S gamma 1 switch rearrangemen t. IL-4 by itself could induce S mu-S gamma 1 switch rearrangement in LPS-s timulated Ec(+)B-cells, Addition of RA inhibited this reaction, RA also sho wed an inhibitory effect on the preceding step, i.e., I gamma 1C gamma 1 tr anscription. Therefore, RA inhibition of S mu-S gamma 1 switch rearrangemen t was regulated at the level of germline C gamma 1 transcription. We furthe r analyzed the amounts of both I gamma 1C gamma 1 and I alpha C alpha expre ssed in LPS-stimulated B-cells exposed to mixtures of the two switch induce rs, RA and IL-4, at various concentrations and found that the two transcrip ts were regulated antagonistically. These results indicated that RA can reg ulate isotype switching at the level of germline transcription and directs switching to IgA with the help of IL-5 and inhibits IgG1 switching. (C) 199 9 Academic Press.