It is well established that TGF-beta1 induces IgA and IgG2b class-switching recombination in murine B cells. In the present study, we assessed the activity of IL-21 along with TGF-beta1 in Ig synthesis by murine spleen B cells. IL-21 showed antiproliferative activity on LPS-activated splenic B cells, comparable with that of TGF-beta1. IL-21 alone had little effect on IgA secretion and decreased other isotypes. Likewise, IL-21 also did not alter the TGF-beta1-induced IgA synthesis and concurrently diminished the syntheses of IgM and IgG2a, which were repressed by TGF-beta1. Unexpectedly, IL-21 inhibited the TGF-beta1-induced IgG2b production. This IL-21 effect was examined using B cells from IL-21R knockout mice, where the IgA production profile was paralleled by that seen in wild-type B cells. However, the inhibitory effect of IL-21 on TGF-beta1-induced IgG2b synthesis was not seen in the IL-21R(-/-) mouse, suggesting that IL-21 causes TGF-beta1-stimulated B cells to decrease IgG2b synthesis. Expression patterns of Ig germ-line alpha(GL alpha)/GL gamma 2b transcripts under the influence of TGF-beta1 and IL-21 were paralleled by IgA/IgG2b secretion. This was also observed in the activities of GL(alpha) and GL(gamma 2b) promoters. These results indicate that IL-21 decreases IgG2b secretion mainly through inhibition of GL(gamma 2b) transcription and is ultimately associated with selective IgA secretion induced by TGF-beta1. Our results showed that IL-21 was expressed in greater magnitude in Peyer's patches (PP) than in spleen. These results suggest that IL-21 has an important effect on selective IgA(+) B cell commitment in PP.