In this study, a potential role for activin A in mouse immunoglobulin (Ig) regulation was investigated. We observed that activin A increased IgA secretion in B lymphoma cells. In contrast, little effect was observed on IgM and IgG2b secretion. Activin A also significantly increased surface IgA expression and Ig germ-line alpha transcript (GLT(alpha)) levels. In parallel, activin A increased GLT(alpha) and post-switch transcripts alpha (PST(alpha)) expression in normal B cells, which was augmented by IL-5. An increase in IgA production by surface IgA negative B cells by activin A was apparent. Finally, the increase of IgA secretion by activin A was blocked by an activin receptor inhibitor (SB431542). The increase of GLT(alpha) by activin A was augmented by Smad3/4 overexpression and abolished by Smad3 dominant negative overexpression. These results suggest that activin A induces IgA isotype switching via Smad3/4-mediated germ line alpha transcription.