Activin A stimulates mouse macrophages to express APRIL via the Smad3 and ERK/CREB pathways

A proliferation-inducing ligand (APRIL) is primarily expressed by macrophages and dendritic cells, and stimulates B cell proliferation, differentiation, survival, and Ig production. In the present study, we investigated the role and signaling mechanisms of activin A in APRIL expression by mouse macrophages. Activin A markedly enhanced APRIL expression in mouse macrophages at both the transcriptional and protein levels. Overexpression of dominant-negative (DN)-Smad3 and SB431542 abrogated activin-induced APRIL transcription. Furthermore, activin A induced Smad3 phosphorylation. These results indicate that activin A enhances APRIL expression through both activin receptor-like kinase 4 (ALK4) and Smad3. In a subsequent analysis of activin A signaling, it was found that PD98059, an extracellular signal-related kinase (ERK) inhibitor, eliminated activin A-induced APRIL expression. On the other hand, overexpression of cAMP responsive element-binding protein (CREB), a molecule downstream of ERK, augmented activin A-induced APRIL expression, and this effect could be abolished by PD98059. This finding that activin A induces ERK and CREB phosphorylation suggests that ERK and CREB act as intermediates in APRIL expression. Taken together, these results demonstrate that activin A can enhance APRIL expression through two different pathways, Smad3 and ERK/CREB.