TGF-β1 Stimulates Mouse Macrophages to Express APRIL through Smad and p38MAPK/CREB Pathways

A proliferation-inducing ligand (APRIL), a new TNF family member, supports B-cell survival and tumor cell proliferation. APRIL is secreted as a soluble protein by macrophages, dendritic cells and activated T cells. However, factors involved in regulation of APRIL expression are as yet unknown. In this study, we investigated the effect of TGF-beta 1 on APRIL expression in P388D1, a mouse macrophage cell line. TGF-beta 1 induced APRIL mRNA expression in a time-and dose-dependent manner. One nanogram per milliliter of TGF-beta 1 was optimal and APRIL transcripts appeared as early as 3 h after stimulation. Based on our studies, which included overexpression of Smad3, DN-Smad3, and sh-Smad3, we found that Smad3 mediates APRIL transcription at least partially. Further, experiments using inhibitors revealed that p38MAPK and CREB are also involved in TGF-beta 1-induced APRIL expression. These results suggest that TGF-beta 1, through Smad3 and p38MAPK/CREB signaling pathways, stimulates APRIL expression in macrophages.