title: Activin A stimulates mouse macrophages to express APRIL via the Smad3 and ERK/CREB pathways.
abstract: 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.
authors.affiliation: Department of Molecular Bioscience, College of Biomedical Science, Chuncheon 200-701, Republic of Korea.
authors.forename: Hwa-Joung
authors.initials: HJ
authors.lastname: Lee
authors.forename: Goo-Young
authors.initials: GY
authors.lastname: Seo
authors.forename: Jae-Hee
authors.initials: JH
authors.lastname: Kim
authors.forename: Mi-Ra
authors.initials: MR
authors.lastname: Lee
authors.forename: Pyeung-Hyeun
authors.initials: PH
authors.lastname: Kim
mesh_terms: D028341:Activins / Q000494:pharmacology*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000276:immunology / Q000378:metabolism*; D004149:Dioxoles / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000276:immunology; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation / Q000235:genetics; D051900:Smad3 Protein / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics; D019076:Transgenes / Q000235:genetics; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D001549:Benzamides; D017362:Cyclic AMP Response Element-Binding Protein; D004149:Dioxoles; D005419:Flavonoids; D051900:Smad3 Protein; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13; C422405:activin A; D028341:Activins; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one