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Published online before print March 11, 2008

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(Journal of Leukocyte Biology. 2008;83:1431-1439.)
© 2008 by Society for Leukocyte Biology

TGF-β1 and IFN- stimulate mouse macrophages to express BAFF via different signaling pathways

Hyun-A Kim^*, Seong-Hyun Jeon^*, Goo-Young Seo^*, Jae-Bong Park and Pyeung-Hyeun Kim^*,,1

^* Department of Molecular Bioscience, School of Bioscience and Biotechnology, and
Vascular System Research Center, Kangwon National University, Chunchon, Republic of Korea; and
Department of Biochemistry, College of Medicine, Hallym University, Chunchon, Republic of Korea

¹Correspondence: Department of Molecular Bioscience, School of Bioscience and Biotechnology, Kangwon National University, Chunchon 200-701, Republic of Korea. E-mail: phkim{at}kangwon.ac.kr

B cell-activating factor belonging to the TNF family (BAFF) is primarily expressed by macrophages and dendritic cells and stimulates the proliferation, differentiation, and survival of B cells and their Ig production. In the present study, we examined the pathways by which TGF-β1 and IFN- induce BAFF expression to see if TGF-β1 and IFN- regulate B cell differentiation via macrophages. We found that TGF-β1 stimulated mouse macrophages to express BAFF and that a typical TGF-β signaling pathway was involved. Thus, Smad3 and Smad4 promoted BAFF promoter activity, and Smad7 inhibited it, and the BAFF promoter was shown to contain three Smad-binding elements. Importantly, TGF-β1 enhanced the expression of membrane-bound and soluble forms of BAFF. IFN- further augmented TGF-β1-induced BAFF expression. IFN- caused phosphorylation of CREB, and overexpression of CREB increased IFN--induced BAFF promoter activity. Furthermore, H89, a protein kinase A (PKA) inhibitor, abrogated the promoter activity. Neither Stat1 (a well-known transducing molecule of IFN-) nor AG490 (a JAK inhibitor) affected BAFF expression in response to IFN-. Taken together, these results demonstrate that TGF-β1 and IFN- up-regulate BAFF expression through independent mechanisms, i.e., mainly Smad3/4 and PKA/CREB, respectively.

Key Words: Smad • CREB • promoter