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TGF‐β1 and IFN‐γ stimulate mouse macrophages to express BAFF via different signaling pathways
Author(s) -
Kim HyunA,
Jeon SeongHyun,
Seo GooYoung,
Park JaeBong,
Kim PyeungHyeun
Publication year - 2008
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.1007676
Subject(s) - b cell activating factor , creb , biology , signal transduction , microbiology and biotechnology , phosphorylation , transforming growth factor , stat1 , cancer research , immunology , transcription factor , b cell , antibody , gene , biochemistry
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‐γ induce BAFF expression to see if TGF‐β1 and IFN‐γ 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‐γ further augmented TGF‐β1‐induced BAFF expression. IFN‐γ caused phosphorylation of CREB, and overexpression of CREB increased IFN‐γ‐induced BAFF promoter activity. Furthermore, H89, a protein kinase A (PKA) inhibitor, abrogated the promoter activity. Neither Stat1α (a well‐known transducing molecule of IFN‐γ) nor AG490 (a JAK inhibitor) affected BAFF expression in response to IFN‐γ. Taken together, these results demonstrate that TGF‐β1 and IFN‐γ up‐regulate BAFF expression through independent mechanisms, i.e., mainly Smad3/4 and PKA/CREB, respectively.