TGF-beta1 and IFN-gamma stimulate mouse macrophages to express BAFF via different signaling pathways.
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-beta1 and IFN-gamma induce BAFF expression to see if TGF-beta1 and IFN-gamma regulate B cell differentiation via macrophages. We found that TGF-beta1 stimulated mouse macrophages to express BAFF and that a typical TGF-beta 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-beta1 enhanced the expression of membrane-bound and soluble forms of BAFF. IFN-gamma further augmented TGF-beta1-induced BAFF expression. IFN-gamma caused phosphorylation of CREB, and overexpression of CREB increased IFN-gamma-induced BAFF promoter activity. Furthermore, H89, a protein kinase A (PKA) inhibitor, abrogated the promoter activity. Neither Stat1alpha (a well-known transducing molecule of IFN-gamma) nor AG490 (a JAK inhibitor) affected BAFF expression in response to IFN-gamma. Taken together, these results demonstrate that TGF-beta1 and IFN-gamma up-regulate BAFF expression through independent mechanisms, i.e., mainly Smad3/4 and PKA/CREB, respectively.
Kim
Hyun-A
HA
Department of Molecular Bioscience, School of Bioscience and Biotechnology, Kangwon National University, Chunchon, Republic of Korea.
Jeon
Seong-Hyun
SH
Seo
Goo-Young
GY
Park
Jae-Bong
JB
Kim
Pyeung-Hyeun
PH
D000818:Animals; D053264:B-Cell Activating Factor / Q000235:genetics*; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D007371:Interferon-gamma / Q000494:pharmacology*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D011401:Promoter Regions, Genetic; D015398:Signal Transduction / Q000502:physiology*; D051900:Smad3 Protein / Q000502:physiology; D051901:Smad4 Protein / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*
D053264:B-Cell Activating Factor; D017362:Cyclic AMP Response Element-Binding Protein; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; C505720:Tnfsf13b protein, mouse; D053773:Transforming Growth Factor beta1; D007371:Interferon-gamma; D017868:Cyclic AMP-Dependent Protein Kinases