Murine BAFF expression is up-regulated by estrogen and interferons: implications for sex bias in the development of autoimmunity.
Systemic lupus erythematosus (SLE) in patients and certain mouse models exhibits a strong sex bias. Additionally, in most patients, increased serum levels of type I interferon (IFN-α) are associated with severity of the disease. Because increased levels of B cell activating factor (BAFF) in SLE patients and mouse models are associated with the development of SLE, we investigated whether the female sex hormone estrogen (E2) and/or IFNs (IFN-α or γ) could regulate the expression of murine BAFF. We found that steady-state levels of BAFF mRNA and protein were measurably higher in immune cells (CD11b(+), CD11c(+), and CD19(+)) isolated from C57BL/6 females than the age-matched male mice. Treatment of immune cells with IFN or E2 significantly increased levels of BAFF mRNA and protein and a deficiency of estrogen receptor-α, IRF5, or STAT1 expression in splenic cells decreased expression of BAFF. Moreover, treatment of RAW264.7 macrophage cells with IFN-α, IFN-γ, or E2 induced expression of BAFF. Interestingly, increased expression of p202, an IFN and estrogen-inducible protein, in RAW264.7 cells significantly increased the expression levels of BAFF and also stimulated the activity of the BAFF-luc-reporter. Accordingly, the increased expression of the p202 protein in lupus-prone B6.Nba2-ABC than non lupus-prone C57BL/6 and B6.Nba2-C female mice was associated with increased expression levels of BAFF. Together, our observations demonstrated that estrogen and IFN-induced increased levels of the p202 protein in immune cells contribute to sex bias in part through up-regulation of BAFF expression.
Department of Environmental Health, University of Cincinnati, 3223 Eden Avenue, P.O. Box-670056, Cincinnati, OH 45267, United States.
Ravichandran
R
Panchanathan
Divaker
D
Choubey
D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology / Q000378:metabolism; D015551:Autoimmunity / Q000276:immunology*; D053264:B-Cell Activating Factor / Q000276:immunology* / Q000378:metabolism; D004967:Estrogens / Q000276:immunology*; D005260:Female; D015151:Immunoblotting; D007372:Interferons / Q000276:immunology*; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012727:Sex Characteristics; D015398:Signal Transduction / Q000276:immunology; D015854:Up-Regulation
D053264:B-Cell Activating Factor; D004967:Estrogens; C092537:Ifi202b protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D012333:RNA, Messenger; C505720:Tnfsf13b protein, mouse; D007372:Interferons