Female and male sex hormones differentially regulate expression of Ifi202, an interferon-inducible lupus susceptibility gene within the Nba2 interval.
Increased expression of IFN-inducible Ifi202 gene in certain strains of female mice is associated with susceptibility to systemic lupus erythematosus (SLE). Although, the development of SLE is known to have a strong sex bias, the molecular mechanisms remain unknown. Here we report that in vivo treatment of orchiectomized (NZB x NZW)F(1) male mice with the female sex hormone 17beta-estradiol significantly increased steady-state levels of Ifi202 mRNA in splenic cells, whereas treatment with the male hormone dihydrotestosterone decreased the levels. Moreover, increased expression of Ifi202 in B6.Nba2 B cells and reduced expression in T cells were associated with increased levels of estrogen receptor-alpha (ERalpha) and androgen receptor, respectively. Furthermore, the steady-state levels of Ifi202 mRNA were higher in splenic cells from C57BL/6, B6.Nba2, NZB, and (NZB x NZW)F(1) female mice as compared with males. 17beta-estradiol treatment of B cells and WT276 cells increased Ifi202 mRNA levels, whereas treatment with dihydrotestosterone decreased the levels. Interestingly, overexpression of ERalpha in WT276 cells increased the expression of Ifi202 and stimulated the activity of the 202-luc-reporter through the c-Jun/AP-1 DNA-binding site. Accordingly, ERalpha preferentially associated with the regulatory region of the Ifi202 gene in female B6.Nba2 B cells than in males. Furthermore, Ifi202 mRNA levels were detectable in splenic cells of wild-type (Esr1(+/+)), but not null (Esr1(-/-)), (NZB x NZW)F(1) female mice. Collectively, our observations demonstrate that the female and male sex hormones differentially regulate the expression of Ifi202, thus providing support for the role of Ifi202 in sex bias in SLE.
Panchanathan
Ravichandran
R
Department of Environmental Health, University of Cincinnati, Cincinnati, OH 45267, USA.
Shen
Hui
H
Bupp
Melanie Gubbels
MG
Gould
Karen A
KA
Choubey
Divaker
D
D000728:Androgens / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D013196:Dihydrotestosterone / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000096:biosynthesis / Q000187:drug effects; D004967:Estrogens / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000187:drug effects*; D020022:Genetic Predisposition to Disease; D012739:Gonadal Steroid Hormones / Q000378:metabolism* / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000187:drug effects* / Q000235:genetics; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D008297:Male; D051379:Mice; D008814:Mice, Inbred NZB; D009919:Orchiectomy; D012333:RNA, Messenger / Q000187:drug effects; D011944:Receptors, Androgen / Q000096:biosynthesis / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012727:Sex Characteristics; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism
D000728:Androgens; D047628:Estrogen Receptor alpha; D004967:Estrogens; D012739:Gonadal Steroid Hormones; C092537:Ifi202b protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D004958:Estradiol