Female and Male Sex Hormones Differentially Regulate Expression ofIfi202, an Interferon-Inducible Lupus Susceptibility Gene within theNba2Interval

Abstract

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 × NZW)F1 male mice with the female sex hormone 17β-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-α (ERα) 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 × NZW)F1 female mice as compared with males. 17β-estradiol treatment of B cells and WT276 cells increased Ifi202 mRNA levels, whereas treatment with dihydrotestosterone decreased the levels. Interestingly, overexpression of ERα 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, ERα 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 × NZW)F1 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.

Absent in melanoma 2 proteins in the development of cancer

“…Notably, the induced levels of the p202 were primarily detected in the cytoplasm. In addition, IL-6 [54] and the female sex hormone estrogen [55] also induce the expression of p202 in immune cells. Accordingly, the constitutive levels of p202 mRNA and protein are higher in cells from female mice than the agematched males [55].…”

“…In addition, IL-6 [54] and the female sex hormone estrogen [55] also induce the expression of p202 in immune cells. Accordingly, the constitutive levels of p202 mRNA and protein are higher in cells from female mice than the agematched males [55]. However, the p202 expression is suppressed by activated p53 [56], growth factors [57], and E2F1 [58].…”

“…Because sex hormone levels are predicted to influence the ratio between p202 and Aim2 protein levels in colon epithelial and stem cells [26,55,72], additional studies will be needed to identify the molecular mechanisms through which Aim2 deficiency in the male and female mice renders them more susceptible to the development of CAC in the AOM/DSS mouse model.…”

Role of Environment and Sex Differences in the Development of Autoimmune Diseases: A Roundtable Meeting Report

“…Interestingly, interactions among the three lupus susceptibility genes are required to develop autoAbs. 45 Recent discoveries from this murine model of autoimmunity include (1) sex hormones regulate the expression of p200 family proteins, 46,47,48 (2) IFN signaling regulates the expression of estrogen receptor a, and (3) polymorphisms in interferonregulated factor 5 (IRF5) predisposes individuals to increased production of IFNs with estrogen further up-regulating the IRF5 expression 49,50 In conclusion, Dr. Choubey stressed the need for further studies to assess the role of p200 family proteins in autoimmunity induced by both estrogen and environmental exposures.…”

Interferon and Apoptosis in Systemic Lupus Erythematosus

“…Liu, et al, 2010;Mathian, et al, 2005), while knocking out or inhibiting interferon-related genes slows or eliminates the development of lupus-like symptoms (Jorgensen, et al, 2007;Sharma, et al, 2005). These mice have been used to clarify the interactions between sex hormones and www.intechopen.com interferon in lupus etiology (Bynote, et al, 2008;Panchanathan, et al, 2009;Panchanathan, et al, 2010), and they serve as an excellent all-around model for spontaneous development of lupus. The role of several interferon-related molecules has been examined using a combination of mouse models.…”