Identification of candidate genes that influence sex hormone-dependent disease phenotypes in mouse lupus

Bupp, Melanie R. Gubbels; Jørgensen, Trine N.; Kotzin, Brian L.

doi:10.1038/sj.gene.6364447

Cited by 41 publications

(34 citation statements)

References 37 publications

(37 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The role of estrogen, which influences both humoral and cellular immunity, has been widely studied and particularly in the NZB/W F1 mouse model of spontaneous SLE [47]. Female NZB/W F1 females die of SLE more rapidly than do males [6, 48].…”

Section: Discussionmentioning

confidence: 99%

Environmental exposure, estrogen and two X chromosomes are required for disease development in an epigenetic model of lupus

Strickland¹,

Hewagama²,

Lu³

et al. 2012

Journal of Autoimmunity

View full text Add to dashboard Cite

Systemic lupus erythematosus (SLE) is an autoimmune disease primarily afflicting women. The reason for the gender bias is unclear, but genetic susceptibility, estrogen and environmental agents appear to play significant roles in SLE pathogenesis. Environmental agents can contribute to lupus susceptibility through epigenetic mechanisms. We used (C57BL/6 × SJL)F1 mice transgenic for a dominant-negative MEK (dnMEK) that was previously shown to be inducibly and selectively expressed in T cells. In this model, induction of the dnMEK by doxycycline treatment suppresses T cell ERK signaling, decreasing DNA methyltransferase expression and resulting in DNA demethylation, overexpression of immune genes Itgal (CD11a) and Tnfsf7 (CD70), and anti-dsDNA antibody. To examine the role of gender and estrogen in this model, male and female transgenic mice were neutered and implanted with time-release pellets delivering placebo or estrogen. Doxycycline induced IgG anti-dsDNA antibodies in intact and neutered, placebo-treated control female but not male transgenic mice. Glomerular IgG deposits were also found in the kidneys of female but not male transgenic mice, and not in the absence of doxycycline. Estrogen enhanced anti-dsDNA IgG antibodies only in transgenic, ERK-impaired female mice. Decreased ERK activation also resulted in overexpression and demethylation of the X-linked methylation-sensitive gene CD40lg in female but not male mice, consistent with demethylation of the second X chromosome in the females. The results show that both estrogen and female gender contribute to the female predisposition in lupus susceptibility through hormonal and epigenetic X chromosome effects and through suppression of ERK signaling by environmental agents.

show abstract

Section: Discussionmentioning

confidence: 99%

Environmental exposure, estrogen and two X chromosomes are required for disease development in an epigenetic model of lupus

Strickland¹,

Hewagama²,

Lu³

et al. 2012

Journal of Autoimmunity

View full text Add to dashboard Cite

show abstract

“…Male (NZB × NZW)F 1 mice were orchiectomized at 3 months of age as described (35). After orchiectomy, pellets (Innovative Research of America, Sarasota, FL, USA) releasing E2, DHT, or placebo (P) for up to 3 weeks were inserted subcutaneously with a 10-gauge needle.…”

Section: Methodsmentioning

confidence: 99%

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

Panchanathan

Shen

Bupp

et al. 2009

The Journal of Immunology

View full text Add to dashboard Cite

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.

show abstract

“…Several studies have suggested that gender differences in lupus susceptibility are mediated by sex hormones, consistent with the fact that 90% of SLE sufferers are female [54–56]. For example, there is an increased risk of developing SLE in postmenopausal women who received estrogen hormone replacement therapy [57].…”

Section: Influence Of Estrogen In Cytokine Networkmentioning

confidence: 96%

Cytokine Networks in Systemic Lupus Erythematosus

Lee

Sugino

Nishimoto

2010

Journal of Biomedicine and Biotechnology

View full text Add to dashboard Cite

Systemic lupus erythematosus (SLE) is an autoimmune disease more prominent in women and characterized by multiple organ damage. Imbalance in cytokine production and cytokine levels correlates with SLE progression, making the understanding of SLE cytokine networks very important for SLE treatment strategy and drug development. In this article, we review cytokine networks that may be involved in the pathogenesis of SLE by briefly describing abnormal cytokine production and serum cytokine levels in SLE patients. We also focus on the pathological roles of cytokines and their interactions in immunoregulatory networks and suggest how their disturbances may implicate in pathological conditions in SLE. Finally, we further discuss the influence of estrogen on these cytokine networks.

show abstract

Identification of candidate genes that influence sex hormone-dependent disease phenotypes in mouse lupus

Cited by 41 publications

References 37 publications

Environmental exposure, estrogen and two X chromosomes are required for disease development in an epigenetic model of lupus

Environmental exposure, estrogen and two X chromosomes are required for disease development in an epigenetic model of lupus

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

Cytokine Networks in Systemic Lupus Erythematosus

Contact Info

Product

Resources

About