1. ¹Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, USA
2. ²Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, NE, USA
3. ³Receptor Biology Section, National Institute of Environmental Health Sciences, National Institutes of Health (NIH), Research Triangle Park, NC, USA
4. ⁴Department of Biochemistry, University of Missouri, Columbia, MO, USA
5. ⁵Department of Child Health, University of Missouri, Columbia, MO, USA
6. ⁶Department of Animal Sciences, University of Missouri, Columbia, MO, USA
7. ⁷MU Center for Phytonutrient and Phytochemical Studies, University of Missouri, Columbia, MO, USA
8. ⁸Department of Pediatrics, University of Nebraska Medical Center, Omaha, NE, USA

Correspondence: Dr KA Gould, Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198-5805, USA. E-mail: kagould@unmc.edu

Received 17 October 2007; Revised 7 December 2007; Accepted 7 December 2007; Published online 17 January 2008.

Abstract

Estrogens promote lupus in humans and some mouse models of this disease. Nonetheless, little is known about the role of estrogen receptors in lupus pathogenesis. Here, we report that in females on the lupus-prone (NZB NZW)F₁ background, disruption of estrogen receptor- (ER or Esr1) attenuated glomerulonephritis and increased survival. ER deficiency also retarded development of anti-histone/DNA antibodies, suggesting that ER promotes loss of immunologic tolerance. Furthermore, ER deficiency in (NZB NZW)F₁ females attenuated the subsequent development of anti-double-stranded DNA (dsDNA) IgG antibodies, which are associated with glomerulonephritis in this model. We provide evidence that ER may promote lupus, at least in part, by inducing interferon-, an estrogen-regulated cytokine that impacts this disease. ER deficiency in (NZB NZW)F₁ males increased survival and reduced anti-dsDNA antibodies, suggesting that ER also modulates lupus in males. These studies demonstrate that ER, rather than ER, plays a major role in regulating autoimmunity in (NZB NZW)F₁ mice. Furthermore, our results suggest for the first time that ER promotes lupus, at least in part, by impacting the initial loss of tolerance. These data suggest that targeted therapy disrupting ER, most likely within the immune system, may be effective in the prevention and/or treatment of lupus.