Estrogen receptor-α deficiency attenuates autoimmune disease in (NZB × NZW)F1 mice
| Autor: | Kenneth S. Korach, J M Hackenberg, D B Lubahn, Kimberly K. Bynoté, Karen A. Gould, Pascale H. Lane |
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| Rok vydání: | 2008 |
| Předmět: |
Male
medicine.medical_specialty medicine.drug_class Immunology Estrogen receptor Biology medicine.disease_cause Autoimmunity Pathogenesis Mice Glomerulonephritis immune system diseases Internal medicine Genetics medicine Animals Lupus Erythematosus Systemic Inbreeding skin and connective tissue diseases Genetics (clinical) Estrogen receptor beta Mice Knockout Autoimmune disease Systemic lupus erythematosus Mice Inbred NZB Estrogen Receptor alpha medicine.disease Endocrinology Estrogen Female Estrogen receptor alpha |
| Zdroj: | Genes & Immunity. 9:137-152 |
| ISSN: | 1476-5470 1466-4879 |
| DOI: | 10.1038/sj.gene.6364458 |
| Popis: | 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 x NZW)F(1) background, disruption of estrogen receptor-alpha (ER alpha or Esr1) attenuated glomerulonephritis and increased survival. ER alpha deficiency also retarded development of anti-histone/DNA antibodies, suggesting that ER alpha promotes loss of immunologic tolerance. Furthermore, ER alpha deficiency in (NZB x NZW)F(1) 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 alpha may promote lupus, at least in part, by inducing interferon-gamma, an estrogen-regulated cytokine that impacts this disease. ER alpha deficiency in (NZB x NZW)F(1) males increased survival and reduced anti-dsDNA antibodies, suggesting that ER alpha also modulates lupus in males. These studies demonstrate that ER alpha, rather than ER beta, plays a major role in regulating autoimmunity in (NZB x NZW)F(1) mice. Furthermore, our results suggest for the first time that ER alpha promotes lupus, at least in part, by impacting the initial loss of tolerance. These data suggest that targeted therapy disrupting ER alpha, most likely within the immune system, may be effective in the prevention and/or treatment of lupus. |
| Databáze: | OpenAIRE |
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