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Gender-Specific Exacerbation of Murine Lupus by Gonadotropin-Releasing Hormone: Potential Role of G_q/11¹

Section of Endocrinology, Children’s Mercy Hospital, University of Missouri-Kansas City School of Medicine and the School of Pharmacy, University of Missouri-Kansas City, Kansas City, Missouri 64108

Address all correspondence and requests for reprints to: Jill D. Jacobson, M.D., Section of Endocrinology, Children’s Mercy Hospital, 2401 Gillham Road, Kansas City, Missouri 64108. E-mail: jjacobson{at}cmh.edu

We have previously demonstrated that GnRH and its analogues modulate the severity of murine systemic lupus erythematosus. In the present study, we demonstrate that GnRH alters disease severity in a sexually dimorphic fashion, even in gonadectomized mice. GnRH administration leads to an exacerbation of lupus in ovariectomized females, whereas it exerts no effect in castrated males. We initially hypothesized that gender differences in lymphocytic expression of GnRH receptor might explain these observations. Using competitive RT-PCR and binding studies to quantitate GnRH receptor expression in lymphoid organs, we found that GnRH administration led to decreased expression of GnRH receptor messenger RNA (mRNA) and GnRH binding, compared with vehicle, in spleens of ovariectomized females after 2 weeks of treatment. These decreases occurred concurrently with increased expression of interleukin-2 receptor mRNA and protein in females. GnRH administration did not alter GnRH receptor or interleukin-2 receptor mRNA or protein in castrated males. GnRH exerts actions on the pituitary through G protein signal transduction, specifically through G_q/11. Competitive RT-PCR revealed that GnRH administration was associated with increases in the expression of G_q/11 mRNA, compared with vehicle, in spleens in ovariectomized females but not in castrated males. Immunoblot analysis revealed a similar pattern. We conclude that gender differences in expression of G_q/11 may contribute to gender differences in immunity and/or autoimmune disease.

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