Gender-specific exacerbation of murine lupus by gonadotropin-releasing hormone: Potential role of G alpha(q/11)

We have previously demonstrated that GnRH and its analogues modulate the se verity of murine systemic lupus erythematosus. In the present study, we dem onstrate 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 castrate d males. We initially hypothesized that gender differences in lymphocytic e xpression of GnRH receptor might explain these observations. Using competit ive RT-PCR and binding studies to quantitate GnRH receptor expression in ly mphoid organs, we found that GnRH administration led to decreased expressio n of GnRH receptor messenger RNA (mRNA) and GnRH binding, compared with veh icle, in spleens of ovariectomized females after 2 weeks of treatment. Thes e decreases occurred concurrently with increased expression of interleukin- 2 receptor mRNA and protein in females. GnRH administration did not alter G nRH 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 alpha(q/11). Competitive RT-PCR revealed that GnRH administration was associated with increases in the expression of G alpha(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 alpha(q/11) may contrib ute to gender differences in immunity and/or autoimmune disease.