Gonadotropin-releasing hormone and G proteins: potential roles in autoimmunity

The hypothalamic homone gonadotropin-releasing hormone (GnRH) displays gender-specific actions. Pituitary responsiveness to GnRH is generally increased by estrogens and decreased by androgens. GnRH is now known to be produced by the immune system and to exert potent immunologic actions. Our central hypothesis is that gender differences in responsiveness to GnRH in the immune system play a pivotal role in the gender differences in immunity and autoimmunity. Studies in lupus-prone mice demonstrate that GnRH exacerbates murine lupus in a gender-specific fashion. Subsequent studies from our laboratory suggest that the gender differences in immunologic responsiveness to GnRH may relate to differences in the expression of the signal transducers through which GnRH acts, namely, the G proteins, Gs, and Gq/11. We have further demonstrated gender differences in second messengers for GnRH, IP3, and cAMF in immune cells. We have also demonstrated that GnRH agonist increases the quantities and/or activity of G proteins in immune cells in a gender-specific fashion. We speculate that gender differences in GnRH production and action, and in G protein expression play a role in a variety of autoimmune diseases that affect females predominantly.