Enhancement of collagen-induced arthritis in female mice by estrogen receptor blockage

Objective. To determine whether estrogen-mediated suppression of collagen-i nduced arthritis (CIA) in mice acts via the nuclear estrogen receptors (ERs ). Methods. CIA was induced in noncastrated normal (B10.Q x DBA/1)F-1 (QD) fem ale mice. The mice were treated with the ER antagonist ICI 182,780, which b inds to both ER alpha and ER beta, either on days 2, 6, 10, and 14 or on da ys 14, 18, 22, and 26 after type II collagen (CII) immunization. The effect s of treatment and development of arthritis were correlated with the estrus cycle by inspection of vaginal smears (VS). By a combination of treatments with both estriol (E-3) and ICI 182,780 during the time of expected onset of CIA in castrated QD female mice, the protective effect of E3 in CIA was analyzed. Results. Treatment with ICI 182,780 of QD female mice immunized with CII tr iggered an earlier onset of arthritis during the period when the estrus cyc le was blocked. The arthritis-modulating effect of ICI 182,780 was even obt ained at doses that were insufficient to block estrus cycling, as observed in the VS response. E3 is an estrogen with low estrogenic potency but with a relatively potent antiarthritis effect. Doses of ICI 182,780 that were su boptimal for blocking estrus cycling blocked the E-3-mediated suppression o f CIA in castrated female mice. Conclusion. These findings show that estrogen-induced suppression of CIA is mediated via the nuclear ERs and is operating at physiologic, possibly eve n subphysiologic, levels of estrogens.