Suppression of experimental autoimmune encephalomyelitis using estrogen receptor-selective ligands

被引:79
作者
Elloso, MM
Phiel, K
Henderson, RA
Harris, HA
Adelman, SJ
机构
[1] Wyeth Res, Cardiovasc & Metab Dis, Collegeville, PA 19426 USA
[2] Wyeth Res, Womens Hlth Res Inst, Collegeville, PA 19426 USA
关键词
D O I
10.1677/joe.1.06063
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Estrogens have been shown to modulate disease activity in experimental autoimmune encephalomyelitis (EAE), the mouse model for multiple sclerosis. Consistent with these findings, the severity of disease is reduced in pregnant women with multiple sclerosis when levels of estrogens are high. Estrogens bind to two known estrogen receptors (ER), ER alpha and ER beta. The relative contribution of these receptors to estrogen-mediated suppression of EAE was explored using ER-selective ligands. The ER antagonist ICI 182 780 reversed the suppressive effects of 17 beta-estradiol (E2), demonstrating that the protective effects of E2 on disease are dependent upon ER signaling. Treatment of SJL mice with the ER alpha-selective agonist proteolipid protein (PPT) prior to the induction of disease resulted in suppression of clinical symptoms of disease, whereas treatment with an ER beta-selective agonist (WAY-202041) had no effect. Treatment of mice with PLP peptide 139-151 (PPT) was also associated with decreased immune responses associated with disease. Consistent with its lack of effect on disease, the ER beta agonist had minimal effects on immune responses. The use of selective estrogen receptor modulators (SERMs) in this model was also explored, and we show that raloxifene and WAY-138923 were also effective in suppressing disease. These results demonstrate the beneficial effects of estrogen receptor ligands, in particular ER alpha-selective ligands, and may have implications in the development of therapeutic strategies for multiple sclerosis.
引用
收藏
页码:243 / 252
页数:10
相关论文
共 54 条
[1]   PREGNANCY AND MULTIPLE-SCLEROSIS [J].
ABRAMSKY, O .
ANNALS OF NEUROLOGY, 1994, 36 :S38-S41
[2]   The effect of a selective estrogen receptor modulator on the progression of spontaneous autoimmune disease in MRL lpr/lpr mice [J].
Apelgren, LD ;
Bailey, DL ;
Fouts, RL ;
Short, L ;
Bryan, N ;
Evans, GF ;
Sandusky, GE ;
Zuckerman, SH ;
Glasebrook, A ;
Bumol, TF .
CELLULAR IMMUNOLOGY, 1996, 173 (01) :55-63
[3]   Low-dose estrogen therapy ameliorates experimental autoimmune encephalomyelitis in two different inbred mouse strains [J].
Bebo, BF ;
Fyfe-Johnson, A ;
Adlard, K ;
Beam, AG ;
Vandenbark, AA ;
Offner, H .
JOURNAL OF IMMUNOLOGY, 2001, 166 (03) :2080-2089
[4]   THE CLINICAL COURSE OF MULTIPLE-SCLEROSIS DURING PREGNANCY AND THE PUERPERIUM [J].
BIRK, K ;
FORD, C ;
SMELTZER, S ;
RYAN, D ;
MILLER, R ;
RUDICK, RA .
ARCHIVES OF NEUROLOGY, 1990, 47 (07) :738-742
[5]   Estrogen up-regulates Bcl-2 and blocks tolerance induction of naive B cells [J].
Bynoe, MS ;
Grimaldi, CM ;
Diamond, B .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2000, 97 (06) :2703-2708
[6]   ESTROGEN ACCELERATES IMMUNE-COMPLEX GLOMERULONEPHRITIS BUT AMELIORATES T-CELL-MEDIATED VASCULITIS AND SIALADENITIS IN AUTOIMMUNE MRL LPR/LPR MICE [J].
CARLSTEN, H ;
NILSSON, N ;
JONSSON, R ;
BACKMAN, K ;
HOLMDAHL, R ;
TARKOWSKI, A .
CELLULAR IMMUNOLOGY, 1992, 144 (01) :190-202
[7]   Rate of pregnancy-related relapse in multiple sclerosis [J].
Confavreux, C ;
Hutchinson, M ;
Hours, MM ;
Cortinovis-Tourniaire, P ;
Moreau, T .
NEW ENGLAND JOURNAL OF MEDICINE, 1998, 339 (05) :285-291
[8]  
Correale J, 1998, J IMMUNOL, V161, P3365
[9]   Protective effects of estrogen and selective estrogen receptor modulators in the brain [J].
Dhandapani, KM ;
Brann, DW .
BIOLOGY OF REPRODUCTION, 2002, 67 (05) :1379-1385
[10]   EFFECT OF ANTI-ESTROGEN, NAFOXIDINE, ON NZB-W AUTO-IMMUNE DISEASE [J].
DUVIC, M ;
STEINBERG, AD ;
KLASSEN, LW .
ARTHRITIS AND RHEUMATISM, 1978, 21 (04) :414-417