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GPR30, but not estrogen receptor-alpha, is crucial in the treatment of experimental autoimmune encephalomyelitis by oral ethinyl estradiol.

Yates MA, Li Y, Chlebeck PJ, Offner H - BMC Immunol. (2010)

Bottom Line: In the current study, the influence of estrogen receptor-alpha (ERalpha) and the G-protein coupled estrogen receptor (GPR30 or GPER) on EE's ability to treat EAE was explored.Differential production of IL-10 following EE treatment in ERKO and GPR30KO animals may be responsible for the distinctly different effects on disease severity.Increased IL-10 in ERKO-EE compared to ERKO-Controls is likely to be an important factor in reducing established disease.

View Article: PubMed Central - HTML - PubMed

Affiliation: Neuroimmunology Research, Portland VA Medical Center, Portland, OR, USA.

ABSTRACT

Background: Remission of multiple sclerosis during periods of high ovarian hormone secretion (such as pregnancy) has led to a great deal of interest in the potential for estrogens to treat autoimmune disease. Previous work has established that 17beta-estradiol can inhibit onset of experimental autoimmune encephalomyelitis (EAE), while ethinyl estradiol (EE) can reduce the severity of established disease. In the current study, the influence of estrogen receptor-alpha (ERalpha) and the G-protein coupled estrogen receptor (GPR30 or GPER) on EE's ability to treat EAE was explored.

Results: EE reduced disease severity in wild-type and ERalpha knockout (ERKO) mice, but did not alter disease in the GPR30KO group. Production of anti-inflammatory IL-10 increased in EE-ERKO mice (which showed reduced disease) but not in EE-GPR30KO mice (who did not have improved disease).

Conclusions: Differential production of IL-10 following EE treatment in ERKO and GPR30KO animals may be responsible for the distinctly different effects on disease severity. Increased IL-10 in ERKO-EE compared to ERKO-Controls is likely to be an important factor in reducing established disease. The inability of EE to reduce disease in GPR30KO mice indicates an important but still undefined role for GPR30 in regulating immune reactivity.

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Related in: MedlinePlus

Treatment with ethinyl estradiol (EE; 1 mg/day) reduced disease severity in ovariectomized wild-type (WT) mice (A) and estrogen receptor-α knockout (ERKO) mice (B), while mice lacking the G-protein coupled estrogen receptor (GPR30KO; C) showed no improvement in disease severity. WT: N = 12 per group. ERKO: Ctrl N = 9, EE N = 10. GPR30KO: Ctrl N = 13, EE N = 12. * indicates p < .04
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Figure 1: Treatment with ethinyl estradiol (EE; 1 mg/day) reduced disease severity in ovariectomized wild-type (WT) mice (A) and estrogen receptor-α knockout (ERKO) mice (B), while mice lacking the G-protein coupled estrogen receptor (GPR30KO; C) showed no improvement in disease severity. WT: N = 12 per group. ERKO: Ctrl N = 9, EE N = 10. GPR30KO: Ctrl N = 13, EE N = 12. * indicates p < .04

Mentions: From D17-D26, disease was significantly inhibited in WT mice treated with EE (p < .03, Figure 1A). While cumulative disease index (CDI) was also reduced (p < .01), disease onset and peak disease scores did not differ (Table 1). ERKO mice treated with EE also had reduced disease severity (p < .04; D17-20, 23-26, Figure 1B). Peak disease scores and CDI were also reduced in ERKO EE animals (p < .03, Table 1). However, GPR30KO animals showed no alteration in disease course with EE treatment (Figure 1C and Table 1). Within Ctrl mice, there was no difference in peak disease severity or onset between WT-Ctrl and GPR30KO-Ctrl mice. However, GPR30KO mice did show lower average disease scores (D16-26) and a reduced CDI compared to WT (p < .02). There were no differences between WT-Ctrl and ERKO-Ctrl mice.


GPR30, but not estrogen receptor-alpha, is crucial in the treatment of experimental autoimmune encephalomyelitis by oral ethinyl estradiol.

Yates MA, Li Y, Chlebeck PJ, Offner H - BMC Immunol. (2010)

Treatment with ethinyl estradiol (EE; 1 mg/day) reduced disease severity in ovariectomized wild-type (WT) mice (A) and estrogen receptor-α knockout (ERKO) mice (B), while mice lacking the G-protein coupled estrogen receptor (GPR30KO; C) showed no improvement in disease severity. WT: N = 12 per group. ERKO: Ctrl N = 9, EE N = 10. GPR30KO: Ctrl N = 13, EE N = 12. * indicates p < .04
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2864220&req=5

Figure 1: Treatment with ethinyl estradiol (EE; 1 mg/day) reduced disease severity in ovariectomized wild-type (WT) mice (A) and estrogen receptor-α knockout (ERKO) mice (B), while mice lacking the G-protein coupled estrogen receptor (GPR30KO; C) showed no improvement in disease severity. WT: N = 12 per group. ERKO: Ctrl N = 9, EE N = 10. GPR30KO: Ctrl N = 13, EE N = 12. * indicates p < .04
Mentions: From D17-D26, disease was significantly inhibited in WT mice treated with EE (p < .03, Figure 1A). While cumulative disease index (CDI) was also reduced (p < .01), disease onset and peak disease scores did not differ (Table 1). ERKO mice treated with EE also had reduced disease severity (p < .04; D17-20, 23-26, Figure 1B). Peak disease scores and CDI were also reduced in ERKO EE animals (p < .03, Table 1). However, GPR30KO animals showed no alteration in disease course with EE treatment (Figure 1C and Table 1). Within Ctrl mice, there was no difference in peak disease severity or onset between WT-Ctrl and GPR30KO-Ctrl mice. However, GPR30KO mice did show lower average disease scores (D16-26) and a reduced CDI compared to WT (p < .02). There were no differences between WT-Ctrl and ERKO-Ctrl mice.

Bottom Line: In the current study, the influence of estrogen receptor-alpha (ERalpha) and the G-protein coupled estrogen receptor (GPR30 or GPER) on EE's ability to treat EAE was explored.Differential production of IL-10 following EE treatment in ERKO and GPR30KO animals may be responsible for the distinctly different effects on disease severity.Increased IL-10 in ERKO-EE compared to ERKO-Controls is likely to be an important factor in reducing established disease.

View Article: PubMed Central - HTML - PubMed

Affiliation: Neuroimmunology Research, Portland VA Medical Center, Portland, OR, USA.

ABSTRACT

Background: Remission of multiple sclerosis during periods of high ovarian hormone secretion (such as pregnancy) has led to a great deal of interest in the potential for estrogens to treat autoimmune disease. Previous work has established that 17beta-estradiol can inhibit onset of experimental autoimmune encephalomyelitis (EAE), while ethinyl estradiol (EE) can reduce the severity of established disease. In the current study, the influence of estrogen receptor-alpha (ERalpha) and the G-protein coupled estrogen receptor (GPR30 or GPER) on EE's ability to treat EAE was explored.

Results: EE reduced disease severity in wild-type and ERalpha knockout (ERKO) mice, but did not alter disease in the GPR30KO group. Production of anti-inflammatory IL-10 increased in EE-ERKO mice (which showed reduced disease) but not in EE-GPR30KO mice (who did not have improved disease).

Conclusions: Differential production of IL-10 following EE treatment in ERKO and GPR30KO animals may be responsible for the distinctly different effects on disease severity. Increased IL-10 in ERKO-EE compared to ERKO-Controls is likely to be an important factor in reducing established disease. The inability of EE to reduce disease in GPR30KO mice indicates an important but still undefined role for GPR30 in regulating immune reactivity.

Show MeSH
Related in: MedlinePlus