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

Abstract

BackgroundRemission 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 17β-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-α (ERα) and the G-protein coupled estrogen receptor (GPR30 or GPER) on EE's ability to treat EAE was explored.ResultsEE reduced disease severity in wild-type and ERα 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).ConclusionsDifferential 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.

Medium-dose estrogen ameliorates experimental autoimmune encephalomyelitis in ovariectomized mice

“…This difference in cytokine production may be an important contributor to the disease reduction seen in the high-/medium-dose estrogen mice. Increased IL-10 secretion is frequently associated with improvement in disease, while IL-10-deficient animals have a greater T-cell response to antigen and develop more severe EAE compared to WT mice (Yates et al 2010).…”

International Union of Basic and Clinical Pharmacology. XCVII. G Protein–Coupled Estrogen Receptor and Its Pharmacologic Modulators

“…It exhibits an affinity for ERa/b approximately twofold better than E2 (Blair et al, 2000), but its affinity for GPER has not been reported. In the animal model of multiple sclerosis (EAE), E2 can prevent onset of disease but it cannot treat established disease, whereas EE can reduce the severity of existing disease (Yates et al, 2010). The protective effects of E2 have been reported to be reduced in both ERa knockout (Morales et al, 2006) as well as GPER knockout mice .…”

“…The protective effects of G-1 were absent in GPER knockout mice, confirming the selectivity of G-1 for GPER in vivo . Furthermore, the therapeutic efficacy of ethynyl estradiol in established disease required expression of GPER but not ERa and were associated with anti-inflammatory cytokine interleukin (IL)-10 production (Yates et al, 2010). Mechanistic studies revealed that G-1 not only enhanced the suppressive activity of CD4 + Foxp3 + T regulatory cells through upregulation of programmed death 1 ), but also inhibited inflammatory cytokine production by macrophages (Blasko et al, 2009), suggesting multiple coordinated or perhaps independent effects on the immune system.…”

“…The protective effects of E2 have been reported to be reduced in both ERa knockout (Morales et al, 2006) as well as GPER knockout mice . In subsequent studies the effects of EE were shown to be entirely mediated through GPER, as they were completely absent in GPER knockout mice but maintained in ERa knockout mice (Yates et al, 2010). The lack of disease improvement in EEtreated GPER knockout mice indicates a crucial role for GPER in altering disease severity, likely through the production of IL-10 and associated antiinflammatory effects (Bodhankar and Offner, 2011).…”

Oral contraceptive use and clinical outcomes in patients with multiple sclerosis

“…All oestrogens are not exactly alike [5,23]. Importantly and unlike 17β-oestradiol, the common oestrogen found in pills ethynil oestradiol [24,25] and progesterone [26] reduce the clinical severity of EAE when given after the onset of disease signs. Because the large majority of our patients have used different combinations of ethynil oestradiol and a progestogen, we cannot exclude that these hormones could have different impacts on the observed protective effects.…”