TY - JOUR
T1 - Estrogen receptor-1 (Esr1) and -2 (Esr2) regulate the severity of clinical experimental allergic encephalomyelitis in male mice
AU - Polanczyk, Magdalena
AU - Yellayi, Srikanth
AU - Zamora, Alex
AU - Subramanian, Sandhya
AU - Tovey, Micah
AU - Vandenbark, Arthur A.
AU - Offner, Halina
AU - Zachary, James F.
AU - Fillmore, Parley D.
AU - Blankenhorn, Elizabeth P.
AU - Gustafsson, Jan Åke
AU - Teuscher, Cory
N1 - Funding Information:
Supported by the National Institutes of Health (grants NS36526 to C.T. and E.P.B., AI4515 to C.T., AI41747 to C.T., AI42376 to H.O., NS23444 to H.O. ), the National Multiple Sclerosis Society (grants RG-3129 to C.T. and E.P.B. and RG-3108 to H.O. ), the Swedish Cancer Fund, and KaroBio AB.
PY - 2004/6
Y1 - 2004/6
N2 - Estrogens and estrogen-receptor signaling function in establishing and regulating the female immune system and it is becoming increasingly evident that they may play a similar role in males. We report that B10.PL/SnJ male mice with a disrupted estrogen receptor-1 (α) gene (Esr1-/-) develop less severe clinical experimental allergic encephalomyelitis (EAE) compared to either Esr1+/- or wild-type (Esr1+/+) controls when immunized with myelin basic protein peptide Ac1-11 (MBP Ac1-11). In contrast, the disease course in B10.PL/SnJ male mice with a disrupted estrogen receptor-2 (β) gene (Esr2-/-) does not differ from that of wild-type (Esr2+/+) mice. However, Esr2 +/- mice do develop more severe clinical disease with an earlier onset indicating that heterosis at Esr2 plays a significant role in regulating EAE in males. No significant differences in central nervous system histopathology or MBPAc1-11-specific T-cell responses as assessed by proliferation and interleukin-2 production were observed as a function of either Esr1 or Esr2 genotype. An analysis of cytokine/chemokine secretion by MBPAc1-11-specific T cells revealed unique Esr1 and Esr2 genotype-dependent regulation. Interferon-γ secretion was found to be negatively regulated by Esr1 whereas interleukin-6 and tumor necrosis factor-α secretion exhibited classical Esr2 gene dose responses. Interestingly, MCP-1 displayed distinctively unique patterns of genotype-dependent regulation by Esr1 and Esr2. The contribution of the hematopoietic and nonhematopoietic cellular compartments associated with the heterotic effect at Esr2 in regulating the severity of clinical EAE was identified using reciprocal hematopoietic radiation bone marrow chimeras generated between male wild-type and Esr2+/- mice. Wild-type → Esr2+/- mice exhibited EAE equivalent in severity to that seen in Esr2+/- → Esr2+/- control constructs; both of which were more severe than the clinical signs observed in Esr2+/- → wild-type and wild-type → wild-type mice. These results indicate that the heterotic effect at Esr2 is a function of the nonhematopoietic compartment.
AB - Estrogens and estrogen-receptor signaling function in establishing and regulating the female immune system and it is becoming increasingly evident that they may play a similar role in males. We report that B10.PL/SnJ male mice with a disrupted estrogen receptor-1 (α) gene (Esr1-/-) develop less severe clinical experimental allergic encephalomyelitis (EAE) compared to either Esr1+/- or wild-type (Esr1+/+) controls when immunized with myelin basic protein peptide Ac1-11 (MBP Ac1-11). In contrast, the disease course in B10.PL/SnJ male mice with a disrupted estrogen receptor-2 (β) gene (Esr2-/-) does not differ from that of wild-type (Esr2+/+) mice. However, Esr2 +/- mice do develop more severe clinical disease with an earlier onset indicating that heterosis at Esr2 plays a significant role in regulating EAE in males. No significant differences in central nervous system histopathology or MBPAc1-11-specific T-cell responses as assessed by proliferation and interleukin-2 production were observed as a function of either Esr1 or Esr2 genotype. An analysis of cytokine/chemokine secretion by MBPAc1-11-specific T cells revealed unique Esr1 and Esr2 genotype-dependent regulation. Interferon-γ secretion was found to be negatively regulated by Esr1 whereas interleukin-6 and tumor necrosis factor-α secretion exhibited classical Esr2 gene dose responses. Interestingly, MCP-1 displayed distinctively unique patterns of genotype-dependent regulation by Esr1 and Esr2. The contribution of the hematopoietic and nonhematopoietic cellular compartments associated with the heterotic effect at Esr2 in regulating the severity of clinical EAE was identified using reciprocal hematopoietic radiation bone marrow chimeras generated between male wild-type and Esr2+/- mice. Wild-type → Esr2+/- mice exhibited EAE equivalent in severity to that seen in Esr2+/- → Esr2+/- control constructs; both of which were more severe than the clinical signs observed in Esr2+/- → wild-type and wild-type → wild-type mice. These results indicate that the heterotic effect at Esr2 is a function of the nonhematopoietic compartment.
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U2 - 10.1016/S0002-9440(10)63752-2
DO - 10.1016/S0002-9440(10)63752-2
M3 - Article
C2 - 15161628
AN - SCOPUS:2442637923
SN - 0002-9440
VL - 164
SP - 1915
EP - 1924
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 6
ER -