Endogenous estrogen regulation of inflammatory arthritis and cytokine expression in male mice, predominantly via estrogen receptor alpha.
OBJECTIVE
A number of experimental observations have associated elevated estrogen levels with amelioration of inflammation. The involvement of estrogen and estrogen receptor (ER) isotypes in the regulation of inflammation in males is not well understood. In this study, we used specific ERalpha and ERbeta agonists in male mice deficient in estrogen because of a deletion of aromatase (aromatase-knockout [ArKO] mice) to investigate ER isotype utilization in estrogen regulation of inflammation.


METHODS
Lipopolysaccharide (LPS)-induced cytokine expression and antigen-induced arthritis (AIA) were investigated in male ArKO and WT littermate mice, as well as in response to selective agonists of ERalpha (16alpha-LE2) and ERbeta (8beta-VE2). The therapeutic effect of selective ER agonists was also examined in mice with collagen-induced arthritis (CIA).


RESULTS
Estrogen deficiency in ArKO mice was associated with significant increases in LPS-induced serum interleukin-6 (IL-6), tumor necrosis factor, monocyte chemotactic protein 1, and interferon-gamma levels, which were significantly abrogated by administration of 16alpha-LE2, but not 8beta-VE2. In contrast, both 16alpha-LE2 and 8beta-VE2 significantly increased LPS-induced IL-10 levels. Estrogen deficiency was also associated with significant exacerbation of AIA and antigen-specific T cell proliferation, which was reversed by administration of either 16alpha-LE2 or 8beta-VE2. ArKO mice showed increased antigen-specific T cell proliferation in response to immunization with type II collagen (CII). Administration of 16alpha-LE2, but not 8beta-VE2, significantly reduced the severity of CIA, which was associated with inhibition of anti-CII-specific IgG.


CONCLUSIONS
These data indicate that endogenous estrogen plays an essential inhibitory role in inflammation in male mice and that ERalpha is the dominant receptor that mediates these effects.
Monash University Department of Medicine and Monash Medical Centre, Clayton, Victoria 3168, Australia. yuan.yang@med.monash.edu.au
Y H
YH
Yang
D
D
Ngo
M
M
Jones
E
E
Simpson
K H
KH
Fritzemeier
E F
EF
Morand
D000818:Animals; D001141:Aromatase / Q000172:deficiency / Q000235:genetics; D001168:Arthritis / Q000097:blood / Q000139:chemically induced; D003433:Crosses, Genetic; D016207:Cytokines / Q000097:blood / Q000235:genetics*; D004958:Estradiol / Q000097:blood; D047628:Estrogen Receptor alpha / Q000502:physiology*; D047629:Estrogen Receptor beta / Q000502:physiology; D004967:Estrogens / Q000502:physiology; D005091:Exons / Q000235:genetics; D005260:Female; D006706:Homeostasis; D006801:Humans; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D012016:Reference Values; D017384:Sequence Deletion
D016207:Cytokines; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D008070:Lipopolysaccharides; D004958:Estradiol; D001141:Aromatase