Endogenous Estrogen Regulation of Inflammatory Arthritis and Cytokine Expression in Male Mice, Predominantly via Estrogen Receptor α

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 ER alpha and ER beta 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 ER alpha (16 alpha-LE2) and ER beta (8 beta-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 16 alpha-LE2, but not 8 beta-VE2. In contrast, both 16 alpha-LE2 and 8 beta-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 16 alpha-LE2 or 8 beta-VE2. ArKO mice showed increased antigen-specific T cell proliferation in response to immunization with type II collagen (CII). Administration of 16 alpha-LE2, but not 8 beta-VE2, significantly reduced the severity of CIA, which was associated with inhibition of anti-CII-specific IgG. Conclusion. These data indicate that endogenous estrogen plays an essential inhibitory role in inflammation in male mice and that ER alpha is the dominant receptor that mediates these effects.