Endogenous estrogen regulation of inflammatory arthritis and cytokine expression in male mice, predominantly via estrogen receptor α

✍ Scribed by Y. H. Yang; D. Ngo; M. Jones; E. Simpson; K. H. Fritzemeier; E. F. Morand

• Publisher: John Wiley and Sons
• Year: 2010
• Tongue: English
• Weight: 306 KB
• Volume: 62
• Category: Article
• ISSN: 0004-3591
• DOI: 10.1002/art.27330

✦ Synopsis

Abstract

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 ERα and ERβ 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 ERα (16α‐LE2) and ERβ (8β‐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‐γ levels, which were significantly abrogated by administration of 16α‐LE2, but not 8β‐VE2. In contrast, both 16α‐LE2 and 8β‐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 16α‐LE2 or 8β‐VE2. ArKO mice showed increased antigen‐specific T cell proliferation in response to immunization with type II collagen (CII). Administration of 16α‐LE2, but not 8β‐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 ERα is the dominant receptor that mediates these effects.