Suppression of the inflammatory response in experimental arthritis is mediated via estrogen receptor alpha but not estrogen receptor beta.

Abstract

INTRODUCTION:

The immune modulatory role of estrogens in inflammation is complex. Both pro- and anti-inflammatory effects of estrogens have been described. Estrogens bind both estrogen receptor (ER)alpha and beta. The contribution of ERalpha and ERbeta to ER-mediated immune modulation was studied in delayed type hypersensitivity (DTH) and in experimental arthritis

METHODS:

ER-mediated suppression of rat adjuvant arthritis (AA) was studied using ethinyl-estradiol (EE) and a selective ERbeta agonist (ERB-79). Arthritis was followed for 2 weeks. Next, effects of ER agonists (ethinyl-estradiol, an ERalpha selective agonist (ERA-63) and a selective ERbeta agonist (ERB-79) on the development of a tetanus toxoid (TT)-specific delayed type hypersensitivity response in wild type (WT) and in ERalpha- or ERbeta-deficient mice were investigated. Finally, EE and ERA-63 were tested for their immune modulating potential in established collagen induced arthritis in DBA/1J mice. Arthritis was followed for three weeks. Joint pathology was examined by histology and radiology. Local synovial cytokine production was analyzed using Luminex technology. Sera were assessed for COMP as a biomarker of cartilage destruction.

RESULTS:

EE was found to suppress clinical signs and symptoms in rat AA. The selective ERbeta agonist ERB-79 had no effect on arthritis symptoms in this model. In the TT-specific DTH model, EE and the selective ERalpha agonist ERA-63 suppressed the TT-specific swelling response in WT and ERbetaKO mice but not in ERalphaKO mice. As seen in the AA model, the selective ERbeta agonist ERB-79 did not suppress inflammation. Treatment with EE or ERA-63 suppressed clinical signs in collagen induced arthritis (CIA) in WT mice. This was associated with reduced inflammatory infiltrates and decreased levels of proinflammatory cytokines in CIA joints.

CONCLUSIONS:

ERalpha, but not ERbeta, is key in ER-mediated suppression of experimental arthritis. It remains to be investigated how these findings translate to human autoimmune disease.

• Authors: John Dulos, Peter Vijn, Cindy van Doorn, Claudia L Hofstra, Desiree Veening-Griffioen, Jan de Graaf, Fred A Dijcks, Annemieke M H Boots
• Journal: Arthritis research & therapy (Arthritis Res Ther) Vol. 12 Issue 3 Pg. R101 ( 2010) ISSN: 1478-6362 [Electronic] England
• PMID: 20497523 (Publication Type: Journal Article)

Chemical References

• (7-alpha,17-alpha)-7-methyl-3-methylene-19-norpregn-5(10)-en-20-yn-17-ol
• Cytokines
• Estrogen Receptor alpha
• Estrogen Receptor beta
• Tetanus Toxoid
• Ethinyl Estradiol

Topics

• Animals
• Arthritis, Experimental (drug therapy, metabolism)
• Cytokines (metabolism)
• Disease Models, Animal
• Estrogen Receptor alpha (agonists, genetics, metabolism)
• Estrogen Receptor beta (agonists, genetics, metabolism)
• Ethinyl Estradiol (analogs & derivatives, therapeutic use)
• Female
• Hypersensitivity, Delayed (chemically induced, drug therapy)
• Inflammation (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Inbred DBA
• Mice, Knockout
• Rats
• Synovial Membrane (metabolism)
• Tetanus Toxoid (adverse effects)