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Arthritis Res Ther. 2010; 12(3): R101.
Published online May 24, 2010. doi:  10.1186/ar3032
PMCID: PMC2911889
Suppression of the inflammatory response in experimental arthritis is mediated via estrogen receptor α but not estrogen receptor β
John Dulos,corresponding author1 Peter Vijn,1 Cindy van Doorn,1 Claudia L Hofstra,1 Desiree Veening-Griffioen,1 Jan de Graaf,1 Fred A Dijcks,1 and Annemieke MH Boots1
1Schering-Plough Research Institute, PO box 20, 5340 BH Oss, The Netherlands
corresponding authorCorresponding author.
John Dulos: john.dulos/at/spcorp.com; Peter Vijn: peter.vijn/at/spcorp.com; Cindy van Doorn: cindy.van.doorn/at/spcorp.com; Claudia L Hofstra: claudia.hofstra/at/spcorp.com; Desiree Veening-Griffioen: desiree.veening/at/spcorp.com; Jan de Graaf: jan.de.graaf/at/spcorp.com; Fred A Dijcks: fred.dijcks/at/spcorp.com; Annemieke MH Boots: mieke.boots/at/spcorp.com
Received October 30, 2009; Revised March 9, 2010; Accepted May 24, 2010.
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)α and β. The contribution of ERα and ERβ 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 ERβ agonist (ERB-79). Arthritis was followed for 2 weeks. Next, effects of ER agonists (ethinyl-estradiol, an ERα selective agonist (ERA-63) and a selective ERβ agonist (ERB-79) on the development of a tetanus toxoid (TT)-specific delayed type hypersensitivity response in wild type (WT) and in ERα - or ERβ-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 ERβ agonist ERB-79 had no effect on arthritis symptoms in this model. In the TT-specific DTH model, EE and the selective ERα agonist ERA-63 suppressed the TT-specific swelling response in WT and ERβKO mice but not in ERαKO mice. As seen in the AA model, the selective ERβ 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
ERα, but not ERβ, is key in ER-mediated suppression of experimental arthritis. It remains to be investigated how these findings translate to human autoimmune disease.
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