학술논문
Suppression of the inflammatory response in experimental arthritis is mediated via estrogen receptor [alpha] but not estrogen receptor [beta]
Research article
Research article
Document Type
Report
Author
Source
Arthritis Research & Therapy. May 24, 2010, Vol. 12, R101
Subject
Language
English
ISSN
1478-6354
Abstract
Authors: John Dulos (corresponding author) [1]; Peter Vijn [1]; Cindy van Doorn [1]; Claudia L Hofstra [1]; Desiree Veening-Griffioen [1]; Jan de Graaf [1]; Fred A Dijcks [1]; Annemieke MH [...]
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 ER[alpha] and ER[beta] 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 ER[beta] agonist (ERB-79). Arthritis was followed for 2 weeks. Next, effects of ER agonists (ethinyl-estradiol, an ER[alpha] selective agonist (ERA-63) and a selective ER[beta] agonist (ERB-79) on the development of a tetanus toxoid (TT)-specific delayed type hypersensitivity response in wild type (WT) and in ER[alpha] - or ER[beta]-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 ER[beta] agonist ERB-79 had no effect on arthritis symptoms in this model. In the TT-specific DTH model, EE and the selective ER[alpha] agonist ERA-63 suppressed the TT-specific swelling response in WT and ER[beta]KO mice but not in ER[alpha]KO mice. As seen in the AA model, the selective ER[beta] 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 ER[alpha], but not ER[beta], is key in ER-mediated suppression of experimental arthritis. It remains to be investigated how these findings translate to human autoimmune disease.
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 ER[alpha] and ER[beta] 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 ER[beta] agonist (ERB-79). Arthritis was followed for 2 weeks. Next, effects of ER agonists (ethinyl-estradiol, an ER[alpha] selective agonist (ERA-63) and a selective ER[beta] agonist (ERB-79) on the development of a tetanus toxoid (TT)-specific delayed type hypersensitivity response in wild type (WT) and in ER[alpha] - or ER[beta]-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 ER[beta] agonist ERB-79 had no effect on arthritis symptoms in this model. In the TT-specific DTH model, EE and the selective ER[alpha] agonist ERA-63 suppressed the TT-specific swelling response in WT and ER[beta]KO mice but not in ER[alpha]KO mice. As seen in the AA model, the selective ER[beta] 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 ER[alpha], but not ER[beta], is key in ER-mediated suppression of experimental arthritis. It remains to be investigated how these findings translate to human autoimmune disease.