title: Suppression of the inflammatory response in experimental arthritis is mediated via estrogen receptor alpha but not estrogen receptor beta.
abstract: BACKGROUND
  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.affiliation: Schering-Plough Research Institute, PO box 20, 5340 BH Oss, The Netherlands. john.dulos@spcorp.com
authors.forename: John
authors.initials: J
authors.lastname: Dulos
authors.forename: Peter
authors.initials: P
authors.lastname: Vijn
authors.forename: Cindy
authors.initials: C
authors.lastname: van Doorn
authors.forename: Claudia L
authors.initials: CL
authors.lastname: Hofstra
authors.forename: Desiree
authors.initials: D
authors.lastname: Veening-Griffioen
authors.forename: Jan
authors.initials: J
authors.lastname: de Graaf
authors.forename: Fred A
authors.initials: FA
authors.lastname: Dijcks
authors.forename: Annemieke M H
authors.initials: AM
authors.lastname: Boots
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D004997:Ethinyl Estradiol / Q000031:analogs & derivatives / Q000627:therapeutic use; D005260:Female; D006968:Hypersensitivity, Delayed / Q000139:chemically induced / Q000188:drug therapy; D007249:Inflammation / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D051381:Rats; D013583:Synovial Membrane / Q000378:metabolism; D013745:Tetanus Toxoid / Q000009:adverse effects
chemical_list: C532665:(7-alpha,17-alpha)-7-methyl-3-methylene-19-norpregn-5(10)-en-20-yn-17-ol; D016207:Cytokines; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D013745:Tetanus Toxoid; D004997:Ethinyl Estradiol