title: 17 beta-estradiol inhibits cytokine, chemokine, and chemokine receptor mRNA expression in the central nervous system of female mice with experimental autoimmune encephalomyelitis.
abstract: Cytokines and chemokines govern leukocyte trafficking, thus regulating inflammatory responses. In this study, the anti-inflammatory effects of low dose 17 beta-estradiol were evaluated on chemokine, chemokine receptor, and cytokine expression in the spinal cords (SC) of BV8S2 transgenic female mice during acute and recovery phases of experimental autoimmune encephalomyelitis (EAE). In EAE protected mice, 17 beta-estradiol strongly inhibited mRNA expression of the chemokines RANTES, MIP-1 alpha, MIP-2, IP-10, and MCP-1, and of the chemokine receptors CCR1, CCR2 and CCR5 at both time points. Conversely, ovariectomy, which abrogated basal 17 beta-estradiol levels and increased the severity of EAE, enhanced the expression of MIP-1 alpha and MIP-2 that were over-expressed by inflammatory mononuclear cells in SC. 17 beta-estradiol inhibited expression of LT-beta, TNF-alpha, and IFN-gamma in SC, but had no effect on IL-4 or IL-10, indicating reduced inflammation but no deviation toward a Th2 response. Interestingly, elevated expression of CCR1 and CCR5 by lymph node cells was also inhibited in 17 beta-estradiol treated mice with EAE. Low doses of 17 beta-estradiol added in vitro to lymphocyte cultures had no direct effect on the activation of MBP-Ac1-11 specific T cells, and only at high doses diminished production of IFN-gamma, but not IL-12 or IL-10. These results suggest that the beneficial effects of 17 beta-estradiol are mediated in part by strong inhibition of recruited inflammatory cells, resulting in reduced production of inflammatory chemokines and cytokines in CNS, with modest effects on encephalitogenic T cells that seem to be relatively 17 beta-estradiol insensitive.
authors.affiliation: Department of Neurology, Oregon Health Sciences University, Portland, Oregon, USA.
authors.forename: A
authors.initials: A
authors.lastname: Matejuk
authors.forename: K
authors.initials: K
authors.lastname: Adlard
authors.forename: A
authors.initials: A
authors.lastname: Zamora
authors.forename: M
authors.initials: M
authors.lastname: Silverman
authors.forename: A A
authors.initials: AA
authors.lastname: Vandenbark
authors.forename: H
authors.initials: H
authors.lastname: Offner
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000276:immunology; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D054407:Chemokine CCL4; D054426:Chemokine CXCL2; D018925:Chemokines / Q000235:genetics*; D016207:Cytokines / Q000235:genetics*; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008198:Lymph Nodes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D019402:Macrophage Inflammatory Proteins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D010052:Ovariectomy; D012333:RNA, Messenger / Q000187:drug effects* / Q000378:metabolism; D054389:Receptors, CCR1; D019713:Receptors, CCR5 / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D019707:Receptors, Chemokine / Q000187:drug effects / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D018417:Th1 Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D018418:Th2 Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D016896:Treatment Outcome
chemical_list: C515301:Ccr1 protein, mouse; D054407:Chemokine CCL4; D054426:Chemokine CXCL2; D018925:Chemokines; C404915:Cxcl2 protein, mouse; D016207:Cytokines; D019402:Macrophage Inflammatory Proteins; D012333:RNA, Messenger; D054389:Receptors, CCR1; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D004958:Estradiol