title: 2-Methoxyestradiol inhibits experimental autoimmune encephalomyelitis through suppression of immune cell activation.
abstract: The endogenous metabolite of estradiol, 2-Methoxyestradiol (2ME2), is an antimitotic and antiangiogenic cancer drug candidate that also exhibits disease-modifying activity in animal models of rheumatoid arthritis (RA). We found that 2ME2 dramatically suppresses development of mouse experimental autoimmune encephalomyelitis (EAE), a rodent model of multiple sclerosis (MS). 2ME2 inhibits in vitro lymphocyte activation, cytokine production, and proliferation in a dose-dependent fashion. 2ME2 treatment of lymphocytes specifically reduced the nuclear translocation and transcriptional activity of nuclear factor of activated T-cells (NFAT) c1, whereas NF-κB and activator protein 1 (AP-1) activation were not adversely affected. We therefore propose that 2ME2 attenuates EAE through disruption of the NFAT pathway and subsequent lymphocyte activation. By extension, our findings provide a molecular rationale for the use of 2ME2 as a tolerable oral immunomodulatory agent for the treatment of autoimmune disorders such as MS in humans.
authors.affiliation: Campbell Family Institute for Breast Cancer Research,  University Health Network, Toronto, ON,  Canada M5G 2C1.
authors.forename: Gordon S
authors.initials: GS
authors.lastname: Duncan
authors.forename: Dirk
authors.initials: D
authors.lastname: Brenner
authors.forename: Michael W
authors.initials: MW
authors.lastname: Tusche
authors.forename: Anne
authors.initials: A
authors.lastname: Brüstle
authors.forename: Christiane B
authors.initials: CB
authors.lastname: Knobbe
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Elia
authors.forename: Thomas
authors.initials: T
authors.lastname: Mock
authors.forename: Mark R
authors.initials: MR
authors.lastname: Bray
authors.forename: Peter H
authors.initials: PH
authors.lastname: Krammer
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
mesh_terms: D000077584:2-Methoxyestradiol; D000818:Animals; D015551:Autoimmunity; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D016207:Cytokines / Q000096:biosynthesis; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy*; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000276:immunology; D016328:NF-kappa B / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism; D050257:Tubulin Modulators / Q000494:pharmacology
chemical_list: D016207:Cytokines; D016328:NF-kappa B; D050778:NFATC Transcription Factors; C494003:NFATC1 protein, human; D018808:Transcription Factor AP-1; D050257:Tubulin Modulators; D004958:Estradiol; D000077584:2-Methoxyestradiol