title: Increased X-linked inhibitor of apoptosis protein (XIAP) expression exacerbates experimental autoimmune encephalomyelitis (EAE).
abstract: Dysregulated apoptotic signaling has been implicated in most forms of cancer and many autoimmune diseases, such as multiple sclerosis (MS). We have previously shown that the anti-apoptotic protein X-linked inhibitor of apoptosis (XIAP) is elevated in T cells from mice with experimental autoimmune encephalomyelitis (EAE). In MS and EAE, the failure of autoimmune cells to undergo apoptosis is thought to exacerbate clinical symptoms and contribute to disease progression and CNS tissue damage. Antisense-mediated knockdown of XIAP, in vivo, increases the susceptibility of effector T cells to apoptosis, thus attenuating CNS inflammation and thereby alleviating the clinical signs of EAE. We report for the first time, generation of transgenic mice whereby the ubiquitin promoter drives expression of XIAP (ubXIAP), resulting in increased XIAP expression in a variety of tissues, including cells comprising the immune system. Transgenic ubXIAP mice and wild-type (WT) littermates were immunized with myelin oligodendrocyte glycoprotein (MOG35-55) in complete Freund's adjuvant and monitored daily for clinical symptoms of EAE over a 21-day period. The severity of EAE was increased in ubXIAP mice relative to WT-littermates, suggesting that XIAP overexpression enhanced the resistance of T cells to apoptosis. Consistent with this finding, T cells derived from MOG35-55-immunized ubXIAP mice and cultured in the presence of antigen were more resistant to etoposide-mediated apoptosis compared to WT-littermates. This work identifies XIAP is an important apoptotic regulator in EAE and a potential pharmacological target for treating autoimmune diseases such as MS.
authors.affiliation: Department of Pharmacology, Dalhousie University, Faculty of Medicine, Sir Charles Tupper Building, 5850 College Street, Halifax, NS, Canada B3H 1X5.
authors.forename: Craig S
authors.initials: CS
authors.lastname: Moore
authors.forename: Andrea L O
authors.initials: AL
authors.lastname: Hebb
authors.forename: Mathieu M
authors.initials: MM
authors.lastname: Blanchard
authors.forename: Candice E
authors.initials: CE
authors.lastname: Crocker
authors.forename: Peter
authors.initials: P
authors.lastname: Liston
authors.forename: Robert G
authors.initials: RG
authors.lastname: Korneluk
authors.forename: George S
authors.initials: GS
authors.lastname: Robertson
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001522:Behavior, Animal; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000503:physiopathology*; D005260:Female; D015870:Gene Expression / Q000276:immunology; D016259:Genes, myc / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000276:immunology; D007114:Immunization; D007150:Immunohistochemistry; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009103:Multiple Sclerosis / Q000276:immunology / Q000503:physiopathology; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000276:immunology; D063308:Myelin-Oligodendrocyte Glycoprotein; D011247:Pregnancy; D012720:Severity of Illness Index; D013116:Spinal Cord / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D025822:Ubiquitin C / Q000235:genetics; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: D005904:Glial Fibrillary Acidic Protein; D051034:Inhibitor of Apoptosis Proteins; C571327:Mog protein, mouse; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D025822:Ubiquitin C; D051636:X-Linked Inhibitor of Apoptosis Protein