Administration of antisense oligonucleotides to Galpha(Q/11) reduces the severity of murine lupus.
Our principle hypothesis is that the hypothalamic hormone, gonadotropin-releasing hormone (GnRH), is an immunostimulatory hormone and plays a pivotal role in the gender differences in immunity and/or autoimmunity. As a general rule, females display heightened immune responses and heightened endocrinological responsiveness to GnRH compared to males. We have previously demonstrated that GnRH receptor antagonists are effective in ameliorating murine lupus and that GnRH receptor agonists exacerbate murine lupus. GnRH exerts its actions via stimulatory G proteins, specifically via Galpha(s) and the homologous G proteins Galpha(q) and Galpha(11) (referred to together as Galpha(q/11)). We have previously demonstrated that females express higher levels of Galpha(q/11) mRNA and protein compared to males. We hypothesized that antisense inhibition of these specific G proteins would lead to a reduction in inflammatory cytokines and to an amelioration of disease in a mouse model of lupus. We randomized gonadectomized female (NZB x NZW) F1 hybrid mice to treatment with antisense oligonucleotides to Galpha(q/11) or to missense oligonucleotides. Administration of antisense oligonucleotides to Galpha(q/11) led to significant reductions in autoantibody levels, serum IgG levels, hematuria, and proteinuria compared to missense oligos. A trend toward prolonged survival was also noted. In vitro co-culture experiments demonstrated that antisense to Galpha(q/11) significantly inhibited IL-6 production compared to control.
Ansari
Mansoor A
MA
Section of Endocrinology, Children's Mercy Hospital, Kansas City School of Medicine, University of Missouri, 2401 Gillham Road, Kansas City, MO 64110, USA.
Dhar
Minati
M
Muthukrishnan
Venkateswari
V
Morton
Terri L
TL
Bakht
Noshaba
N
Jacobson
Jill D
JD
D000818:Animals; D000974:Antibodies, Antinuclear / Q000032:analysis; D001835:Body Weight / Q000187:drug effects; D016207:Cytokines / Q000032:analysis; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics / Q000378:metabolism*; D015316:Genetic Therapy; D006728:Hormones / Q000032:analysis; D007074:Immunoglobulin G / Q000032:analysis; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D016376:Oligonucleotides, Antisense / Q000494:pharmacology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015996:Survival Rate
D000974:Antibodies, Antinuclear; D016207:Cytokines; D044385:GTP-Binding Protein alpha Subunits; D006728:Hormones; D007074:Immunoglobulin G; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger