Inhibition of the p50 (NKkappaB1) subunit of NF-kappaB by phosphorothioate-modified antisense oligodeoxynucleotides reduces NF-kappaB expression and immunoglobulin synthesis in murine B cells.
NF-kappaB is a regulatory protein of immune response genes and a candidate for targeting in immunosuppressive therapy. NF-kappaB proteins are formed from components of which p50 (NFkappaB1) is a subunit. By targeting p50 gene expression with specific antisense 3' phosphorothioate-oligodeoxynucleotides (3' PS-ODNs), an effect upon NF-kappaB regulation and immunoglobulin synthesis in murine B cells was achieved. A 49% decrease in p50 protein was induced by treatment of WEHI 231 B cells with p50 antisense 3' PS-ODNs and not by control 3' PS-ODNs. p50 antisense specifically reduced the expression of NF-kappaB by 51%, but not the transcription factor, Oct-1. In the BXSB murine model of autoimmunity, p50 antisense inhibited NF-kappaB expression and total IgM and IgG synthesis, but, more importantly, dsDNA antibodies were reduced 90%. These results validate the use of p50 antisense to reduce NF-kappaB expression and, by downregulating the immune response, has application in the treatment of autoimmune disorders.
Khaled
A R
AR
Department of Molecular Genetics and Microbiology, University of Florida, Gainesville 32620, USA.
Soares
L S
LS
Butfiloski
E J
EJ
Stekman
I
I
Sobel
E S
ES
Schiffenbauer
J
J
D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis; D001323:Autoantibodies / Q000032:analysis; D001327:Autoimmune Diseases / Q000175:diagnosis; D015551:Autoimmunity / Q000502:physiology; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004247:DNA / Q000276:immunology; D004195:Disease Models, Animal; D007136:Immunoglobulins / Q000096:biosynthesis*; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D052002:NF-kappa B p50 Subunit; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D013154:Spleen / Q000166:cytology; D013873:Thionucleotides / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000974:Antibodies, Antinuclear; D001323:Autoantibodies; D007136:Immunoglobulins; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D016376:Oligonucleotides, Antisense; D013873:Thionucleotides; D004247:DNA