IL-23 is increased in dendritic cells in multiple sclerosis and down-regulation of IL-23 by antisense oligos increases dendritic cell IL-10 production.
IL-23 is a heterodimeric cytokine comprising a p19 subunit associated with the IL-12/23p40 subunit. Like IL-12, IL-23 is expressed predominantly by activated dendritic cells (DCs) and phagocytic cells, and both cytokines induce IFN-gamma secretion by T cells. The induction of experimental autoimmune encephalitis, the animal model of multiple sclerosis (MS), occurs in mice lacking IL-12, but not in mice with targeted disruption of IL-23 or both IL-12 and IL-23. Thus, IL-23 expression in DCs may play an important role in the pathogenesis of human autoimmune diseases such as MS. We quantified the expression of IL-23 in monocyte-derived DCs in MS patients and healthy donors and found that DCs from MS patients secrete elevated amounts of IL-23 and express increased levels of IL-23p19 mRNA. Consistent with this abnormality, we found increased IL-17 production by T cells from MS patients. We then transfected monocyte-derived DCs from healthy donors with antisense oligonucleotides specific for the IL-23p19 and IL-12p35 genes and found potent suppression of gene expression and blockade of bioactive IL-23 and IL-12 production without affecting cellular viability or DCs maturation. Inhibition of IL-23 and IL-12 was associated with increased IL-10 and decreased TNF-alpha production. Furthermore, transfected DCs were poor allostimulators in the MLR. Our results demonstrate that an abnormal Th1 bias in DCs from MS patients related to IL-23 exists, and that antisense oligonucleotides specific to IL-23 can be used for immune modulation by targeting DC gene expression.
Vaknin-Dembinsky
Adi
A
Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA 02115, USA.
Balashov
Konstantin
K
Weiner
Howard L
HL
D000328:Adult; D017951:Antigen Presentation / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D016130:Immunophenotyping; D016753:Interleukin-10 / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D053765:Interleukin-12 Subunit p35; D020381:Interleukin-17 / Q000096:biosynthesis; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics; D008213:Lymphocyte Activation / Q000276:immunology; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009103:Multiple Sclerosis / Q000276:immunology*; D016376:Oligonucleotides, Antisense / Q000138:chemical synthesis / Q000378:metabolism*; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*
C508858:IL12A protein, human; C508840:IL23A protein, human; D053765:Interleukin-12 Subunit p35; D020381:Interleukin-17; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins; D016376:Oligonucleotides, Antisense; D021122:Protein Subunits; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D018664:Interleukin-12