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

• Published in: The Journal of immunology (1950) Vol. 176; no. 12; pp. 7768 - 7774
• Main Authors: Vaknin-Dembinsky, Adi, Balashov, Konstantin, Weiner, Howard L
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 15.06.2006
• Subjects: Adult; Antigen Presentation - genetics; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; Cell Differentiation - genetics; Cell Differentiation - immunology; Cells, Cultured; Dendritic Cells - immunology; Dendritic Cells - metabolism; Dendritic Cells - pathology; Humans; Immunophenotyping; Interleukin-10 - biosynthesis; Interleukin-12 - antagonists & inhibitors; Interleukin-12 - biosynthesis; Interleukin-12 - genetics; Interleukin-12 Subunit p35; Interleukin-17 - biosynthesis; Interleukin-23; Interleukin-23 Subunit p19; Interleukins - antagonists & inhibitors; Interleukins - biosynthesis; Interleukins - genetics; Lymphocyte Activation - immunology; Middle Aged; Monocytes - immunology; Monocytes - metabolism; Monocytes - pathology; Multiple Sclerosis - immunology; Oligonucleotides, Antisense - chemical synthesis; Oligonucleotides, Antisense - metabolism; Protein Subunits - antagonists & inhibitors; Protein Subunits - biosynthesis; Protein Subunits - genetics; RNA, Messenger - biosynthesis; Transfection; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - biosynthesis; Up-Regulation - genetics; Up-Regulation - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.176.12.7768

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-γ 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-α 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.