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

Abstract

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.

The role of Th17 lymphocytes in the autoimmune and chronic inflammatory diseases

“…Interestingly, evidence is accumulating in recent years that psoriasis may be a multisystem disease involving even coronary arteries and the heart [25,39,40]. Epidermal thickening (acanthosis) of the skin is a hallmark of psoriasis.…”

Cytokine Production Profile of CD4+ T Cells from Patients with Active Churg-Strauss Syndrome Tends Toward Th17

“…In contrast, it is well known that dysregulated production of IL-17 is associated with human autoimmune diseases, including multiple sclerosis, inflammatory bowel disease, and psoriasis [6,7,8,9]. Importantly, studies in a murine experimental arthritis model showed IL-17 to be involved in both the initiation and the progression of disease.…”

Changes in Gene Expression Pattern of Human Primary Macrophages Induced by Carbosilane Dendrimer 2G-NN16

“…IL17, IL17F and its regulator IL23 appear to be important in host defense against extracellular bacteria and fungi (28)(29)(30). Additionally, a number of autoimmune diseases, such as psoriasis and inflammatory bowel disease, are associated with over-production of these cytokines and interference with IL17 production or action attenuates autoimmune disease (31)(32)(33)(34)(35)(36). Polymorphisms in 5.…”