ZSTK474, a novel PI3K inhibitor, modulates human CD14+ monocyte-derived dendritic cell functions and suppresses experimental autoimmune encephalomyelitis.

Abstract

ZSTK474 [2-(2-difluoromethylbenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine] is a novel phosphatidylinositol 3-kinase (PI3K) inhibitor that exhibits potent antitumor effects. Recent studies have shown that ZSTK474 is also with anti-inflammatory properties in collagen-induced arthritis. However, the effects of ZSTK474 on dendritic cells and inflammatory Th17 cell-mediated autoimmune central nervous system inflammation are not understood. In this study, we demonstrated that ZSTK474 suppressed human CD14(+) monocyte-derived dendritic cell differentiation, maturation, and endocytosis, and further inhibited the stimulatory function of mature dendritic cell on allogeneic T cell proliferation. In addition, ZSTK474 inhibited the expression of dendritic cell-derived Th1 and Th17 cells polarizing cytokines interferon-γ/interleukin (IL)-12 and IL-6/IL-23. Furthermore, our results indicated that the in vivo administration of ZSTK474, which targets the dendritic cell and inflammatory Th1 and Th17 cell, led to a reduction of clinical score, central nervous system inflammation, and demyelination of mouse experimental autoimmune encephalomyelitis. Therefore, ZSTK474 significantly suppressed the human CD14(+) monocyte-derived dendritic cell functions and ameliorated mouse experimental autoimmune encephalomyelitis. We further found that ZSTK474 inhibited the phosphorylation of PI3K downstream signaling Akt and glycogen synthase kinase 3 beta in the dendritic cell. These data suggested that ZSTK474 exerted potent anti-inflammatory and immunosuppressive properties via PI3K signaling and may serve as a potential therapeutic drug for multiple sclerosis and other autoimmune inflammatory diseases. Key messages: STK474 inhibits dendritic cell (DC) differentiation and maturation. ZSTK474 inhibits DC-derived Th1 and Th17-polarizing cytokines. ZSTK474 ameliorates EAE and suppresses DCs, Th1, and Th17 cells in EAE. ZSTK474 reduces CNS inflammation and demyelination of EAE mice. ZSTK474 could be a potential therapeutic drug for multiple sclerosis.

• Authors: Zhenyi Xue, Wen Li, Huafeng Wang, Biao Huang, Zhenzhen Ge, Chao Gu, Ying Liu, Kai Zhang, Juhong Yang, Rong Han, Meiyu Peng, Yan Li, Da Zhang, Yurong Da, Zhi Yao, Rongxin Zhang
• Journal: Journal of molecular medicine (Berlin, Germany) (J Mol Med (Berl)) Vol. 92 Issue 10 Pg. 1057-68 (Oct 2014) ISSN: 1432-1440 [Electronic] Germany
• PMID: 24844601 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• Antigens, CD
• Cytokines
• Phosphoinositide-3 Kinase Inhibitors
• Triazines
• ZSTK474

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology, therapeutic use)
• Antigens, CD (immunology)
• Cell Differentiation (drug effects)
• Cells, Cultured
• Cytokines (immunology)
• Dendritic Cells (cytology, drug effects)
• Encephalomyelitis, Autoimmune, Experimental (drug therapy, immunology)
• Endocytosis (drug effects)
• Humans
• Mice, Inbred C57BL
• Monocytes (cytology)
• Phosphoinositide-3 Kinase Inhibitors
• T-Lymphocytes (cytology, drug effects, immunology)
• Triazines (pharmacology, therapeutic use)