ZSTK474, a novel PI3K inhibitor, modulates human CD14+ monocyte-derived dendritic cell functions and suppresses experimental autoimmune encephalomyelitis.
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.
Laboratory of Immunology and Inflammation, Research Center of Basic Medical Science, Tianjin Medical University, Tianjin, 300070, China.
Zhenyi
Z
Xue
Wen
W
Li
Huafeng
H
Wang
Biao
B
Huang
Zhenzhen
Z
Ge
Chao
C
Gu
Ying
Y
Liu
Kai
K
Zhang
Juhong
J
Yang
Rong
R
Han
Meiyu
M
Peng
Yan
Y
Li
Da
D
Zhang
Yurong
Y
Da
Zhi
Z
Yao
Rongxin
R
Zhang
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D015703:Antigens, CD / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology; D004705:Endocytosis / Q000187:drug effects; D006801:Humans; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000166:cytology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D014227:Triazines / Q000494:pharmacology / Q000627:therapeutic use*
D000893:Anti-Inflammatory Agents; D015703:Antigens, CD; D016207:Cytokines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D014227:Triazines; C510150:ZSTK474