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.