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

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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

• ZSTK474 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.

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Abbreviations

PI3K:

Phosphatidylinositol 3-kinase

DC:

Dendritic cell

CNS:

Central nervous system

EAE:

Experimental autoimmune encephalomyelitis

MS:

Multiple sclerosis

GSK3β:

Glycogen synthase kinase 3 beta

mTOR:

Mammalian target of rapamycin

APC:

Antigen-presenting cell

TLR:

Toll-like receptor

PKB:

Protein kinase B

LPS:

Lipopolysaccharide

GM-CSF:

Granulocyte macrophage-colony stimulating factor

MFI:

Mean fluorescence intensity

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Acknowledgments

We thank the Tianjin Blood Center for providing us with the buffy coat. We also thank the Experimental Animal Center of Tianjin Medical University (Tianjin, China) for their work in animal husbandry. This work is supported by the Ministry of Science and Technology of China through grant nos. 2012CB932503 and 2011CB933100; the National Natural Science Foundation of China through grant nos. 91029705, 81272317, and 81172864; and the Natural Science Foundation of Tianjin through grant no. 12JCZDJC23500.

Disclosure

The authors have nothing to disclose.

Author information

Authors and Affiliations

  1. Laboratory of Immunology and Inflammation, Research Center of Basic Medical Science, Tianjin Medical University, Tianjin, 300070, China

    Zhenyi Xue, Wen Li, Huafeng Wang, Biao Huang, Zhenzhen Ge, Kai Zhang, Rong Han, Meiyu Peng, Yan Li, Yurong Da & Rongxin Zhang

  2. Department of Immunology, Basic Medical College, Tianjin Medical University, Tianjin, 300070, China

    Zhenyi Xue, Chao Gu, Yan Li, Yurong Da, Zhi Yao & Rongxin Zhang

  3. Tianjin Key Laboratory of Cellular and Molecular Immunology, Tianjin Medical University, Tianjin, China

    Zhenyi Xue, Yurong Da, Zhi Yao & Rongxin Zhang

  4. Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Medical University, Tianjin, China

    Zhenyi Xue, Yurong Da, Zhi Yao & Rongxin Zhang

  5. Department of Neurology, Tianjin First Central Hospital, Tianjin, China

    Ying Liu

  6. Tianjin Metabolic Diseases Hospital, Tianjin Medical University, Tianjin, China

    Juhong Yang

  7. School of Medical Imaging, Tianjin Medical University, Tianjin, 300070, China

    Da Zhang

  8. Research Center of Basic Medical Science, Tianjin Medical University, Tianjin, 300070, China

    Rongxin Zhang

Authors
  1. Zhenyi Xue
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  2. Wen Li
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  12. Yan Li
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  13. Da Zhang
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  14. Yurong Da
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  15. Zhi Yao
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  16. Rongxin Zhang
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Corresponding authors

Correspondence to Zhi Yao or Rongxin Zhang.

Additional information

Zhenyi Xue, Wen Li, and Huafeng Wang contributed equally to this work.

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Xue, Z., Li, W., Wang, H. et al. ZSTK474, a novel PI3K inhibitor, modulates human CD14+ monocyte-derived dendritic cell functions and suppresses experimental autoimmune encephalomyelitis. J Mol Med 92, 1057–1068 (2014). https://doi.org/10.1007/s00109-014-1158-x

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  • DOI: https://doi.org/10.1007/s00109-014-1158-x

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