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Cellular FLIP Inhibits Myeloid Cell Activation by Suppressing Selective Innate Signaling.

Publication ,  Journal Article
Wu, Y-J; Wu, Y-H; Mo, S-T; Hsiao, H-W; He, Y-W; Lai, M-Z
Published in: J Immunol
September 15, 2015

Cellular FLIP (c-FLIP) specifically inhibits caspase-8 and suppresses death receptor-induced apoptosis. c-FLIP has also been reported to transmit activation signals. In this study, we report a novel function of c-FLIP involving inhibition of myeloid cell activation through antagonizing the selective innate signaling pathway. We found that conditional knockout of c-FLIP in dendritic cells (DCs) led to neutrophilia and splenomegaly. Peripheral DC populations, including CD11b(+) conventional DCs (cDCs), CD8(+) cDCs, and plasmacytoid DCs, were not affected by c-FLIP deficiency. We also found that c-FLIP knockout cDCs, plasmacytoid DCs, and bone marrow-derived DCs (BMDCs) displayed enhanced production of TNF-α, IL-2, or G-CSF in response to stimulation of TLR4, TLR2, and dectin-1. Consistent with the ability of c-FLIP to inhibit the activation of p38 MAPK, the enhanced activation of c-FLIP-deficient BMDCs could be partly linked to an elevated activation of p38 MAPK after engagement of innate receptors. Increased activation was also found in c-FLIP(+/-) macrophages. Additionally, the increased activation in c-FLIP-deficient DCs was independent of caspase-8. Our results reveal a novel inhibitory role of c-FLIP in myeloid cell activation and demonstrate the unexpected anti-inflammatory activity of c-FLIP. Additionally, our observations suggest that cancer therapy targeting c-FLIP downregulation may facilitate DC activation and increase T cell immunity.

Duke Scholars

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Published In

J Immunol

DOI

EISSN

1550-6606

Publication Date

September 15, 2015

Volume

195

Issue

6

Start / End Page

2612 / 2623

Location

United States

Related Subject Headings

  • p38 Mitogen-Activated Protein Kinases
  • Tumor Necrosis Factor-alpha
  • Toll-Like Receptor 4
  • Toll-Like Receptor 2
  • T-Lymphocytes
  • Splenomegaly
  • Signal Transduction
  • RNA, Small Interfering
  • RNA Interference
  • Neutrophils
 

Citation

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Wu, Y.-J., Wu, Y.-H., Mo, S.-T., Hsiao, H.-W., He, Y.-W., & Lai, M.-Z. (2015). Cellular FLIP Inhibits Myeloid Cell Activation by Suppressing Selective Innate Signaling. J Immunol, 195(6), 2612–2623. https://doi.org/10.4049/jimmunol.1402944
Wu, Yu-Jung, Yung-Hsuan Wu, Shu-Ting Mo, Huey-Wen Hsiao, You-Wen He, and Ming-Zong Lai. “Cellular FLIP Inhibits Myeloid Cell Activation by Suppressing Selective Innate Signaling.J Immunol 195, no. 6 (September 15, 2015): 2612–23. https://doi.org/10.4049/jimmunol.1402944.
Wu Y-J, Wu Y-H, Mo S-T, Hsiao H-W, He Y-W, Lai M-Z. Cellular FLIP Inhibits Myeloid Cell Activation by Suppressing Selective Innate Signaling. J Immunol. 2015 Sep 15;195(6):2612–23.
Wu, Yu-Jung, et al. “Cellular FLIP Inhibits Myeloid Cell Activation by Suppressing Selective Innate Signaling.J Immunol, vol. 195, no. 6, Sept. 2015, pp. 2612–23. Pubmed, doi:10.4049/jimmunol.1402944.
Wu Y-J, Wu Y-H, Mo S-T, Hsiao H-W, He Y-W, Lai M-Z. Cellular FLIP Inhibits Myeloid Cell Activation by Suppressing Selective Innate Signaling. J Immunol. 2015 Sep 15;195(6):2612–2623.

Published In

J Immunol

DOI

EISSN

1550-6606

Publication Date

September 15, 2015

Volume

195

Issue

6

Start / End Page

2612 / 2623

Location

United States

Related Subject Headings

  • p38 Mitogen-Activated Protein Kinases
  • Tumor Necrosis Factor-alpha
  • Toll-Like Receptor 4
  • Toll-Like Receptor 2
  • T-Lymphocytes
  • Splenomegaly
  • Signal Transduction
  • RNA, Small Interfering
  • RNA Interference
  • Neutrophils