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SHPS-1 and a synthetic peptide representing its ITIM inhibit the MyD88, but not TRIF, pathway of TLR signaling through activation of SHP and PI3K in THP-1 cells

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Abstract

Background

Src homology 2 domain-containing protein tyrosine phosphatase substrate (SHPS)-1 is known to have regulatory effects on myeloid cells. However, its role in macrophage activation is not clearly understood.

Methods and results

In order to investigate the role of SHPS-1 in Toll-like receptor (TLR)-mediated activation, human monocytic cell lines were treated with anti-SHPS-1 monoclonal antibody. The triggering of SHPS-1 blocked the expression of IL-8 and TNF-α in cells treated with a TLR4 ligand that induces a signaling pathway involving myeloid differentiation factor 88 (MyD88) and Toll-interleukin-1 receptor (TIR)-domain-containing adapter-inducing interferon-β (TRIF). Interestingly, SHPS-1 inhibited TLR9/MyD88-mediated, but not TLR3/TRIF-mediated, expression of IL-8. Accordingly, a synthetic peptide representing the immunoreceptor tyrosine-based inhibition motif (ITIM) of SHPS-1 suppressed only the MyD88 pathway. Utilization of specific inhibitors and Western blot analysis indicated that the inhibitory effects were mediated by Src homology 2 domain-containing phosphatases (SHPs) and phosphoinositide 3-kinase (PI3K).

Conclusion

SHPS-1 negatively regulates the MyD88-dependent TLR signaling pathway through the inhibition of NF-κB activation.

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Acknowledgments

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2012R1A1A4A01005809) and Kyungpook National University Research Fund, 2012.

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Authors and Affiliations

  1. School of Life Sciences and Biotechnology, Kyungpook National University, Daegu, 702-701, Korea

    Eun-Ju Kim & Won-Ha Lee

  2. Department of Pharmacology, Brain Science and Engineering Institute, School of Medicine, Kyungpook National University, Daegu, 702-701, Korea

    Kyoungho Suk

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  1. Eun-Ju Kim
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Correspondence to Won-Ha Lee.

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Responsible Editor: Liwu Li.

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Kim, EJ., Suk, K. & Lee, WH. SHPS-1 and a synthetic peptide representing its ITIM inhibit the MyD88, but not TRIF, pathway of TLR signaling through activation of SHP and PI3K in THP-1 cells. Inflamm. Res. 62, 377–386 (2013). https://doi.org/10.1007/s00011-013-0589-0

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  • DOI: https://doi.org/10.1007/s00011-013-0589-0

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