, Volume 41, Issue 2, pp 555–561 | Cite as

PI3K Is a Linker Between L-selectin and PSGL-1 Signaling to IL-18 Transcriptional Activation at the Promoter Level

  • Jixian Luo


L-selectin and P-selectin glycoprotein ligand-1 (PSGL-1) are adhesion molecules which induce similar physiological events. Our previous paper showed that phosphatidylinositol 3-kinase (PI3K) played a crucial role in L-selectin- and PSGL-1-mediated F-actin redistribution and assembly during neutrophil rolling on E-selectin. However, it is not clear whether L-selectin and PSGL-1 induce other similar physiology events by PI3K. Here, we investigated the possibility of PI3K linking the signaling pathways of L-selectin and PSGL-1 to IL-18 transcription. We first demonstrated that L-selectin and PSGL-1 stimulation upregulated IL-18 transcription level in Jurkat cells. Then we found that PI3K inhibitor LY294002 reduced L-selectin- and PSGL-1-induced mRNA upregulation of IL-18 in Jurkat cells. Transfection of phosphatase and tensin homolog expressing plasmid inhibited the transcription level of IL-18. Therefore, PI3K is a signal linker between L-selectin and PSGL-1 in IL-18 transcriptional activation at the promoter level. To our knowledge, this is the first time to directly link PI3K to L-selectin- and PSGL-1-mediated IL-18 transcription, providing a foundation for intervention of PI3K-related inflammation.


inflammation adhesion molecules signal transduction pro-inflammatory cytokines 



This work was supported by the National Natural Science Foundation of China (31401216) and Research Project Supported by Shanxi Scholarship Council of China (2017-012). We appreciate Shanzhi Wang for all his work in the manuscript revision, including reading, editing, and revising in detail.

Compliance with Ethical Standards

Conflict of interest

The author declares that he has no conflict of interest.


  1. 1.
    van Buul, J.D., and P.L. Hordijk. 2004. Signaling in leukocyte transendothelial migration. Arteriosclerosis, Thrombosis, and Vascular Biology 24 (5): 824–833.CrossRefPubMedGoogle Scholar
  2. 2.
    Alon, R., and M.L. Dustin. 2007. Force as a facilitator of integrin conformational changes during leukocyte arrest on blood vessels and antigen-presenting cells. Immunity 26 (1): 17–27.CrossRefPubMedGoogle Scholar
  3. 3.
    Bruehl, R.E., K.L. Moore, D.E. Lorant, N. Borregaard, G.A. Zimmerman, R.P. McEver, and D.F. Bainton. 1997. Leukocyte activation induces surface redistribution of P-selectin glycoprotein ligand-1. Journal of Leukocyte Biology 61 (4): 489–499.CrossRefPubMedGoogle Scholar
  4. 4.
    Abbal, C., M. Lambelet, D. Bertaggia, C. Gerbex, M. Martinez, A. Arcaro, M. Schapira, and O. Spertini. 2006. Lipid raft adhesion receptors and Syk regulate selectin-dependent rolling under flow conditions. Blood 108 (10): 3352–3359.CrossRefPubMedGoogle Scholar
  5. 5.
    Urzainqui, A., J.M. Serrador, F. Viedma, M. Yanez-Mo, A. Rodriguez, A.L. Corbi, J.L. Alonso-Lebrero, A. Luque, M. Deckert, J. Vazquez, et al. 2002. ITAM-based interaction of ERM proteins with Syk mediates signaling by the leukocyte adhesion receptor PSGL-1. Immunity 17 (4): 401–412.CrossRefPubMedGoogle Scholar
  6. 6.
    Ivetic, A., J. Deka, A. Ridley, and A. Ager. 2002. The cytoplasmic tail of L-selectin interacts with members of the ezrin-radixin-moesin (ERM) family of proteins: cell activation-dependent binding of moesin but not ezrin. The Journal of Biological Chemistry 277 (3): 2321–2329.CrossRefPubMedGoogle Scholar
  7. 7.
    Ivetic, A., O. Florey, J. Deka, D.O. Haskard, A. Ager, and A.J. Ridley. 2004. Mutagenesis of the ezrin-radixin-moesin binding domain of L-selectin tail affects shedding, microvillar positioning, and leukocyte tethering. The Journal of Biological Chemistry 279 (32): 33263–33272.CrossRefPubMedGoogle Scholar
  8. 8.
    Chen, C., X. Shang, T. Xu, L. Cui, J. Luo, X. Ba, S. Hao, and X. Zeng. 2007. c-Abl is required for the signaling transduction induced by L-selectin ligation. European Journal of Immunology 37 (11): 3246–3258.CrossRefPubMedGoogle Scholar
  9. 9.
    Chen, C., X. Shang, L. Cui, T. Xu, J. Luo, X. Ba, and X. Zeng. 2008. L-selectin ligation-induced CSF-1 gene transcription is regulated by AP-1 in a c-Abl kinase-dependent manner. Human Immunology 69 (8): 501–509.CrossRefPubMedGoogle Scholar
  10. 10.
    Luo, J., T. Xu, X. Wang, X. Ba, X. Feng, V. Deepak, and X. Zeng. 2010. PI3K is involved in L-selectin- and PSGL-1-mediated neutrophil rolling on E-selectin via F-actin redistribution and assembly. Journal of Cellular Biochemistry 110 (4): 910–919.CrossRefPubMedGoogle Scholar
  11. 11.
    Kalesnikoff, J., L.M. Sly, M.R. Hughes, T. Buchse, M.J. Rauh, L.P. Cao, V. Lam, A. Mui, M. Huber, and G. Krystal. 2003. The role of SHIP in cytokine-induced signaling. Reviews of Physiology, Biochemistry and Pharmacology 149: 87–103.CrossRefPubMedGoogle Scholar
  12. 12.
    Kisseleva, M.V., M.P. Wilson, and P.W. Majerus. 2000. The isolation and characterization of a cDNA encoding phospholipid-specific inositol polyphosphate 5-phosphatase. The Journal of Biological Chemistry 275 (26): 20110–20116.CrossRefPubMedGoogle Scholar
  13. 13.
    Rohrschneider, L.R., J.F. Fuller, I. Wolf, Y. Liu, and D.M. Lucas. 2000. Structure, function, and biology of SHIP proteins. Genes & Development 14 (5): 505–520.Google Scholar
  14. 14.
    Stambolic, V., A. Suzuki, J.L. de la Pompa, G.M. Brothers, C. Mirtsos, T. Sasaki, J. Ruland, J.M. Penninger, D.P. Siderovski, and T.W. Mak. 1998. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell 95 (1): 29–39.CrossRefPubMedGoogle Scholar
  15. 15.
    Micallef, M.J., T. Ohtsuki, K. Kohno, F. Tanabe, S. Ushio, M. Namba, T. Tanimoto, K. Torigoe, M. Fujii, M. Ikeda, et al. 1996. Interferon-gamma-inducing factor enhances T helper 1 cytokine production by stimulated human T cells: synergism with interleukin-12 for interferon-gamma production. European Journal of Immunology 26 (7): 1647–1651.CrossRefPubMedGoogle Scholar
  16. 16.
    Ushio, S., M. Namba, T. Okura, K. Hattori, Y. Nukada, K. Akita, F. Tanabe, K. Konishi, M. Micallef, M. Fujii, et al. 1996. Cloning of the cDNA for human IFN-gamma-inducing factor, expression in Escherichia coli, and studies on the biologic activities of the protein. Journal of Immunology 156 (11): 4274–4279.Google Scholar
  17. 17.
    Hunter, C.A., J. Timans, P. Pisacane, S. Menon, G. Cai, W. Walker, M. Aste-Amezaga, R. Chizzonite, J.F. Bazan, and R.A. Kastelein. 1997. Comparison of the effects of interleukin-1 alpha, interleukin-1 beta and interferon-gamma-inducing factor on the production of interferon-gamma by natural killer. European Journal of Immunology 27 (11): 2787–2792.CrossRefPubMedGoogle Scholar
  18. 18.
    Zhu, Q., and T.D. Kanneganti. 2017. Cutting edge: distinct regulatory mechanisms control proinflammatory cytokines IL-18 and IL-1beta. Journal of Immunology 198 (11): 4210–4215.CrossRefGoogle Scholar
  19. 19.
    Wang, H., M. Hua, S. Wang, J. Yu, C. Chen, X. Zhao, C. Zhang, C. Zhong, R. Wang, N. He, et al. 2017. Genetic polymorphisms of IL-18 rs1946518 and IL-1beta rs16944 are associated with prognosis and survival of acute myeloid leukemia. Inflammation Research 66 (3): 249–258.CrossRefPubMedGoogle Scholar
  20. 20.
    Pui, C.H., M.V. Relling, and J.R. Downing. 2004. Acute lymphoblastic leukemia. The New England Journal of Medicine 350 (15): 1535–1548.CrossRefPubMedGoogle Scholar
  21. 21.
    Alexandrakis, M.G., F.H. Passam, K. Sfiridaki, J. Moschandrea, C. Pappa, D. Liapi, E. Petreli, P. Roussou, and D.S. Kyriakou. 2004. Interleukin-18 in multiple myeloma patients: serum levels in relation to response to treatment and survival. Leukemia Research 28 (3): 259–266.CrossRefPubMedGoogle Scholar
  22. 22.
    Liu, Y., Z.P. Han, S.S. Zhang, Y.Y. Jing, Bu XX, C.Y. Wang, K. Sun, G.C. Jiang, X. Zhao, R. Li, et al. 2011. Effects of inflammatory factors on mesenchymal stem cells and their role in the promotion of tumor angiogenesis in colon cancer. The Journal of Biological Chemistry 286 (28): 25007–25015.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Reynaud, D., E. Pietras, K. Barry-Holson, A. Mir, M. Binnewies, M. Jeanne, O. Sala-Torra, J.P. Radich, and E. Passegue. 2011. IL-6 controls leukemic multipotent progenitor cell fate and contributes to chronic myelogenous leukemia development. Cancer Cell 20 (5): 661–673.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Uzan, B., S. Poglio, B. Gerby, C.L. Wu, J. Gross, F. Armstrong, J. Calvo, X. Cahu, C. Deswarte, F. Dumont, et al. 2014. Interleukin-18 produced by bone marrow-derived stromal cells supports T-cell acute leukaemia progression. EMBO Molecular Medicine 6 (6): 821–834.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Ahn, I.E., Ju JH, S.Y. Lee, J.S. Park, Oh. HJ, H.R. Kim, S.H. Lee, S.H. Park, H.Y. Kim, and M.L. Cho. 2012. Upregulation of stromal cell-derived factor by IL-17 and IL-18 via a phosphatidylinositol 3-kinase-dependent pathway. Scandinavian Journal of Immunology 76 (4): 433–439.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2017

Authors and Affiliations

  1. 1.School of Life ScienceShanxi UniversityTaiyuanChina

Personalised recommendations