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The Role of TLR4 and Fyn Interaction on Lipopolysaccharide-Stimulated PAI-1 Expression in Astrocytes

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Abstract

Plasminogen activator inhibitor-1 (PAI-1) is an endogenous inhibitor of tissue plasminogen activator (tPA) that acts as a neuromodulator in various neurophysiological and pathological conditions. Several researchers including us reported the induction of PAI-1 during inflammatory condition; however, the mechanism regulating PAI-1 induction is not yet clear. In this study, we investigated the role of non-receptor tyrosine kinase Fyn in the regulation of lipopolysaccharide (LPS)-induced upregulation of PAI-1 in rat primary astrocyte. The activation of toll-like receptor 4 (TLR4) signaling, induced by its ligand LPS, stimulated a physical interaction between TLR4 and Fyn along with phosphorylation of tyrosine residue in both molecules as determined by co-immunoprecipitation experiments. Immunofluorescence staining also showed increased co-localization of TLR4-Fyn on cultured rat primary astrocytes after LPS treatment. The increased TRLR4-Fyn interaction induced expression of PAI-1 through the activation of PI3k/Akt/NFĸB pathway. Treatment with Src kinase inhibitor (PP2) or transfection of Fyn small interfering RNA (siRNA) into cultured rat primary astrocytes inhibited phosphorylation of tyrosine residue of TLR4 and blocked the interaction between TLR4 and Fyn resulting to the inhibition of LPS-induced expression of PAI-1. The activation of PI3K/Akt/NFĸB signaling cascades was also inhibited by Fyn knockdown in rat primary astrocytes. The induction of PAI-1 in rat primary astrocytes, which resulted in downregulation of tPA activity in culture supernatants, inhibited neurite outgrowth in cultured rat primary cortical neuron. The inhibition of neurite extension was prevented by PP2 or Fyn siRNA treatment in rat primary astrocytes. These results suggest the critical physiological role of TRL4-Fyn interaction in the modulation of PAI-1-tPA axis in astrocytes during neuroinflammatory responses such as ischemia/reperfusion injuries.

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Acknowledgments

This work was supported by a grant of the Korean Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (No. A120029).

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The authors declare no conflict of interest or competing commercial interests.

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Authors and Affiliations

  1. Department of Neuroscience, School of Medicine and Center for Neuroscience Research, IBST, Konkuk University, Hwayang-dong, Gwangjin-gu, Seoul, 143-701, South Korea

    Hyun Myung Ko, Sung Hoon Lee, Ki Chan Kim, So Hyun Joo & Chan Young Shin

  2. KU Open Innovation Center, Konkuk University, Hwayang-dong, Gwangjin-gu, Seoul, 143-701, South Korea

    Hyun Myung Ko, So Hyun Joo, Wahn Soo Choi & Chan Young Shin

  3. Department of Immunology and Physiology, School of Medicine, Konkuk University, Chungju, 380-701, South Korea

    Wahn Soo Choi

  4. Department of Neuroscience, School of Medicine and Center for Neuroscience research, IBST, Konkuk University, Hwayang-Dong, Gwangjin-Gu, Seoul, 143-701, South Korea

    Chan Young Shin

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  1. Hyun Myung Ko
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Hyun Myung Ko and Sung Hoon Lee contributed equally to this work.

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Ko, H.M., Lee, S.H., Kim, K.C. et al. The Role of TLR4 and Fyn Interaction on Lipopolysaccharide-Stimulated PAI-1 Expression in Astrocytes. Mol Neurobiol 52, 8–25 (2015). https://doi.org/10.1007/s12035-014-8837-z

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