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Lipoteichoic Acid Induces Matrix Metalloproteinase-9 Expression via Transactivation of PDGF Receptors and NF-κB Activation in Rat Brain Astrocytes

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Abstract

Bacterial infections have been shown to be involved in several inflammatory diseases such as brain inflammation. A major factor for these findings is due to the secretion of pro-inflammatory mediators by host cells triggered by the components released from the bacteria. Among these components, lipoteichoic acid (LTA), a component of Gram-positive bacterial cell wall, has been found to be elevated in cerebrospinal fluid of patients suffering from meningitis. Moreover, increased plasma levels of matrix metalloproteinases (MMPs), in particular MMP-9, have been observed in patients with brain inflammatory diseases and may contribute to disease pathology. However, the molecular mechanisms underlying LTA-induced MMP-9 expression in rat brain astrocytes (RBA-1 cells) remain poorly defined. Here, the data with zymographic, Western blotting, RT-PCR, and immunofluorescent staining analyses showed that LTA induced MMP-9 expression and activation via a TLR2-activated c-Src-dependent transactivation of PDGFR pathway. Transactivation of PDGFR led to activation of PI3K/Akt and p42/p44 MAPK and then activated the IKK/NF-κB cascade. The activated-NF-κB translocated into nucleus which bound to κB-binding site of MMP-9 promoter, and thereby turned on transcription of MMP-9. Eventually, upregulation of MMP-9 by LTA enhanced cell migration of astrocytes. Taken together, these results suggested that in RBA-1 cells, activation of NF-κB by a c-Src-dependent PI3K/Akt-p42/p44 MAPK activation mediated through transactivation of PDGFR is essential for MMP-9 gene upregulation induced by LTA. Understanding the regulation of MMP-9 expression and functional changes by LTA/TLR system on astrocytes may provide potential therapeutic targets of Gram-positive bacterial infection in brain disorders.

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Acknowledgments

The authors appreciate Dr. C.C. Chen (Department of Pharmacology, National Taiwan University, Taipei, Taiwan), Dr. J. Han (Department of Immunology, The Scripps Research Institute, La Jolla, CA), Dr. R. Lee (Section of Immunology, Yale School of Medicine, New Haven, CT), Dr. K.L. Guan (Department of Biological Chemistry, University of Michigan, MI), Dr. M.H. Cobb (Department of Pharmacology, University of Texas Southwestern Medical Center, TX), Dr. R.D. Yeh (Department of Pharmacology, University of Illinois at Chicago), and Dr. C.P. Tseng (Department of Medical Biotechnology and Laboratory Science, University of Chang Gung) for providing dominant negative mutants of c-Src (K295M), TLR2, MyD88, MEK1/2 (MEK K97R), ERK1, Akt, and EGFR shRNA, respectively. This work was supported by grants from NSC95-2320-B-182-047-MY3, NSC95-2320-B-182-010, NSC97-2321-B-182-007, CMRPF170021, CMRPD150313, CMRPD140253, CMRPD150253, and CMRPD170491.

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  1. Department of Nursing, Division of Basic Medical Sciences, Chang Gung Institute of Technology, Kwei-San, Tao-Yuan, Taiwan

    Hsi-Lung Hsieh

  2. Department of Pharmacology, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-San, Tao-Yuan, Taiwan

    Hui-Hsin Wang, Cheng-Ying Wu, Wei-Hsuan Tung & Chuen-Mao Yang

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  1. Hsi-Lung Hsieh
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Correspondence to Chuen-Mao Yang.

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Hsi-Lung Hsieh and Hui-Hsin Wang have contributed equally to this work.

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Hsieh, HL., Wang, HH., Wu, CY. et al. Lipoteichoic Acid Induces Matrix Metalloproteinase-9 Expression via Transactivation of PDGF Receptors and NF-κB Activation in Rat Brain Astrocytes. Neurotox Res 17, 344–359 (2010). https://doi.org/10.1007/s12640-009-9111-4

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