Lipoteichoic acid induces matrix metalloproteinase-9 expression via transactivation of PDGF receptors and NF-kappaB activation in rat brain astrocytes.
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-kappaB cascade. The activated-NF-kappaB translocated into nucleus which bound to kappaB-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-kappaB 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.
Hsieh
Hsi-Lung
HL
Department of Nursing, Division of Basic Medical Sciences, Chang Gung Institute of Technology, Kwei-San, Tao-Yuan, Taiwan.
Wang
Hui-Hsin
HH
Wu
Cheng-Ying
CY
Tung
Wei-Hsuan
WH
Yang
Chuen-Mao
CM
D000704:Analysis of Variance; D000818:Animals; D001253:Astrocytes / Q000187:drug effects*; D001921:Brain / Q000166:cytology; D002461:Cell Line, Transformed; D002465:Cell Movement / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D051381:Rats; D017479:Receptors, Platelet-Derived Growth Factor / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D013682:Teichoic Acids / Q000494:pharmacology*; D013997:Time Factors; D014162:Transfection / Q000379:methods
D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D016328:NF-kappa B; D013682:Teichoic Acids; C009900:lipoteichoic acid; D017479:Receptors, Platelet-Derived Growth Factor; D020780:Matrix Metalloproteinase 9