Differential regulation of matrix metalloproteinase-9 and tissue plasminogen activator activity by the cyclic-AMP system in lipopolysaccharide- stimulated rat primary astrocytes

Soon Young Lee, Hee Jin Kim, Woo Jong Lee, So Hyun Joo, Se Jin Jeon, Ji Woon Kim, Hee Sun Kim, Seol Heui Han, Jongmin Lee, Seung Hwa Park, Jae Hoon Cheong, Won Ki Kim, Kwang Ho Ko, Chan Young Shin

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24 Citations (Scopus)

Abstract

We investigated the effect of the cAMP system on lipopolysaccharide (LPS)-induced changes in the activity of matrix metalloproteinases (MMPs) and tissue plasminogen activator (tPA) in rat primary astrocytes. LPS stimulation increased MMP-9 and decreased tPA activity in rat primary astrocytes. Co-treatment with a cAMP analog, dibutyryl-cAMP (db-cAMP), or the cAMP elevating beta-adrenergic agonist, isoproterenol, concentration-dependently inhibited LPS-induced MMP-9 activity. In contrast, db-cAMP concentration-dependently increased tPA activity in both basal and LPS-stimulated rat primary astrocytes. To confirm the effect of cAMP on MMP-9 and tPA activity, we treated LPS-stimulated astrocytes with cAMP phosphodiesterase inhibitors, IBMX or rolipram, and they exhibited similar effects to db-cAMP, namely decreasing MMP-9 activity and increasing tPA activity. RT-PCR analysis of MMP-9 mRNA expression and MMP-9 promoter luciferase reporter assays revealed transcriptional upregulation by LPS stimulation and downregulation by db-cAMP. In contrast, the level of tPA mRNA expression was increased both by LPS and by cAMP treatment. Consistent with RT-PCR analysis, tPA promoter reporter assays showed increased activity by both LPS and cAMP stimulation. Interestingly, the level of mRNA encoding plasminogen activator inhibitor-1 (PAI-1) was increased by LPS stimulation and decreased back to control level after co-treatment with db-cAMP, suggesting that PAI-1 expression plays a major role in the regulation of tPA activity. To examine PKA involvement in the effects of db-cAMP on MMP-9 and tPA activity, we added the PKA inhibitors, H89 or rp-cAMP, along with db-cAMP, and they inhibited db-cAMP-mediated changes in tPA activity without affecting MMP-9 activity. These data suggest that cAMP differentially modulates MMP-9 and tPA activity through a mechanism related to PKA activation. The differential regulation of MMP-9 and tPA by the cAMP system may confer more sophisticated regulation of physiological processes, such as extracellular matrix remodeling and cell migration, by activated astrocytes.

Original languageEnglish
Pages (from-to)2324-2334
Number of pages11
JournalNeurochemical Research
Volume33
Issue number11
DOIs
Publication statusPublished - 2008 Nov

Keywords

  • Isoproterenol
  • PAI-1
  • Post-transcriptional control
  • Promoter activity
  • RT-PCR
  • Zymography

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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  • Cite this

    Lee, S. Y., Kim, H. J., Lee, W. J., Joo, S. H., Jeon, S. J., Kim, J. W., Kim, H. S., Han, S. H., Lee, J., Park, S. H., Cheong, J. H., Kim, W. K., Ko, K. H., & Shin, C. Y. (2008). Differential regulation of matrix metalloproteinase-9 and tissue plasminogen activator activity by the cyclic-AMP system in lipopolysaccharide- stimulated rat primary astrocytes. Neurochemical Research, 33(11), 2324-2334. https://doi.org/10.1007/s11064-008-9737-2