Differential regulation of matrix metalloproteinase-9 and tissue plasminogen activator activity by the Cyclic-AMP system in lipopolysaccharide-stimulated rat primary astrocytes
- Authors
- Lee, Soon Young; Kim, Hee Jin; Lee, Woo Jong; Joo, So Hyun; Jeon, Se-Jin; Kim, Ji Woon; Kim, Hee Sun; Han, Seol-Heui; Lee, Jongmin; Park, Seung Hwa; Cheong, Jae Hoon; Kim, Won-Ki; Ko, Kwang Ho; Shin, Chan Young
- Issue Date
- 11월-2008
- Publisher
- SPRINGER/PLENUM PUBLISHERS
- Keywords
- zymography; PAI-1; post-transcriptional control; promoter activity; RT-PCR; isoproterenol
- Citation
- NEUROCHEMICAL RESEARCH, v.33, no.11, pp.2324 - 2334
- Indexed
- SCIE
SCOPUS
- Journal Title
- NEUROCHEMICAL RESEARCH
- Volume
- 33
- Number
- 11
- Start Page
- 2324
- End Page
- 2334
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/122467
- DOI
- 10.1007/s11064-008-9737-2
- ISSN
- 0364-3190
- 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.
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Collections - Graduate School > Department of Biomedical Sciences > 1. Journal Articles
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