HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 280, Issue 9, 7845-7853, March 4, 2005

This Article Full Text Full Text (PDF) All Versions of this Article: 280/9/7845    most recent M409101200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lee, E. O. Articles by Chong, Y. H. Search for Related Content PubMed PubMed Citation Articles by Lee, E. O. Articles by Chong, Y. H. Social Bookmarking                      What's this?

The Amyloid- Peptide Suppresses Transforming Growth Factor-1-induced Matrix Metalloproteinase-2 Production via Smad7 Expression in Human Monocytic THP-1 Cells^*

Eun Ok Lee, Jihee Lee Kang, and Young Hae Chong¶

From the Departments of Microbiology and Physiology, College of Medicine, Division of Molecular Biology and Neuroscience, Ewha Medical Research Institute, Ewha Womans University, 911-1, Mok-6-dong, Yangcheonku, Seoul 158-710, Korea

Accumulation of the amyloid- (A) peptide in the brain is a crucial factor in the development of Alzheimer disease. Expression of transforming growth factor-1 (TGF-1), an immunosuppressive cytokine, has been associated in vivo with A accumulation in transgenic mice and recently with A clearance by activated microglia, suggesting its deleterious and beneficial effects in neuronal cells. In this study, we demonstrated that TGF-1 stimulated the production of matrix metalloproteinase-2 (MMP-2) in a time- and dose-dependent manner in a human monocytic THP-1 cell line. Notably, we found that A1–42 consistently inhibited the TGF-1-induced production of MMP-2, the endogenous gene containing Smad response elements, whereas the reverse peptide, A42–1, evidenced little effect. Additionally, A1–42 reduced TGF-1-induced increase in plasminogen activator inhibitor-1 (PAI-1). This inhibitory effect of A1–42 was also seen in human astroglial T98G cell line. Furthermore, A1–42 significantly induced the expression of Smad7, which appears in turn to mediate the A suppression of the TGF-1-induced MMP-2 production. Indeed, Smad7 overexpression mimicked the inhibitory effect of A1–42 on TGF-1-induced MMP-2 production. Importantly, A1–42 markedly suppressed the transactivation of the transfected reporter construct, p3TP-Lux, which contains TGF-1-inducible Smad response elements. This was concomitant with a decreased MMP-2 production in TGF-1-treated cells. Inhibition of cellular Smad7 levels via the small interference RNA method significantly ameliorated the A1–42-mediated suppression of TGF-1-inducible transcription reporter activity, thereby restoring MMP-2 induction, whereas Smad7 transfection down-regulated TGF-1-inducible transcription reporter activity. Collectively, these data suggest that A1–42 may play an important role in the negative regulation of TGF-1-induced MMP-2 production via Smad7 expression.

Received for publication, August 9, 2004 , and in revised form, December 1, 2004.

^* This work was supported fully by the Ministry of Health and Welfare grant for Biomedical Brain Research (Neurodegenerative and Psychological Disease Research Grant 0405-NS01-0704–0001) and by Korea Research Foundation Grant KRF-2002-015-EP0071 (to Y. H. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Dept. of Microbiology, College of Medicine, Ewha Woman's University, 911-1, Mok-6-dong, Yangcheonku, Seoul 158-710, Korea. Tel.: 822-02-2650-5739; Fax: 822-02-2653-8891; E-mail: younghae{at}ewha.ac.kr.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				F. G. Spinale Myocardial Matrix Remodeling and the Matrix Metalloproteinases: Influence on Cardiac Form and Function Physiol Rev, October 1, 2007; 87(4): 1285 - 1342. [Abstract] [Full Text] [PDF]

				Y. H. Chong, Y. J. Shin, E. O. Lee, R. Kayed, C. G. Glabe, and A. J. Tenner ERK1/2 Activation Mediates Abeta Oligomer-induced Neurotoxicity via Caspase-3 Activation and Tau Cleavage in Rat Organotypic Hippocampal Slice Cultures J. Biol. Chem., July 21, 2006; 281(29): 20315 - 20325. [Abstract] [Full Text] [PDF]