SEARCH:   Advanced

Prepublished online as a Blood First Edition Paper on January 2, 2003; DOI 10.1182/blood-2002-07-1992. This Article Full Text (PDF) All Versions of this Article: 2002-07-1992v1 101/9/3534    most recent Alert me when this article is cited Alert me if a correction is posted 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 Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Kang, M.-A. Articles by Won, J. Search for Related Content PubMed PubMed Citation Articles by Kang, M.-A. Articles by Won, J. Social Bookmarking                   What's this? Submitted July 5, 2002 Accepted December 15, 2002 Rosmarinic acid inhibits Ca2+-dependent pathways of T-cell antigen receptor-mediated signaling by inhibiting the PLC-1 and Itk activity Mi-Ae Kang, Su-Young Yun, and Jonghwa Won* Signal Transduction Laboratory, Mogam Biotechnology Research Institute, Yonginsi, Gyunggido, South Korea * Corresponding author; email: agnes{at}greencross.com. Rosmarinic acid (RosA) is a hydroxylated compound frequently found in herbal plants and is mostly responsible for anti-inflammatory and anti-oxidative activity. Previously, we observed that RosA inhibited T-cell antigen receptor (TCR)-induced interleukin (IL)-2 expression and subsequent T-cell proliferation in vitro. In this study, we investigated in detail the inhibitory mechanism of RosA on the TCR-signaling, which ultimately activates IL-2 promoter by activating transcription factors, such as nuclear factor of activated T cells (NF-AT) and activating protein-1 (AP-1). Interestingly, RosA inhibited NF-AT activation but not AP-1, suggesting that RosA inhibits Ca2+-dependent signaling pathways only. Signaling events upstream of NF-AT activation, such as the generation of inositol 1,4,5-trisphosphate and Ca2+ mobilization, and tyrosine phosphorylation of phospholipase C-1 (PLC-1) were strongly inhibited by RosA. Tyrosine phosphorylation of PLC-1 is largely dependent on three kinds of protein tyrosine kinases (PTK), i.e., Lck, ZAP-70 and Itk. We found that RosA efficiently inhibited TCR-induced tyrosine phosphorylation and subsequent activation of Itk but did not inhibit Lck or ZAP-70. ZAP-70-dependent signaling pathways such as the tyrosine phosphorylation of LAT and SLP-76 and serine/threonine phosphorylation of mitogen activated protein kinases (MAPK) were intact in the presence of RosA, confirming that RosA suppresses TCR-signaling in a ZAP-70-independent manner. Therefore, we conclude that RosA inhibits TCR-signaling leading to Ca2+ mobilization and NF-AT activation by blocking membrane-proximal events, specifically, the tyrosine phosphorylation of Itk and PLC-1. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: K. A. Scheckel, S. C. Degner, and D. F. Romagnolo Rosmarinic Acid Antagonizes Activator Protein-1-Dependent Activation of Cyclooxygenase-2 Expression in Human Cancer and Nonmalignant Cell Lines J. Nutr., November 1, 2008; 138(11): 2098 - 2105. [Abstract] [Full Text] [PDF] C.-P. Liu, Y.-C. Kuo, C.-C. Shen, M.-H. Wu, J.-F. Liao, Y.-L. Lin, C.-F. Chen, and W.-J. Tsai (S)-Armepavine inhibits human peripheral blood mononuclear cell activation by regulating Itk and PLC{gamma} activation in a PI-3K-dependent manner J. Leukoc. Biol., May 1, 2007; 81(5): 1276 - 1286. [Abstract] [Full Text] [PDF] Y.-G. Hur, Y. Yun, and J. Won Rosmarinic Acid Induces p56lck-Dependent Apoptosis in Jurkat and Peripheral T Cells via Mitochondrial Pathway Independent from Fas/Fas Ligand Interaction J. Immunol., January 1, 2004; 172(1): 79 - 87. [Abstract] [Full Text] [PDF]

	Copyright © 2003 by American Society of Hematology         Online ISSN: 1528-0020