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Prepublished online as a Blood First Edition Paper on January 2, 2003; DOI 10.1182/blood-2002-07-1992.
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Blood, 1 May 2003, Vol. 101, No. 9, pp. 3534-3542
IMMUNOBIOLOGY
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
From the Signal Transduction Laboratory, Mogam
Biotechnology Research Institute, Gyunggido, Korea.
Rosmarinic acid (RosA) is a hydroxylated compound frequently found
in herbal plants and is mostly responsible for anti-inflammatory and
antioxidative activity. Previously, we observed that RosA inhibited
T-cell antigen receptor (TCR)- induced interleukin 2 (IL-2)
expression and subsequent T-cell proliferation in vitro. In this study,
we investigated in detail inhibitory mechanism of RosA on 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-triphosphate 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 3 kinds of protein tyrosine kinases (PTKs), ie,
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 (MAPKs) 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
inducible T cells kinase (Itk) and PLC-1.
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