Rosmarinic acid inhibits TCR-induced T cell activation and proliferation in an Lck-dependent manner.
Lck is a T cell-restricted Src family protein tyrosine kinase that plays pivotal roles in TCR-mediated signaling. We aimed to identify novel agents that could disrupt the molecular interaction of the Src homology 2-domain of Lck (Lck SH2) with its binding partners, with the expectation that this would impair TCR signaling and generate immunosuppression. Large-scale screening of plant extracts indicated that rosmarinic acid (RosA) in extracts of Prunella vulgaris consistently inhibits the interaction between Lck SH2 and a peptide containing its consensus binding sequence (pYEEI). The inhibitory effect of RosA was specific for SH2 domains of Src family protein tyrosine kinase. RosA inhibited TCR-induced-Ca(2+) mobilization and IL-2 promoter activation but not phorbol 12-myristate 13-acetate/ionomycin-induced IL-2 promoter activation, indicating its point of inhibition at the membrane proximal site of TCR signaling. Furthermore, RosA inhibited TCR-induced splenocyte proliferation as well as one-way MLR at an IC(50) of 25-50 microM and inhibited cytokine expression such as IL-2 and IFN-gamma. Here, we first report RosA as an inhibitor of TCR-signaling and subsequent T cell proliferation.
Won
Jonghwa
J
Signal Transduction Laboratory, Mogam Biotechnology Research Institute, Yonginsi, Korea.
Hur
Yun-Gyoung
YG
Hur
Eun Mi
EM
Park
See-Hyoung
SH
Kang
Mi-Ae
MA
Choi
Youngbong
Y
Park
Changwon
C
Lee
Keun-Hyeung
KH
Yun
Yungdae
Y
D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002934:Cinnamates / Q000737:chemistry / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D053630:Depsides; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics; D017136:Ion Transport / Q000187:drug effects; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects*; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000737:chemistry / Q000502:physiology*; D010748:Phosphopeptides / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors*; D013154:Spleen / Q000276:immunology; D020349:Surface Plasmon Resonance; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D015533:Transcriptional Activation; D051746:ZAP-70 Protein-Tyrosine Kinase; D018909:src Homology Domains; D000097123:Rosmarinic Acid
D002118:Calcium; D002934:Cinnamates; D016207:Cytokines; D053630:Depsides; D007376:Interleukin-2; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D010748:Phosphopeptides; D011505:Protein-Tyrosine Kinases; D011948:Receptors, Antigen, T-Cell; D051746:ZAP-70 Protein-Tyrosine Kinase; D000097123:Rosmarinic Acid; C497261:ZAP70 protein, human