Rosmarinic acid inhibits Ca2+-dependent pathways of T-cell antigen receptor-mediated signaling by inhibiting the PLC-γ1 and Itk activity

Kang, Mi Ae; Yun, Su; Won, Jonghwa

doi:10.1182/blood-2002-07-1992

Cited by 51 publications

(39 citation statements)

References 61 publications

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“…Our data parallel those of recent investigations (47) reporting that the treatment of H9c2 cardiac muscle cells with higher concentrations of RA than those used in this study (55 vs. 10 mmol/L) for up to 2 h antagonized the adriamycin-dependent activation of c-Jun N-terminal kinase and ERK and partially inhibited the binding of AP-1 members to a control AP-1 oligonucleotide. However, our results contrast with those of other studies (48) documenting that the cotreatment with RA (30 mmol/L for 16 h) did not prevent, but rather slightly induced, TPA-dependent AP-1 activation in transfected Jurkat T cells. One possible interpretation for these contrasting results is that the ability of RA to either stimulate or repress AP-1 activity may be due to cell-specific differences or related to higher doses and longer times of incubation.…”

Section: Discussioncontrasting

confidence: 99%

Rosmarinic Acid Antagonizes Activator Protein-1–Dependent Activation of Cyclooxygenase-2 Expression in Human Cancer and Nonmalignant Cell Lines

Scheckel

Degner

Romagnolo

2008

The Journal of Nutrition

119

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One mechanism through which bioactive food components may exert anticancer effects is by reducing the expression of the proinflammatory gene cyclooxygenase-2 (COX-2), which has been regarded as a risk factor in tumor development.Rosmarinic acid (RA) is a phenolic derivative of caffeic acid present in rosemary (Rosmarinus officinalis). Previous research documented that RA may exert antiinflammatory effects. However, the mechanisms of action of RA on COX-2 expression have not been investigated. Here, we report that in colon cancer HT-29 cells, RA (5, 10, and 20 mmol/L) reduced the 12-Otetradecanoylphorbol-13-acetate (TPA)-induced COX-2 promoter activity (P , 0.05) and protein levels (P , 0.05). In addition, the cotreatment with RA reduced (5 mmol/L, P , 0.05; 10 and 20 mmol/L, P , 0.01) TPA-induced transcription from a control activator protein-1 (AP-1) promoter-luciferase construct and repressed binding of the AP-1 factors c-Jun (10 mmol/L; P , 0.01) and c-Fos (10 mmol/L; P , 0.05) to COX-2 promoter oligonucleotides harboring a cAMP-response element (CRE). The anti-AP1 effects of RA were also examined in a nonmalignant breast epithelial cell line (MCF10A) in which RA antagonized the stimulatory effects of TPA on COX-2 protein expression (5 mmol/L, P , 0.05; 10 and 20 mmol/L, P , 0.01), the recruitment of c-Jun and c-Fos (10 mmol/L; P , 0.01) to the COX-2/CRE oligonucleotides, and activation of the extracellular signal-regulated protein kinase-1/2 (ERK1/2) (10 mmol/L; P , 0.01), a member of the mitogen-activated protein kinase pathway. Additionally, RA antagonized ERK1/2 activation in colon HT-29 and breast MCF-7 cancer cells (10 mmol/L; P , 0.01). Thus, we propose that RA may be an effective preventative agent against COX-2 activation by AP-1-inducing agents in both cancer and nonmalignant mammary epithelial cells.

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Section: Discussioncontrasting

confidence: 99%

Rosmarinic Acid Antagonizes Activator Protein-1–Dependent Activation of Cyclooxygenase-2 Expression in Human Cancer and Nonmalignant Cell Lines

Scheckel

Degner

Romagnolo

2008

The Journal of Nutrition

119

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“…2B). Previously we reported that RosA inhibits Lck SH2-pYEEI interaction and does not inhibit Lck kinase activity (25,26). Therefore, our current data are consistent with our previous reports, and RosA is not expected to inhibit AICD.…”

Section: Discussionsupporting

confidence: 82%

“…As this Lck-dependent proliferation inhibition was observed in the absence of TCR stimulus, we assumed that another mechanism might be inhibiting Jurkat T cell proliferation besides blocking TCR-induced signaling (25,26). We looked for the possible participation of Lck in RosA-induced apoptosis by comparing RosAmediated apoptosis in Jurkat and J.CaM1.6 cells.…”

Section: Rosa-mediated Apoptosis Is Lck Sh2 Dependent But Is Not Depmentioning

confidence: 99%

“…Previously, we demonstrated that RosA inhibited TCR-induced Ca 2ϩ flux and IL-2 promoter activation by inhibiting inducible T cell kinase and phospholipase C␥-1 activity (25,26). As 1) RosA was screened out as an Lck SH2 inhibitor in ELISA, and 2) RosA did not inhibit Lck kinase activity, we suggested that the inhibitory activity of RosA on TCR-induced signaling and subsequent proliferation is ascribed from its interaction with the Lck SH2 domain (25).…”

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confidence: 99%

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Rosmarinic Acid Induces p56lck-Dependent Apoptosis in Jurkat and Peripheral T Cells via Mitochondrial Pathway Independent from Fas/Fas Ligand Interaction

Hur¹,

Yun

Won³

2004

The Journal of Immunology

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Apoptosis is one way of controlling immune responses, and a variety of immunosuppressive drugs suppress harmful immune responses by inducing apoptosis of lymphocytes. In this study we observed that rosmarinic acid, a secondary metabolite of herbal plants, induced apoptosis in an p56lck (Lck)-dependent manner; Lck+ Jurkat T cells undergo apoptosis in response to rosmarinic acid (RosA) treatment, whereas Lck− Jurkat subclone J.CaM1.6 cells do not. J.CaM1.6 cells with various Lck mutants indicated that Lck SH2 domain, but not Lck kinase activity, was required for RosA-induced apoptosis. RosA induced apoptosis in the absence of a TCR stimulus, and this was not prevented by interruption of the Fas/Fas ligand interaction. Instead, RosA-mediated apoptosis involved a mitochondrial pathway as indicated by cytochrome c release and the complete blockage of apoptosis by an inhibitor of mitochondrial membrane depolarization. Both caspase-3 and -8 were indispensable in RosA-induced apoptosis and work downstream of mitochondria and caspase-9 in the order of caspase-9/caspase-3/caspase-8. In freshly isolated human PBMC, RosA specifically induced apoptosis of Lck+ subsets such as T and NK cells, but not Lck-deficient cells, including B cells and monocytes. Moreover, RosA’s ability to kill T and NK cells was restricted to actively proliferating cells, but not to resting cells. In conclusion, Lck-dependent apoptotic activity may make RosA an attractive therapeutic tool for the treatment of diseases in which T cell apoptosis is beneficial.

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“…Phytochemical studies revealed that O. gratissimum (Og) is rich in polyphenols, such as rosmarinic acid (RA) [12], which has recently been shown to have immunomodulatory activity, by suppressing T-cell receptor (TCR) signaling [13]. The rosmarinic acid from another plant species, Perilla frutescens, was able to prevent an eosinophilic airway inflammation in mice.…”

Section: Introductionmentioning

confidence: 99%

Ocimum gratissimum Linn. and rosmarinic acid, attenuate eosinophilic airway inflammation in an experimental model of respiratory allergy to Blomia tropicalis

Costa

Carneiro

Cerqueira-Lima

et al. 2012

International Immunopharmacology

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Allergic asthma has emerged as an important public health problem of urban populations in developed countries. Very often herbal medicine is used to treat this widespread disease, due to the lack of efficacy and the important side effects related to the classical drugs in use. Along this line, Ocimum gratissimum (Og) is a plant widely used in Brazilian folk medicine to treat inflammatory disorders, such as asthma. In the present study we evaluated the immunomodulatory effects of Og and rosmarinic acid (RA, a polyphenolic compound) in a murine model of respiratory allergy induced by the Blomia tropicalis (Bt) mite. The respiratory allergy was induced in A/J mice by administration of Bt extract and the treatment was done using 25, 50 or 100mg/kg of an Og methanolic extract or using 2, 20 or 200mg/kg of RA. We then evaluated the changes induced by these drugs on immunological parameters related to the allergic process, which are up-regulated in this allergic model. The treatment of animals with 100mg/Kg Og and 200mg/Kg RA led to a significant reduction in the numbers of leukocytes/eosinophils in bronchoalveolar lavage (BAL); eosinophil peroxidase activity in BAL; presence of mucus in respiratory tract, histopathological changes in the lung, and IL-4 in BAL. These results suggest that the methanolic extract of Og and the polyphenol RA have therapeutic potential in this murine model of respiratory allergy to a clinically relevant human sensitizer allergen.

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Rosmarinic acid inhibits Ca2+-dependent pathways of T-cell antigen receptor-mediated signaling by inhibiting the PLC-γ1 and Itk activity

Cited by 51 publications

References 61 publications

Rosmarinic Acid Antagonizes Activator Protein-1–Dependent Activation of Cyclooxygenase-2 Expression in Human Cancer and Nonmalignant Cell Lines

Rosmarinic Acid Antagonizes Activator Protein-1–Dependent Activation of Cyclooxygenase-2 Expression in Human Cancer and Nonmalignant Cell Lines

Rosmarinic Acid Induces p56lck-Dependent Apoptosis in Jurkat and Peripheral T Cells via Mitochondrial Pathway Independent from Fas/Fas Ligand Interaction

Ocimum gratissimum Linn. and rosmarinic acid, attenuate eosinophilic airway inflammation in an experimental model of respiratory allergy to Blomia tropicalis

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