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Br J Pharmacol. 2004 Jul;142(6):933-42. Epub 2004 Jun 21.

Irbesartan inhibits human T-lymphocyte activation through downregulation of activator protein-1.

Author information

1
Division of Cardiology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, No 325, Section 2, Cheng-Kung Road, Neihu 114, Taipei, Taiwan, ROC.

Abstract

1 Irbesartan is a promising antihypertensive drug with beneficial effects on atherosclerotic processes. In the progression of atherosclerosis, human T-lymphocytes play an important role, but it is not yet known how irbesartan modulates human T-lymphocytes activation. To gain insight into the mechanisms by which irbesartan acts, we investigated its effects on human T-lymphocytes. 2 Primary human T-lymphocytes were isolated from whole blood. Cytokines were determined by ELISA. Activator protein-1 (AP-1) and related protein activities were determined by electrophoretic mobility shift assays, kinase assays, Western blotting and transfection assays. 3 Irbesartan inhibited the production of both tumor necrosis factor-alpha and interferon-gamma by activated T-cells, especially at therapeutic concentrations. Further investigation at the molecular level indicated that the inhibition of activated human T-lymphocytes specifically correlated with the downregulation of AP-1 DNA-binding activity. In the Jurkat T-cell line, irbesartan also inhibited AP-1 transcriptional activity. Finally, we revealed that irbesartan is unique in its ability to inhibit the activation of both c-Jun NH2-terminal protein kinase and p38 MAPK. 4 Our studies show that irbesartan may modulate inflammation-based atherosclerotic diseases through a cell-mediated mechanism involving suppression of human T-lymphocytes activation via downregulation of AP-1 activity.

PMID:
15210574
PMCID:
PMC1575109
DOI:
10.1038/sj.bjp.0705785
[Indexed for MEDLINE]
Free PMC Article

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