Circulation Research. 2002;90:703-710
Published online before print February 28, 2002, doi: 10.1161/01.RES.0000014225.20727.8F
Published online before print February 28, 2002, doi: 10.1161/01.RES.0000014225.20727.8F
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© 2002 American Heart Association, Inc.
Molecular Medicine |
PPAR Activators as Antiinflammatory Mediators in Human T Lymphocytes
Implications for Atherosclerosis and Transplantation-Associated Arteriosclerosis
From the Department of Internal Medicine II (N.M., B.K., K.K., M.G., W.K., V.H.), Cardiology, University of Ulm, Ulm, Germany, and the Leducq Center for Cardiovascular Research (P.L., J.P.), Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass.
Correspondence to Nikolaus Marx, MD, Department of Internal Medicine II, Cardiology, University of Ulm, Robert-Koch-Str. 8, D-89081 Ulm, Germany. E-mail nikolaus.marx{at}medizin.uni-ulm.de
Activation of T lymphocytes and their ensuing elaboration of proinflammatory cytokines, such as interferon (IFN)-
, represent a critical step in atherogenesis and arteriosclerosis. IFN pathways also appear integral to the development of transplantation-associated arteriosclerosis (Tx-AA), limiting long-term cardiac allograft survival. Although disruption of these IFN signaling pathways limits atherosclerosis and Tx-AA in animals, little is known about inhibitory regulation of proinflammatory cytokine production in humans. The present study investigated whether activators of peroxisome proliferator-activated receptor (PPAR)
and PPAR, with their known antiinflammatory effects, might regulate the expression of proinflammatory cytokines in human CD4-positive T cells. Isolated human CD4-positive T cells express PPAR and PPAR mRNA and protein. Activation of CD4-positive T cells by anti-CD3 monoclonal antibodies significantly increased IFN protein secretion from 0 to 504±168 pg/mL, as determined by ELISA. Pretreatment of cells with well-established PPAR (WY14643 or fenofibrate) or PPAR (BRL49653/rosiglitazone or pioglitazone) activators reduced anti-CD3-induced IFN secretion in a concentration-dependent manner. PPAR activators also inhibited TNF and interleukin-2 protein expression. In addition, PPAR activators markedly reduced cytokine mRNA expression in these cells. Such antiinflammatory actions were also evident in cell-cell interactions with medium conditioned by PPAR activator-treated T cells attenuating human monocyte CD64 expression and human endothelial cell major histocompatibility complex class II induction. Thus, activation of PPAR and PPAR in human CD4-positive T cells limits the expression of proinflammatory cytokines, such as IFN, yielding potential therapeutic benefits in pathological processes, such as atherosclerosis and Tx-AA.
Key Words: atherosclerosis • fibrates • thiazolidinediones • peroxisome proliferator-activated receptors • T cells
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