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on February 16, 2006

Arteriosclerosis, Thrombosis, and Vascular Biology. 2006
Published online before print February 16, 2006, doi: 10.1161/01.ATV.0000210278.67076.8f
A more recent version of this article appeared on May 1, 2006
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Submitted on June 30, 2005
Accepted on February 2, 2006

LXR Activation Reduces Proinflammatory Cytokine Expression in Human CD4-Positive Lymphocytes

Daniel Walcher ; Andreas Kümmel ; Bettina Kehrle ; Helga Bach ; Miriam Grüb ; Renate Durst ; Vinzenz Hombach ; and Nikolaus Marx *

From the Department of Internal Medicine II, Cardiology, University of Ulm, Germany.

* To whom correspondence should be addressed. E-mail: nikolaus.marx{at}medizin.uni-ulm.de.

Background--CD4-positive lymphocytes, the major T-cell population in human atheroma, mainly secrete Th-1-type proinflammatory cytokines, like interferon (IFN){gamma}, tumor necrosis factor (TNF){alpha}, and interleukin (IL)-2, thus promoting atherogenesis. Recent data suggest that the nuclear transcription factors liver X receptor-alpha and liver X receptor-beta (LXR{alpha} and LXR{beta}) limit plaque formation in animal models by modulating macrophage function. Still, the role of LXRs in CD4-positive lymphocytes is currently unexplored.

Methods and Results--Human CD4-positive lymphocytes express LXR{alpha} and LXR{beta} mRNA and protein. Activation of CD4-positive cells by anti-CD3 mAbs, anti-CD3/CD28 mAbs, as well as PMA/ionomycin significantly increased Th1-cytokine mRNA and protein expression. Concomitant treatment with the LXR activator T0901317 reduced this increase of IFN{gamma}, TNF{alpha}, and IL-2 in a concentration-dependent manner with a maximum at 1 µmol/L T0901317. Transient transfection assays revealed an inhibition of IFN{gamma} promoter activity by T0901317 as the underlying molecular mechanism. Such anti-inflammatory actions were also evident in cell-cell interactions with medium conditioned by T0901317-treated CD4-positive cells attenuating human monocyte CD64 expression. Human CD4-positive lymphocytes express both LXR{alpha} and LXR{beta}, and LXR activation can reduce Th-1 cytokine expression in these cells.

Conclusions--These data provide new insight how LXR activators might modulate the inflammatory process in atherogenesis and as such influence lesion development.
Key words: atherosclerosis • IFN{gamma} • LXR • T-lymphocytes




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