LXR activation reduces proinflammatory cytokine expression in human CD4-positive lymphocytes.
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 (LXRalpha and LXRbeta) limit plaque formation in animal models by modulating macrophage function. Still, the role of LXRs in CD4-positive lymphocytes is currently unexplored.


RESULTS
Human CD4-positive lymphocytes express LXRalpha and LXRbeta 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. Treatment with the LXR activator T0901317 reduced this increase of IFNgamma, TNFalpha, and IL-2 in a concentration-dependent manner with a maximum at 1 micromol/L T0901317. Transient transfection assays revealed an inhibition of IFNgamma 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.


CONCLUSIONS
Human CD4-positive lymphocytes express both LXRalpha and LXRbeta, and LXR activation can reduce Th-1 cytokine expression in these cells. These data provide new insight how LXR activators might modulate the inflammatory process in atherogenesis and as such influence lesion development.
Walcher
Daniel
D
Department of Internal Medicine II, Cardiology, University of Ulm, Germany.
Kümmel
Andreas
A
Kehrle
Bettina
B
Bach
Helga
H
Grüb
Miriam
M
Durst
Renate
R
Hombach
Vinzenz
V
Marx
Nikolaus
N
D050197:Atherosclerosis / Q000209:etiology; D018106:CD28 Antigens / Q000502:physiology; D017252:CD3 Complex / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D006801:Humans; D006845:Hydrocarbons, Fluorinated; D007371:Interferon-gamma / Q000096:biosynthesis; D000071518:Liver X Receptors; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D057093:Orphan Nuclear Receptors; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis; D018160:Receptors, Cytoplasmic and Nuclear / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D013449:Sulfonamides / Q000494:pharmacology; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D018106:CD28 Antigens; D017252:CD3 Complex; D016207:Cytokines; D004268:DNA-Binding Proteins; D006845:Hydrocarbons, Fluorinated; D007371:Interferon-gamma; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013449:Sulfonamides; C000605213:NR1H3 protein, human; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides