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.
Department of Internal Medicine II, Cardiology, University of Ulm, Germany.
Daniel
D
Walcher
Andreas
A
Kümmel
Bettina
B
Kehrle
Helga
H
Bach
Miriam
M
Grüb
Renate
R
Durst
Vinzenz
V
Hombach
Nikolaus
N
Marx
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