Liver X receptors interfere with cytokine-induced proliferation and cell survival in normal and leukemic lymphocytes.
Liver X receptors (LXRs) are nuclear receptors regulating lipid and cholesterol metabolism. Recent data indicate an additional role of LXR in immunity by controlling dendritic cell and T-cell function and in breast and prostate cancer cells. Here, we show that LXR activation interferes with IL-2 and IL-7-induced proliferation and cell cycle progression of human T-cell blasts mainly through inhibited phosphorylation of the retinoblastoma protein and decreased expression of the cell cycle protein cyclin B. Comparable results were obtained with IL-2-dependent chronic lymphoblastic leukemia (CLL) T cells. Furthermore, we show for B-CLL cells that LXR are functionally active and inhibit expression of survival genes bcl-2 and MMP-9, and significantly reduce cell viability, suggesting an interference of LXR with cytokine-dependent CLL cell survival. In conclusion, our data reveal LXR as a potent modulator of cytokine-dependent proliferation and survival of normal and malignant T and B lymphocytes. This novel LXR action could find clinical application in immunosuppressive and antileukemic therapies.
Geyeregger
René
R
Department of Internal Medicine III, Medical University of Vienna, A-1090 Vienna, Austria.
Shehata
Medhat
M
Zeyda
Maximilian
M
Kiefer
Florian W
FW
Stuhlmeier
Karl M
KM
Porpaczy
Edit
E
Zlabinger
Gerhard J
GJ
Jäger
Ulrich
U
Stulnig
Thomas M
TM
D015703:Antigens, CD / Q000276:immunology; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism; D016207:Cytokines / Q000494:pharmacology*; D006801:Humans; D007938:Leukemia / Q000276:immunology / Q000473:pathology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology* / Q000473:pathology; D015461:Leukemia, Prolymphocytic, T-Cell / Q000276:immunology / Q000473:pathology; D008055:Lipids / Q000502:physiology; D000071518:Liver X Receptors; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000473:pathology*; D008773:Methylphenazonium Methosulfate / Q000494:pharmacology; D057093:Orphan Nuclear Receptors / Q000276:immunology / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology
D015703:Antigens, CD; D016207:Cytokines; D008055:Lipids; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D008773:Methylphenazonium Methosulfate; D002784:Cholesterol