Ethanol and vitamin D receptor in T cell apoptosis.
Ethanol has been demonstrated to cause T cell apoptosis. In the present study, we evaluated the role of VDR and the renin angiotensin system (RAS) in oxidative stress-induced T cell apoptosis. Ethanol-treated human T cells displayed down regulation of vitamin D receptor (VDR) and the activation of the RAS in the form of enhanced T cell renin expression and angiotensin II (Ang II) production. The silencing of VDR with siRNA displayed the activation of the RAS, and activation of the VDR resulted in the down regulation of the RAS. It suggested that ethanol-induced T cell RAS activation was dependent on the VDR status. T cell ROS generation by ethanol was found to be dose dependent. Conversely, ethanol-induced ROS generation was inhibited if VDR was activated or Ang II was blocked by an angiotensin II type 1 (AT1) receptor blocker (Losartan). Furthermore, it was observed that ethanol not only induced double strand breaks in T cells but also attenuated DNA repair response, whereas, VDR activation inhibited ethanol-induced double strand breaks and also enhanced DNA repairs. Since free radical scavengers inhibited ethanol-induced DNA damage, it would indicate that ethanol-induced DNA damage was mediated through ROS generation. These findings indicated that ethanol-induced T cell apoptosis was mediated through ROS generation in response to ethanol-induced down regulation of VDR and associated activation of the RAS.
Immunology Center, Feinstein Institute for Medical Research, Hofstra North Shore LIJ Medical School, 100 Community Drive, Great Neck, NY 11021, USA.
Shabina
S
Rehman
Nirupama
N
Chandel
Divya
D
Salhan
Partab
P
Rai
Bipin
B
Sharma
Tejinder
T
Singh
Mohammad
M
Husain
Ashwani
A
Malhotra
Pravin C
PC
Singhal
D000804:Angiotensin II / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004260:DNA Repair; D004797:Enzyme-Linked Immunosorbent Assay; D000431:Ethanol / Q000494:pharmacology*; D005455:Fluorescent Antibody Technique; D006801:Humans; D020287:In Situ Nick-End Labeling; D019169:Jurkat Cells; D007700:Kinetics; D019808:Losartan / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000187:drug effects*; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D013601:T-Lymphocytes / Q000187:drug effects*
D047228:Angiotensin II Type 1 Receptor Blockers; D017304:Annexin A5; D002492:Central Nervous System Depressants; D017382:Reactive Oxygen Species; D018167:Receptors, Calcitriol; D000804:Angiotensin II; D000431:Ethanol; D019808:Losartan