title: Vitamin D receptor activation and downregulation of renin-angiotensin system attenuate morphine-induced T cell apoptosis.
abstract: Opiates have been reported to induce T cell loss. We evaluated the role of vitamin D receptor (VDR) and the activation of the renin-angiotensin system (RAS) in morphine-induced T cell loss. Morphine-treated human T cells displayed downregulation of VDR and the activation of the RAS. On the other hand, a VDR agonist (EB1089) enhanced T cell VDR expression both under basal and morphine-stimulated states. Since T cells with silenced VDR displayed the activation of the RAS, whereas activation of the VDR was associated with downregulation of the RAS, it appears that morphine-induced T cell RAS activation was dependent on the VDR status. Morphine enhanced reactive oxygen species (ROS) generation in a dose-dependent manner. Naltrexone (an opiate receptor antagonist) inhibited morphine-induced ROS generation and thus, suggested the role of opiate receptors in T cell ROS generation. The activation of VDR as well as blockade of ANG II (by losartan, an AT(1) receptor blocker) also inhibited morphine-induced T cell ROS generation. Morphine not only induced double-strand breaks (DSBs) in T cells but also attenuated DNA repair response, whereas activation of VDR not only inhibited morphine-induced DSBs but also enhanced DNA repair. Morphine promoted T cell apoptosis; however, this effect of morphine was inhibited by blockade of opiate receptors, activation of the VDR, and blockade of the RAS. These findings indicate that morphine-induced T cell apoptosis is mediated through ROS generation in response to morphine-induced downregulation of VDR and associated activation of the RAS.
authors: Immunology Center, Feinstein Institute for Medical Research, Hofstra North Shore LIJ Medical School, Great Neck, NY 11021, USA.
authors: Nirupama
authors: N
authors: Chandel
authors: Bipin
authors: B
authors: Sharma
authors: Divya
authors: D
authors: Salhan
authors: Mohammad
authors: M
authors: Husain
authors: Ashwani
authors: A
authors: Malhotra
authors: Shilpa
authors: S
authors: Buch
authors: Pravin C
authors: PC
authors: Singhal
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000502:physiology; D009020:Morphine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000502:physiology*
chemical_list: D017382:Reactive Oxygen Species; D018167:Receptors, Calcitriol; D009020:Morphine