Wednesday, August 22, 2012
Topic Discussion: Vitamin D receptor and Renin angiotensin system
Opiate addicts are prone to infection and this has been attributed to ongoing lymphopenia. Morphine is one of the commonly used opiates in pain management. Morphine is also an active metabolite of commonly abused drug, heroine. Recently, vitamin D receptor (VDR) has been demonstrated to play a role in immune cell function.
We evaluated the role of VDR in the activation of the renin angiotensin system (RAS) in morphine-induced T cell loss. Morphine treated human T cells displayed down regulation 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 down regulation of the RAS, it appears that morphine-induced T cell RAS activation was dependent on the VDR status. Morphine also enhanced reactive oxygen species (ROS) generation in a dose dependent manner; however, this effect of morphine was inhibited by an opiate receptor antagonist, naltrexone. These findings confirmed the role of opiate receptors in morphine-induced ROS generation. Interestingly, the activation of VDR as well as blockade of Ang II (by losartan, an AT1 receptor blocker) also inhibited morphine-induced T cell ROS generation. Morphine not only induced DNA damage in T cells but also attenuated DNA repair response; whereas, activation of VDR not only inhibited morphine-induced DNA damage but also enhanced DNA repair. Morphine also 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 down regulation of VDR and associated activation of the RAS.
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Post by Dr. Pravin Singhal
Professor of Medicine
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