Expression of CYP2R1 and VDR in human brain pericytes: the neurovascular vitamin D autocrine/paracrine model.

Abstract

1,25 Dihydroxyvitamin D3 (1,25D) is a hormone produced from vitamin D through two hydroxylating steps catalyzed successively in the liver by the vitamin D 25-hydroxylase Cyp2R1 and in the kidney by the 25-hydroxyvitamin D3 1α-hydroxylase Cyp27B1. 1,25D behaves like a steroid hormone. It regulates gene transcription by interacting with a nuclear receptor named vitamin D receptor (VDR) for the vitamin D receptor. Although the role of vitamin D is historically related to rickets, its physiological function largely encompasses bone tissues. Accumulating evidence has indicated that 1,25D can also be considered a neurosteroid. For example, both VDR and CYP27B1 are expressed in brain cells. Similarly, the neuroprotective and anti-inflammatory potential of 1,25D in nervous tissue has been shown experimentally. The regulation of Cyp27B1, which catalyzes the last step of 1,25D synthesis, by the inflammatory cytokines tumor necrosis factor-α and interferon-γ has been reported recently. However, the fate of Cyp2R1 that catalyzes the first enzymatic reaction of the vitamin D metabolism has not received attention. Using human brain pericytes, we studied the expression of CYP2R1 and VDR genes when these cells were challenged to an inflammatory stimulus. We found a significant upregulation of these two genes in human brain pericytes challenged with tumor necrosis factor-α and interferon-γ. These results suggest the existence of an autocrine/paracrine vitamin D system in the neurovascular unit. The function of this novel signaling system might be critical in the control of neuroinflammation and in brain pathologies.