Expression of CYP2R1 and VDR in human brain pericytes: the neurovascular vitamin D autocrine/paracrine model.
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.
INSERM UA 01, Clinatec, Edmond J. Safra Biomedical Research Center, CEA, Grenoble CHU, Grenoble Alpes University, Grenoble, France.
Michèle
M
El-Atifi
Matthieu
M
Dreyfus
François
F
Berger
Didier
D
Wion
D019898:Autocrine Communication; D001921:Brain / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D002478:Cells, Cultured; D053493:Cholestanetriol 26-Monooxygenase / Q000235:genetics*; D000072467:Cytochrome P450 Family 2; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D019899:Paracrine Communication; D020286:Pericytes / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014807:Vitamin D / Q000378:metabolism*
D018167:Receptors, Calcitriol; D014409:Tumor Necrosis Factor-alpha; C579457:VDR protein, human; D014807:Vitamin D; D007371:Interferon-gamma; D000072467:Cytochrome P450 Family 2; C506833:CYP2R1 protein, human; D053493:Cholestanetriol 26-Monooxygenase