Regulation of the extrarenal CYP27B1-hydroxylase

Abstract

Provided here is a collective review of research on the extrarenal CYP27B1-hydroxylase that shapes our current and expanding vision of the role this enzyme plays in the intracrinonology and paracrinology, as opposed to the traditional endocrinology, of vitamin D to regulate the innate and adaptive immune response, particularly in human granuloma-forming diseases like tuberculosis. Special emphasis is placed on soluble factors (i.e., cytokines) in the local microenvironment of these human diseases that coordinate amplification and feedback inhibition of the macrophage CYP27B1-hydroxylase. Principal among these factors are Type I and Type II interferons (IFNs); the Type II IFN, IFN-γ, stimulates the production of 1,25-dihydroxyvitamin D (1,25(OH)2D) from 25-hydroxyvitamin D (25OHD) by the granuloma-forming disease-activated macrophage, while the Type I IFNs, IFN-α and IFN-ß, block the hydroxylation reaction. The type I IFN response is associated with more aggressive disease, while the Type II IFN response, the one that promotes 1,25(OH)2D production by the macrophage, is associated with more confined disease. Tilting the balance in the human immune response toward a type II IFN, confined disease phenotype in enabled by the presence of extracellular 25OHD levels that are sufficient to enable the type II IFNγ-promoted, substrate 25OHD-driven intracellular synthesis of 1,25(OH)2D.

A kidney-specific genetic control module in mice governs endocrine regulation of the cytochrome P450 gene Cyp27b1 essential for vitamin D3 activation

“…10B). LPS induction of Cyp27b1 expression has been previously described, particularly in immune cells such as macrophages, where it is suggested to be involved in the ability of vitamin D to modulate both innate and acquired immunity (42). Importantly, the ability of LPS to induce the Cyp27b1 gene in these cell types was unaffected by the enhancer deletions introduced into the M1-IKO and M21-IKO mice, although LPS activity appeared to be potentially unmasked in the kidneys of these mutant mice as a consequence of the reduced basal Cyp27b1 expression in both strains (Fig.…”

Two Cases of Mistaken Polyuria and Nephrocalcinosis in Infants with Glucose-Galactose Malabsorption: A Possible Role of 1,25(OH)₂D₃

“…In a recent review by Pinto et al [28], it is described that, in certain pathological states, decreases in intracellular calcium in the endoplasmic reticulum can trigger compensatory mechanisms. It is also known that decreases in intracellular calcium can lead to local production of 1,25(OH) 2 D 3 in the enterocytes [29], such as in subcutaneous fat necrosis, where elevated serum 1,25(OH) 2 D 3 levels are observed secondary to autocrine 1,25(OH) 2 D 3 production. Based on the work of Pinto et al [28], we hypothesize that in patients with GGM, there is a decrease in intracellular calcium in the enterocytes which may trigger increased autocrine production of 1,25(OH) 2 D 3 , resulting in elevated serum 1,25(OH) 2 D 3 .…”

Vitamin D and Immune System

“…In human cells, the expression of the co-receptor of TLR4 and CD14, is strongly regulated by active Vitamin D and a correlation was found between induction by LPS and expression of CYP27B1 via TLR4/CD14 receptor complexes [67,68]. Treatment of human monocytes with active Vitamin D inhibits the expression of TLR2, TLR4, TLR9 and alters the TLR9-dependent production of IL-6 [69].…”

“…The immune system is responsive to the circulating levels of Vitamin D as evidenced by; stimulation of TLR1/2 heterodimers in human macrophages by bacterial lipopeptides induced expression of CYP27B1 and VDR; the downstream VDR-driven responses were strongly dependent on serum concentration of active Vitamin D cultured in the presence of human serum and these responses were attenuated or absent in Vitamin D-deficient individuals and were restored by active Vitamin D supplementation [26,28,68].…”