From an exchange with cool people:
Vitamin D (978-0-12-809965-0) - David Feldman
"It is now widely believed the enzyme [CYP27B1; calcidiol → calcitriol] exists in nonrenal tissues to boost local production of cellular 1,25(OH)2D3 in a paracrine/intracrine system. Such a role would suggest that cellular 1,25(OH)2D3 concentrations in extrarenal CYP27B1 tissues might be higher than in the tissues of the classical endocrine system, which depend on renally synthesized blood-derived 1,25(OH)2D3 at a concentration around 10^−10 to 10^−9 M (e.g., intestine, bone, parathyroid gland). In turn, the genes regulated in extrarenal tissues (e.g., macrophage, colon, prostate) might be a less-sensitive cell differentiation and antiproliferative subset, known to be regulated in cancer cell lines at 1,25(OH)2D3 concentrations of 10^−8 to 10^−7 M under cell culture conditions. A role for the extrarenal CYP27B1 is also consistent with the finding that serum 25(OH)D levels are associated with various health outcomes from bone health to cardiovascular health. In particular, low serum 25(OH)D levels are associated with increased mortality for colon, breast, and prostate cancer; increased autoimmune diseases and greater susceptibility to tuberculosis; increased cardiovascular diseases and hypertension. The presence of CYP27B1 in cells of the colon, breast, prostate, monocyte/macrophage, and vasculature could explain why serum 25(OH)D levels are so critical to the normal functioning of these tissues."
"Patients with hyperthyroidism (high serum levels of thyroxine, T4 and/or triiodothyronine hormone, T3) have been reported to have low circulating levels of 1,25(OH)2D [55,56]. Recent studies in mice with T3-induced hyperthyroidism showed markedly suppressed serum levels of 1,25(OH)2D and renal expression of Cyp27b1 [26]. Functional studies using PCT cells demonstrated the presence of a negative thyroid hormone response element (TRE) −50 to −20 bp upstream of the transcriptional start site of the CYP27B1 gene with this TRE overlapping the sterol regulatory element (1α-SRE) and TATA box [26]. Data in this study indicated that SRE-binding protein 1c acts as a transcriptional inducer of CYP27B1, but this effect is compromised following treatment with T3. Transcriptional repression effects of T3 on CYP27B1 appear to be due to thyroid hormone receptor (TR)α, and TRβ1 heterodimerizing with retinoid X receptor (RXR)α, to prevent binding of SRE-binding protein to its DNA target. In this way, T3 indirectly suppresses expression of CYP27B1 [26]."
"The serum phosphate concentration is another major regulator of renal 1,25(OH)2D production. In adult humans, dietary phosphorus restriction causes an increase in circulating concentrations of 1,25(OH)2D to 80% above control values, an increase not due to accelerated metabolic clearance of this hormone [38]. Dietary phosphorous supplementation has the opposite effect. Although the mechanism by which decreased serum phosphate increases renal 1,25(OH)2D production remains uncertain [39], it is clear that in humans the calcium-phosphorous-PTH axis cooperates to regulate the conversion of 25(OH)D to 1,25(OH)2D in the kidney. For example, decreased serum calcium concentrations are immediately registered by the parathyroid chief cell calcium-sensing receptors, which, in turn, relax inhibition of PTH production and secretion. The resulting rise in circulating PTH levels directly stimulates the renal 1α-OHase, while a PTH-mediated phosphaturic response and a subsequent decrement in the serum phosphate concentrations indirectly promotes 1,25(OH)2D production (Fig. 8.1)."
"In contrast to its renal counterpart, the macrophage 1α-OHase is unaffected by the stimulatory effects of PTH and phosphate [95,102]. The macrophage plasma membrane is not enriched with PTH receptors [103], and there is no evidence macrophages are responsive to PTH or PTH-related protein in terms of stimulating the protein kinase signaling pathways that are associated with induction of renal 1α-OHase. Similarly, the macrophage enzyme appears to be uninfluenced by changes in the extracellular phosphate concentration [95]. Moreover, exposure of activated macrophages expressing 1α-OHase to a calcium ionophore stimulates the hydroxylation reaction [104], while increasing the extracellular calcium concentration has the opposite inhibitory effect on the renal 1α-OHase [105]."
"Although effects of extracellular phosphate and serum FGF23 on macrophage 1α-OHase activity have yet to be documented, decreased expression of the enzyme has been shown in peripheral blood monocytes treated with FGF23 in vitro [106]. However, the general conclusion is that the key extracellular signaling systems for renal 1α-OHase activity are not heeded by the macrophage enzyme. This provides an explanation for why 1,25(OH)2D production by the macrophage in diseases such as sarcoidosis is not subject to the same negative feedback control that is mediated by a drop in the serum PTH concentration and an increase in the circulating calcium and phosphate level. By contrast, macrophage 1α-OHase activity is potently inhibited by antiinflammatory agents such as glucocorticoids which have little or no effect on the renal enzyme. In vivo this is likely to be due in part to the effects of glucocorticoids on macrophage differentiation and apoptosis. However, studies in vitro suggest that there is also direct inhibition of macrophage 1α-OHase activity by glucocorticoids [74]."
"Of the various bioactive cytokines concentrated in the alveolar space of patients with active sarcoidosis [77,78,130,131], interferon γ (IFNγ) was found to be the principal stimulator of the sarcoid macrophage 1α-hydroxylation reaction, with IFNα having minimal affect only at higher concentrations [74]. However, it is now clear that many other cytokines are also able to stimulate macrophage 1α-OHase. Recent studies have shown that interleukin-15 (IL-15) [132] and IL-32 [133] play pivotal roles in the induction of macrophage CYP27B1 during innate immune responses to bacterial infection. Elevated expression of IL-15 is frequently associated with inflammatory diseases, notably sarcoidosis [134]; as such, IL-15-mediated induction of 1α-OHase activity may provide a link between the regulation of 1α-OHase in normal innate immunity and the dysregulated 1,25(OH)2D production associated with granulomatous disease. Other cytokines such as tumor necrosis factor α (TNFα) [43,79] and IL-2 [102] are also know to stimulate macrophage 1α-OHase. As all of these factors have been implicated in the maturation of macrophage responsiveness within the innate immune system, it seems likely that upregulated 1α-OHase activity is a common feature of activated, but not quiescent, macrophages. More recently and in contrast to the effects of type 2 IFN, IFN-γ, it has been shown that type 1 IFN, IFN-β, negatively regulates the expression of 1α-OHase in human monocytes through increasing the expression of IL-10, which, in turn, inhibits CYP27B1 expression. This results in attenuated 1,25(OH)2D synthesis and consequent reduction in the antimicrobial peptide cathelicidin [135]. Similar observations have also been made for IL-4 that potently suppresses 25(OH)D-induced antibacterial responses in macrophages [136]. In this case, the precise effects of IL-4 on CYP27B1 are unclear, and may involve indirect effects via CYP24A1 [136]."
"Signaling via cytokines such as IFNγ may also lead to the activation of other calcium-dependent pathways in the macrophage, specifically the PKC [143] and phospholipase A2 (PLA2) pathways [144,145]. Because the macrophage 1α-OHase was not influenced by attempts to directly stimulate or inhibit PKC, attention has focused on the PLA2 pathway and the endogenous arachidonic acid metabolic cascade as the signal transduction pathway of most influence over the macrophage enzyme. Further dissection of the intracellular arachidonate metabolic pathway in this cell demonstrated that signal transduction through the 5-lipoxygenase pathway, specifically with the generation of leukotriene C4, was most critical to an increase in 1,25(OH)2D synthesis [146]. These studies were extended to investigate another compound with potential actions in the PLA2-arachidonic acid pathway, the 4-amino quinoline derivative chloroquine. Synthesis of 1,25(OH)2D by macrophages was completely inhibited by exposure to chloroquine in vitro [86]. Furthermore, this effect is independent of chloroquine’s apparent ability to alter the pH of intracellular organelles. When given orally to a hypercalcemic patient with sarcoidosis, chloroquine [83,86] or its analog hydroxychloroquine [84] can effectively reduce the serum 1,25(OH)2D and calcium concentration within 36 hours."
"Pathogen-associated molecular patterns such as the bacterial LPS are potent inducers of macrophage 1α-OHase expression and activity [95,102]."
"As outlined above, LPS and IFNγ commonly activate different signal transduction pathways but, as outlined previously, there is potential for cross talk between these pathways, which may have a significant impact on transactivation of CYP27B1. Notably, IFNγ and LPS are also the two most effective stimulators of nitric oxide (NO) synthesis in macrophages, and this has supported the hypothesis that production of NO and 1,25(OH)2D in macrophage-like cells may be functionally linked [151–153]."
"It is therefore interesting that two of the major stimulators of the human macrophage 1α-OHase, IFNγ, and LPS, are also key transcriptional regulators of the iNOS gene (NOS2) [156,157], which is itself a CYP-linked oxidase [158]. These observations coupled with the fact that NO has established inhibitory effects on other CYPs [159,160] suggest a possible link with the enzymes involved in vitamin D metabolism."
Cytochrome P450 Vitamin D Hydroxylases in Inflammation and Cancer
"Regulation of CYP27B1 expression is tissue dependent.
- In the kidney, the main regulators are PTH, serum calcium and phosphate, FGF-23, and 1,25(OH)2D3 (Armbrecht, Boltz, & Hodam, 2003; Perwad & Portale, 2011). Inhibition of CYP27B1 expression by 1,25(OH)2D3 involves complex epigenetic regulation of its promoter through VDR (Kim et al., 2009). However, there are tissues where 1,25(OH)2D3 either induces CYP27B1 expression or has no effect.
- In extrarenal tissues, CYP27B1 expression and activity are independent of circulating PTH. In prostate epithelial cells, the epidermal growth factor (EGF) induces, while 1,25(OH)2D3 inhibits CYP27B1 expression (Wang, Flanagan, et al., 2004). In macrophages and keratinocytes, the expression is increased by different cytokines, e.g., interferon gamma (IFN-γ), or tumor necrosis factor α (TNF-α) (Hewison et al., 2007), while nuclear factor kappa B (NFκB) is a potent inhibitor of CYP27B1 expression (Fig. 4)."
"There is evidence from in vitro studies that inflammatory cytokines influence expression of vitamin D metabolizing enzymes. While renal CYP27B1 expression is tightly controlled by PTH and 1,25(OH)2D3, in extra-renal tissues, CYP27B1 is regulated independently of those factors in a tissue-specific manner (Fig. 4). Soluble factors like cytokines and growth factors from the microenvironment affect cellular levels of this enzyme. IL1, IFN-γ, and TNF-α increase CYP27B1 expression in immune cells (van Etten, Stoffels, Gysemans, Mathieu, & Overbergh, 2008). TNF-α stimulated activity of CYP27B1 in untransformed cells such as human keratinocytes, endothelial cells (Zehnder et al., 2002), and peripheral blood monocytes (Gyetko, Hsu, Wilkinson, Patel, & Young, 1993). In cells of the human placenta, TNF-α induced expression of both CYP27B1 and CYP24A1, the latter to a greater extent (Noyola-Martínez et al., 2014). In the alveolar macrophages of patients with sarcoidosis, an inflammatory granulomatous disorder, CYP27B1 is expressed at a very high level, leading to pathologic increase of systemic 1,25(OH)2D3 levels and to hypercalcemia (Inui et al., 2001; Jones, 2008). In addition to the high CYP27B1 expression and activity, 1,25(OH)2D3-induced upregulation of CYP24A1 leads to the expression of a splice variant that lacks the mitochondrial targeting sequence thereby blunting the negative feedback regulation (Zehnder et al., 2002), contributing to the high circulating 1,25(OH)2D3 levels. CYP27B1 expression in macrophages is controlled by immune signals, such as IFN-γ, LPS, or by viral infections (van Etten et al., 2008)."
"In DCs, as in other extrarenal tissues, the level of the precursor 25(OH)D3 is often the limiting factor in the synthesis of the active metabolite (Jeffery et al., 2012). LPS, the ligand for TLRs, increased gene expression of CYP27B1 in DCs and human macrophages (Liu et al., 2006). 1,25(OH)2D3 synthesis in monocyte-derived DC is impaired due to a truncated, less active CYP27B1, while catabolism is not affected. Regulation of VDR targets in these cells seems to occur in a paracrine manner. It is the 1,25(OH)2D3 produced by macrophages that induces expression of vitamin D target genes in the neighboring DCs, inhibits maturation of DC, and reduces DC-dependent T-cell responses (Kundu, Chain, Coussens, Khoo, & Noursadeghi, 2014)."
"T-cell-derived cytokines regulate expression of the activating enzyme CYP27B1 in monocytes via TLR 2/1. IFN-γ increased the activity of CYP27B1 and decreased that of CYP24A1 (Noyola-Martínez et al., 2014). Mechanistic studies using promoter–reporter constructs in monocytes revealed that IFN-γ-induced increase of CYP27B1 is mediated via JAK– STAT, NFκB, and p38-MAPK pathways (Stoffels et al., 2006). Activation of TLR1 and 2 by Mycobacterium tuberculosis or IFN-γ increases expression of VDR and CYP27B1, (Adams et al., 2009; Liu et al., 2006). The resultant, locally synthesized 1,25(OH)2D3 induces the expression of antimicrobial peptides, such as cathelicidin (Gombart, 2009; Hoyer-Hansen, Nordbrandt, & Jaattela, 2010) or defensin 4β (Wang, Nestel, et al., 2004)."