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ISSN 0233-7657. Biopolymers and Cell. 2010. Vol. 26. N 2
Vitamin D – a novel role in pregnancy
Chander P. Arora , C. J. Hobel
1, 2
1, 2
1
Cedars-Sinai Medical Center, Burns-Allen Research Institute and the Division of Maternal-Fetal Medicine
8635, West Third St., Ste 160W, Los Angeles, CA, USA, 90048
2
David Geffen School of Medicine, University of California Los Angeles
10833, Le Conte Avenue, Los Angeles, CA, USA, 90095
arora@cshs.org
Vitamin D regulates placental development and function. It is a potent regulator of the immune systemstimulating antimicrobial responses while suppressing inflammation. Its deficiency has been linked to
increased risk of serious chronic and inflammatory diseases. Vitamin D deficiency during pregnancy increases susceptibility to infection and inflammation, leading, in turn, to outcome like preterm birth or
preeclampsia. Pregnant women with darker skin pigmentation are more likely to be vitamin D deficient,
particularly when living in regions with low exposure to sunlight. It is possible that during pregnancy, a
primary non-infectious inflammatory process is activated by vitamin D deficiency. Combined assessment of
vitamin D deficiency and inflammatory markers in early pregnancy or during different stages of pregnancy
may facilitate the recognition of the risk of complications.
Keywords: vitamin D, pregnancy, immune response.
Introduction. Beyond its classical effects on bone and
calcium homeostasis causing rickets and osteoporosis,
vitamin D has become increasingly recognized as a potent regulator of multiple physiological functions. Vitamin D can be obtained from limited food sources,
such as fatty fish and fish oil, and, today, from dietary
supplements or we can also make it ourselves, through
a chemical reaction that happens in the skin when it is
exposed to ultraviolet B (UVB) light especially to meet
the increased demands of pregnancy.
The vitamin D deficiency epidemic during pregnancy is caused by a lack of adequate sunlight exposure
needed to synthesize vitamin D3 (cholecalciferol) in the
skin, coupled with oral intakes that are too low even
with regular use of prenatal vitamins containing 400 IU
vitamin D3 [1]. Vitamin D deficiency during pregnanÓ Institute of Molecular Biology and Genetics NAS of Ukraine, 2010
cy has been linked with a number of serious short- and
long-term health problems in offspring, including impaired growth, skeletal problems, type 1 diabetes, asthma, and schizophrenia [2].
Functional aspects of vitamin D. Vitamin D in
humans, refers to Vitamin D3, which is also known as
cholecalciferol. In response to UVB light, it is created
by skin cells called keratinocytes utilizing 7-dehydrocholesterol, a product of cholesterol. This version has
no biological activity in the body till this molecule is
modified primarily in the liver, by a series of related enzymes for hydroxylation, to generate 25-hydroxyvitamin D3 (25(OH)D3). The 25(OH)D3 made by the liver
is nonetheless the major circulating form of vitamin D.
When it is needed in the body, a final conversion to the
biologically active form by the enzyme 1a-hydroxylase (CYP27b1), is required to become 1,25-dihydroxyvitamin D (1,25(OH)2D3). This was first discovered in
97
CHANDER P. ARORA, HOBEL C. J.
20
18
7-dehydro-cholesterol
11
9
12
Skin
(Keratinocytes)
HO
17
26
23
27
15
25
8
OH
7
6
4
3
24 25
22
21
5
2
CH2
10
1
Vit D (D3 / Cholocalciferol)
25
CH2
OH
HO
Liver
25(OH) Vit D3 (circulating form)
CH2
1 a-hydroxylase
(CYP27b1)
Kidneys
and
other tissues
1
HO
OH
1,25(OH)2 Vit D3 (active form)
Fig. 1. Skin keratinocytes convert 7-dehydrocholesterol to vitamin D in response to sunlight exposure. This is converted to the circulating
form 25(OH)D 3 in liver and to 1,25(OH) 2D 3 in the target tissues
the kidney, and renal processing is responsible for generating much of the body’s circulating 1,25(OH)2D3
supply [3] (Fig. 1).
The active form of vitamin D, the 1,25(OH)2D3 molecule virtually functions as an «on/off» switch for genes of every tissue in the human body. This form of vitamin D acts by attaching to the vitamin D receptor
(VDR), which serves as a transcription factor inside a
cell’s nucleus. Once bound to 1,25(OH)2D3, the VDR
protein makes a complex with retinoid-x receptor
(RXR). This complex now binds to a specific region of
the cell’s DNA adjacent to a target gene. Their attachment to the DNA induces cellular machinery to begin
transcribing the neighboring gene to a specific protein.
Recently, many other tissues, including cells of the
immune system and the skin, have been identified to
perform the conversion of 25(OH)D3. Skin is therefore
unique among organs in that it is capable of manufacturing biologically active 1,25(OH)2D3 in the presence of
UVB light from start to finish, although local production of 1,25(OH)2D3 from circulating in other tissues is
a substantial source of vitamin D’s biological activity.
98
By inducing a cell to make a particular protein,
1,25(OH)2D3 affects a range of cellular function, and
this ability to trigger gene activity in different tissues is
the basis of vitamin D’s enormous physiological effects. Precisely, vitamin D is manufactured in one tissue and circulates through the body influencing many
other tissues, and VDR is a nuclear receptor that responds to powerful steroidal hormones such as estrogen and testosterone [4].
At least 1,000 different genes are believed to be
regulated by 1,25(OH)2D3, including several involved
in the body’s calcium processing that account for D’s
well-known role in bone formation as well as genes
with critical roles in a variety of cellular defenses.
Circulating levels of 25(OH)D3 – the biomarker
of vitamin D status. Circulating levels of 25(OH)D3
are a direct reflection of vitamin D status, which depends on access to vitamin D either through exposure
to sunlight or through dietary intake whereas serum
concentrations of 1,25(OH)2D3, are primarily defined
by the endocrine regulators of renal CYP27b1 activity.
The net effect of this is that vitamin D status can vary
VITAMIN D – A NOVEL ROLE IN PREGNANCY
25(OH) D
Sufficient
30–60 ng per milliliter
or 75–150 nmol/l
1ahydroxylase
1,25(OH)2 D
Active Form (Target Tissues)
Insufficient
20–30 ng per milliliter
or 50–75 nmol/l
Deficient
20 ng per milliliter
or 50 nmol/l
Fig. 2. Deficient and Sufficient levels of circulating vitamin D for
getting converted to the active form by the action of 1a-hydroxylase
significantly in populations as a consequence of geographical, social or economic factors. Until recently,
rickets was considered to be the only significant clinical consequence of low serum 25(OH)D3. However, an
entirely new perspective on vitamin D deficiency has
arisen from the observation that serum 25(OH)D3 levels correlate inversely with serum parathyroid hormone below a threshold of 80 nmol/l 25(OH)D3 [5].
This has led to a complete re-evaluation of the optimal
serum level of 25(OH)D3 so that serum concentrations
of 25(OH)D3 up to 75 nmol/l are now considered to be
inadequate and are more commonly referred to as vitamin D «insufficiency» as opposed to «deficiency» [6].
A 25(OH)D3 level of 30 ng per milliliter (75 nmol/l) or
higher provides adequate substrate for 1-OHase to convert 25(OH)D3 to its active form, 1,25(OH)2D3 [6]. We
categorized the serum levels of 25(OH)D3 as: less than
50 nmol/l (< 20 ng per milliliter) as deficient, 50– 75 nmol/l (< 20–30 ng per milliliter) as insufficient, and 75–150 nmol/l (< 30–60 ng per milliliter) as sufficient (Fig. 2). Once 1,25(OH)2D3 completes the task of maintaining normal cellular proliferation and differentiation, it induces expression of the enzyme 25-hydroxyvitamin D-24-hydroxylase (24-OHase), which enhances the catabolism of 1,25(OH)2D3 to biologically inert 1,24,25trihydroxyvitamin D. Locally produced 1,25(OH)2D3 does not enter the circulation and has no influence on calcium metabolism. Therefore circulating levels of 25(OH)D3 are a direct reflection of vitamin D status, which depends on access to vitamin D either through exposure to sunlight or through dietary intake. Vitamin D requirements during pregnancy. In addition to causing poor global mineralization of the skeleton, vitamin D deficiency has implications for numerous other nonskeletal health outcomes. In utero or early life vitamin D deficiency has been linked to an increased risk of type 1 diabetes [7], asthma [8], and schizophrenia [9, 10]. Fascinating new data also show that vitamin D regulates placental development and function [11], which suggests that maternal vitamin D status may be associated with adverse outcomes of pregnancy, such as miscarriage, preeclampsia, and preterm birth. Preterm delivery in the environment of infection is believed to result from the actions of pro-inflammatory cytokines secreted as part of the maternal and/or fetal host response to microbial invasion [12, 13]. Enhanced expression of the pro-inflammatory cytokines IL-1, IL-6 and TNFa are associated with preterm delivery [14]. Such cytokines have been detected in elevated concentrations in the amniotic fluid and plasma of women with preterm labor and human gestational tissues are potentially rich sources of inflammatory cytokines [15]. These cytokines can be induced by a number of stimuli, including bacterial endotoxins, and they have been shown to promote spontaneous labor and rupture of membranes via their actions on the gestational tissues [16–18]. Several studies have reported altered levels of CYP27b1 in placentas from preeclampsia pregnancies [19, 20]. Furthermore, in a recent nested case-control study of pregnant women Bodnar and colleagues showed that vitamin D deficiency significantly increases the risk of preeclampsia [1]. This coupled with evidence of the prevalence of vitamin D insufficiency in pregnant mothers – particularly African-American mothers [1] – has supported a role for vitamin D sufficiency in protecting against this prevalent complication 99 CHANDER P. ARORA, HOBEL C. J. of pregnancy [21]. There was no significantly altered expression of vitamin D receptor (VDR) or CYP27b1 in pregnancies with intrauterine growth restriction (IUGR) [22]. More recent studies of vitamin D insufficiency during pregnancy and lactation have served to underline the magnitude of the problem [1, 3, 4, 23, 24]. Our research group recently reported vitamin D deficiency in a cohort study of spontaneous preterm pregnancies (N = 27) compared to matched case controls (N = 32) in an NIH Behavior In Pregnancy Study (BIPS). In the study, serum samples were collected in 528 ethnically diverse women at 18–20 weeks (T1), 28–30 weeks (T2) and 34–36 weeks (T3). The results indicated deficient vitamin D status in the subjects who delivered preterm (PTB group) but sufficient vitamin D levels in controls at all three visits. We assessed the involvement of vitamin D in the occurrence of IL-6 levels in women with spontaneous preterm birth. At all three time intervals, significantly higher levels of IL-6 were associated with the preterm birth cases as compared to the controls [25]. Significantly higher levels of this pro-inflammatory cytokine, IL-6 were found in subjects with IUGR as compared with controls. This also correlated with lower serum vitamin D levels in this cohort. It is possible that a non-infectious inflammatory response is activated by vitamin D deficiency that is a marker of risk for or causative in preterm birth or development of IUGR [26]. Racial disparity in vitamin D synthesis. Since the most important source of vitamin D is the skin’s synthesis of the vitamin from UVB solar radiation [27]. Any process that reduces UVB photons from entering the epidermis will diminish cholecalciferol (vitamin D3) production. The skin pigment melanin absorbs UVB photons and can reduce vitamin D3 synthesis by 90 % [28]. Consequently, African Americans are at high risk of vitamin D deficiency. According to CDC, 42 % of African-American women in US between the ages of 15–49 years are deficient in vitamin D (less than 20 ng per milliliter of serum levels) [29]. Nevertheless, it is also clear that some groups are more at risk of vitamin D insufficiency than others. The 1988–1994 National Health and Nutrition Examination Survey revealed that 42 % of AfricanAmerican women of child-bearing age had 25(OH)D3 100 levels that were lower than 50 nmol/l, half the current optimal target level. This compares with only 4 % of white women [23]. We recently reported vitamin deficiency in cohort study of African-American pregnancies compared to Caucasians. Although the cohort used had women who delivered at term, the levels of 25(OH)D3 in Caucasians were significantly lower in the subjects with infection than the ones without (p < .001). Women with vitamin D insufficiency in the second trimester were more likely to develop infection during pregnancy but not subjects with sufficient vitamin D at T1. The proportion of infection percent in the Caucasian and AfricanAmerican groups was significantly different at all the time periods as well as their levels of 25(OH)D3. African Americans show a trend to have higher proportion of infections than the Caucasian group at all three visits and had significantly lower 25(OH)D3 (p < .001) at these visits [30]. Our results reveal a positive association between 25(OH)D3 concentrations and elevated risk of infection [31]. Vitamin D insufficiency may, therefore be involved in the pathogenesis of maternal infection during pregnancy. Vitamin D levels could modulate this infection susceptibility during pregnancy. In another study, approximately 29 % of Black pregnant women and 5 % of white pregnant women residing in the northeastern United States had vitamin D deficiency, i. e. serum 25(OH)D3 of less than 50 nmol/l, whereas 54 % of Black women and 47 % of white women had serum 25(OH)D3 levels indicative of vitamin D insufficiency, i. e. 25(OH)D3 of 50–75 nmol/l [1]. Immunomodulation by vitamin D. Recently vitamin D deficiency and even insufficiency has become a worldwide issue affecting the populations across the globe. The broader implications of vitamin D restrictions especially with the growing trend of sun-blocks, have become more evident. Vitamin D status has been found to be a major contributing factor to immune response [32]. Precisely, the active form of vitamin D, 1,25(OH)2D3 has been shown to be the key modulator of immune responses [33, 34]. The degree to which inflammatory pathways play a role in labors that are not associated with clinical signs of infection is unknown, however even normal labor shares certain characteristics with inflammatory processes. VITAMIN D – A NOVEL ROLE IN PREGNANCY Fig. 3. Macrophage cells respond to bacterial cell walls by manufacturing both VDR proteins and the enzyme (1-OHase) that converts circulating 25(OH)D 3 into the biologically active 1,25(OH)2D 3. These events induced the immune cells to start producing cathelicidin that demonstrates antimicrobial activity against a variety of bacteria Liu [35] substantially advanced this line of investigation by showing that human immune cells respond to infection by manufacturing both vitamin D receptor proteins and the enzyme that converts circulating 25(OH)D3 into the biologically active 1,25(OH)2D3 and to induce the immune cells to start producing cathelicidin. Cathelicidin, the naturally produced antimicrobial agent that acts against a variety of bacteria, explaining the tuberculosis sunshine cure: the sun-soaked skin could boost their immune cells to generate the natural antibiotic that fought off the tuberculosis bacteria (TB) (Fig. 3). In particular, the active form of vitamin D, 1,25(OH)2D3 has been shown to be a key modulator of immune responses [36, 37]. Both the receptor for 1,25(OH)2D3, VDR [36, 38] and the enzyme that catalyzes the synthesis of 1,25(OH)2D3 from precursor 25(OH)D, CYP27b1 [39, 40] are abundantly expressed by cells from the immune system. The presence of CYP27b1 in macrophages [41] and dendritic cells [42] indicates that local (autocrine 25(OH)D3 or paracrine) synthesis of 1,25(OH)2D3 is a pivotal feature of vitamin D action within the immune system. Placental production of vitamin D. The placenta was one of the first extra-renal sites shown to synthesize 1,25(OH)2D3 from 25(OH)D3 [43, 44]. Organiza- tion of 1a-hydroxylase, the enzyme needed to convert 25(OH)D3 to the active form is localized both in maternal decidua and fetal trophoblasts and is more abundant in first and second trimester. We detected highest levels of 25(OH)D3 at 18–20 weeks of pregnancy in the study as well as control group. This could also be due to the presence of VDR in the placenta as has been suggested by Bruns and Bruns [45]. This means that vitamin D functions in an autocrine fashion at the fetal-maternal interface [45]. One possible explanation is that 1,25(OH)2D3 functions as a regulator of placental calcium transport in addition to an immunomodulatory function [46]. From the studies highlighting immunological function of the heterogeneous cells that make up the placenta, maternal and fetal cells are able to mediate innate [47, 48] and adaptive [49, 50] immune responses. Furthermore, a series of studies using human placentas [11, 22] have demonstrated the expression of CYP27b1 (gene for producing the enzyme 1a-hydroxylase) in decidua (maternal tissue) and trophoblast (fetal tissue) [11, 22]. Within deciduas, CYP27b1 is expressed by both stromal cells and macrophages, while in trophoblasts CYP27b1 is localized predominantly in the syncytiotrophoblast (the cells that form the barrier between maternal and fetal blood) [22]. In primary cultures of human decidual cells, both 1,25(OH)2D3 and 25(OH)D3 (the latter metabolized endogenously to 1,25(OH)2D3) induced expression of antimicrobial cathelcidin, but suppressed the inflammatory cytokine production [32]. Within the decidua, the gene expression for this enzyme (CYP27b1) was identified in decidual stromal cells as well as the decidual macrophages, suggesting a possible immunomodulatory function for localized synthesis of 1,25(OH)2D3 [11, 22]. Vitamin D appears to be the trigger for antibacterial/anti-inflammatory responses in decidual and trophoblastic cells. Analysis of decidual cells in vitro has endorsed a possible role for 25(OH)D3 and 1,25(OH)2D3 as modulators of immune responses in maternal tissue [32]. Human decidual cells from 1st trimester placentas incubated for 24 hrs with 25(OH)D3 or 1,25(OH)2D3 showed induction of cathelicidin and suppression of cytokines such as IL-1, TNFa and IL-4 [32]. The fact that a physiological dose of 25(OH)D3 (100 nmol/l) was as ef101 CHANDER P. ARORA, HOBEL C. J. fective as a pharmacological dose of 1,25(OH)2D3 (100 nmol/l), underlines the importance of localized (placental) versus endocrine (systemic) synthesis of 1,25(OH)2D3. Using primary human placental tissue and trophoblastic cells it has been shown that the fetal side of the placenta also induces cathelicidin-mediated antibacterial response to treatment with vitamin D metabolites. Collectively these data indicate that exogenous 1,25(OH)2D3 or locally metabolized 25(OH)D3 are capable of inducing anti-bacterial and anti-inflammatory responses in both the maternal and fetal components of the placenta [22]. In addition to stromal and trophoblastic cells, the placenta is made up of an array of leukocytes that are fundamental to the immunology of gestation. It has been shown that the most abundant of the decidual immune cells, uNK, do not express CYP27b1 [22] but are potential targets for paracrine responses to 1,25(OH)2D3 synthesized by stromal cells or macrophages. By contrast, decidual macrophages express abundant levels of CYP27b1 and may therefore support the same autocrine vitamin D-induced innate immunity demonstrated in peripheral blood-derived macrophage ... Purchase answer to see full attachment