JOURNAL OF PATHOLOGY,

MICROBIOLOGY AND IMMUNOLOGY

APMIS 127: 681–687 © 2019 APMIS. Published by John Wiley & Sons Ltd.
DOI 10.1111/apm.12982

Effect of single-dose injection of vitamin D on immune

cytokines in ulcerative colitis patients: a randomized
placebo-controlled trial

AMROLLAH SHARIFI,1 HOMAYOON VAHEDI,2 SAHARNAZ NEDJAT,3 HOSSEIN RAFIEI4 and

MOHAMMAD JAVAD HOSSEINZADEH-ATTAR5
1
Golestan Research Center of Gastroenterology and Hepatology (GRCGH), Faculty of Health, Golestan
University of Medical Sciences (GOUMS), Gorgan; 2Digestive Disease Research Center, Digestive Research
Institute, Shariati Hospital; 3Epidemiology and Biostatistics Department, School of Public Health, Tehran
University of Medical Sciences, Tehran, Iran; 4Faculty of Health and Social Development, College of Health
and Exercise Sciences, University of British Columbia Okanagan, Kelowna, BC, Canada; and 5Department of
Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences,
Tehran, Iran

Sharifi A, Vahedi H, Nedjat S, Rafiei H, Hosseinzadeh-Attar MJ. Effect of single-dose injection of vitamin D on
immune cytokines in ulcerative colitis patients: a randomized placebo-controlled trial. APMIS 2019; 127: 681–687.
Ulcerative colitis (UC) is a chronic recurrent inflammation of the colon. It has been proposed that the UC pathogenesis
may be related to vitamin D deficiency and/or vitamin D administration in UC patients may have an ameliorating effect
on the intestinal inflammation. The aim of this study was to assess the effect of vitamin D on the serum levels of immune
cytokines in UC patients. In this double-blind randomized controlled trial, 90 mild-to-moderate UC patients were assigned
to get either a single muscular injection of 7.5 mg vitamin D3 or 1 mL normal saline as placebo. Three months later serum
levels of IL-4, IL-10, IL-12p70, IFN-c, and TNF-a were measured. Two group variables were compared using independent
t-test and analysis of covariance (ANCOVA). There was a significant increase in vitamin D only in the vitamin D group.
Compared to placebo, vitamin D had significant decreasing effects on serum TNF-a, IFN-c, and IL12p70 levels, but it had
no significant effect on serum levels of IL4 and IL10. Vitamin D seems to inhibit Th1 immune responses and have no effect
on Th2 responses. The findings of this study support several in vitro studies, which suggest a therapeutic immunomodula-
tory potential of vitamin D.
Key words: Vitamin D; ulcerative colitis; inflammation; immunity; interleukin.
Mohammad Javad Hosseinzadeh-Attar, Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics,
Tehran University of Medical Sciences, No: 44, Hojjat-dost Alley, Naderi St., Keshavarz Blvd, Tehran, Iran.
e-mails: mhosseinzadeh@tums.ac.ir; hosseinzadeh.md.phd@gmail.com

Ulcerative colitis (UC) and Crohn’s disease (CD)
are two forms of inflammatory bowel disease
(IBD). UC is a chronic recurrent superficial inflam-
mation of the large intestine that begins in the rec-
tum and may extend proximally toward the
terminal ileum (1). The annual incidence rate of
UC is 1.2–20.3 per 100 000, and its prevalence is
7.6–246 per 100 000, mostly in the developed coun-
tries (2). However, over recent decades, a trend
change in the incidence of IBD has been indicated
(4). There is evidence that IBD incidence is
Received 26 March 2019. Accepted 1 July 2019
increasing in Asian countries (4). Although some of
these increases may be because of improvement in
diagnostic methods, there is still a need to pay
attention to the role of changes in the various envi-
ronmental factors including the diet patterns and
nutrition transition in developing countries (3–5).
The pathogenesis of IBD is complex, and its con-
tributing factors are not still well understood.
According to the twin studies, the concordance rate
for IBD between identical twins is between 20 and
50 percent, which indicates that environmental fac-
tors have an important role in the pathogenesis of
IBD (6). It seems that the interaction between

681
 SHARIFI et al.
genetic and environmental factors lead to abnormal
activation of the immune system (7, 8), which
results in overproduction of pro-inflammatory
cytokines such as interferon gamma (IFN-c) and
tumor necrosis factor alpha (TNF-a) (8, 9).
Vitamin D, the fat-soluble vitamin, is well known
for its role in the regulation of calcium and bone
homeostasis. Vitamin D in the body and in the diet
comprises vitamin D2 and vitamin D3. Most body
stores are vitamin D3, which is mainly synthesized
by the skin under direct action of sunlight. A small
part of vitamin D is obtained from the diet, which
is mainly obtained from seafood, fish oil, or supple-
ments (10). Vitamin D deficiency is common and
affects an estimated one billion people worldwide
(11). IBD patients are prone to vitamin D intestinal
malabsorption (12). Furthermore, vitamin D defi-
ciency is thought to have an implication in the
pathogenesis of immune-mediated diseases includ-
ing IBD (12–15). However, the underlying mecha-
nisms are still unknown.
Many experimental studies have implicated cal-
citriol (the active form of vitamin D) and vitamin
D receptor (VDR) in IBD (16, 17). VDR has a role
in maintaining the integrity of the intestinal muco-
sal barrier (18), and it has been demonstrated that
mucosal VDR proteins are lower in ulcerative coli-
tis patients compared to healthy individuals (19). A
VDR knockout murine model has been associated
with spontaneous colitis (20).
We have previously shown that vitamin D defi-
ciency in UC patients is common (21), and vitamin
D administration leads to a decrease in inflamma-
tion in patients with ulcerative colitis (22). There-
fore, to clarify the possible mechanisms, we
investigated the effect of vitamin D administration
on the serum levels of some inflammatory or regu-
latory processes in mild-to-moderate UC patients.
MATERIALS AND METHODS
This study was a parallel designed double-blind
randomized controlled trial. The methods and
materials have been explained in detail before (22).
Considering 80% power, using a 2-sided test, at the
5% significance level and expecting 5% loss to fol-
low-up, a total sample size of 90 patients was calcu-
lated. To conduct the study, 165 patients were
invited consecutively based on the pre-provided reg-
istry list of UC patients, between December 2014
and January 2015; of which 39 persons declined to
participate and 36 persons did not meet the inclu-
sion criteria (age between 18 and 50 years; body
mass index (BMI) between 18.5 and 30 kg/m2; Not
taking anti-TNF-alpha therapy, and any form of
682
vitamin D3 supplement in the 3 months preceding
the study; without the history of hyperparathy-
roidism, nephrolithiasis, malignancy, or renal or
hepatic failure). Pregnant and breastfeeding women
were not also included. All the patients were previ-
ously diagnosed for UC by the standard clinical,
endoscopic, radiographic, and histopathologic crite-
ria and were not at the relapse phase. Finally,
ninety UC patients were randomized using stratified
blocked randomization method, in which the strata
were based on age (equal or lower than 35 years/
higher than 35 years) and BMI (equal or lower
than 25/higher than 25 kg/m2) with blocks of 4.
Each patient received a single muscular injection
of 300 000 IU vitamin D3 (Vitamin D group) or
1 mL sterile normal saline (Placebo group). Investi-
gators and participants were blinded to allocation.
The staff who did the injections were not involved
in the data collection.
At baseline and 90 days following the interven-
tion, blood samples were taken, sera were separated
and measurements were done.
Previously, 25(OH)D3, hs-CRP, parathyroid hor-
mone (PTH), calcium (Ca), and erythrocyte sedi-
mentation rate (ESR) levels had been obtained.
Serum levels of interleukin 4 (IL-4), IL-10, IL-
12p70, IFN-c, and TNF-a were also measured
using commercial ELISA kits (Bioassay Technol-
ogy, Shanghai, China).
Statistical analyses were performed using STATA
version 14 (Stata Statistical Software, College Sta-
tion, TX, USA). The results are expressed as
mean  standard deviation (SD). Independent t-
test was done to compare the normally distributed
data. Analyses of covariance (ANCOVA) were
done for the adjustment of the baseline values of
each variable.
Ethical considerations
The study was approved by Tehran University of
Medical Sciences Ethics Committee, and written
informed consent was obtained from all partici-
pants before enrollment. This study protocol was
registered at the Iranian Registry of Clinical Trials
(IRCT): IRCT2014062318207N1.
RESULTS
Data of 86 participants (40 patients in the placebo
group, and 46 patients in the vitamin D group)
were available; four patients in the placebo group
declined to complete the study. The CONSORT
flow diagram of the trial is presented in Fig. 1.
As has been reported before, the baseline values
of vitamin D, calcium, parathormone (PTH), hs-
© 2019 APMIS. Published by John Wiley & Sons Ltd
 VITAMIN D & IMMUNE CYTOKINES IN UC

CRP, erythrocyte sedimentation rate (ESR), total

Assessed for eligibility = 165
calorie intake and macronutrient composition, age,
duration of UC disease, systolic and diastolic blood
Not meeng inclusion criteria = 36
pressure, body mass index (BMI), heart rate, and
body temperature were not statistically different
Declined to parcipate = 39
between the two groups. Drug regimen and gender
proportion were also comparable (22).
Randomized = 90 At baseline, mean serum concentrations of 25
(OH)D3 of vitamin D and placebo groups were
33.3  7.0 vs 32.9  9.6 ng/mL, respectively,
Received vitamin D = 46 Received placebo = 44 (p = 0.82) and 3 months after the intervention,
serum vitamin D levels raised only in the vitamin D
group which was significantly higher than the pla-
Lost to follow-up = 0 Lost to follow-up = 4 cebo group (40.8  5.2 and 33.9  10.6, respec-
tively, p < 0.001) (22).
First, we used independent sample t-test to com-
Analyzed = 46 Analyzed = 40 pare two groups for serum levels of IL-4, IL-10,
IL-12p70, IFN-c, and TNF-a, which showed no
significant differences between the two groups.
Fig. 1. CONSORT flow diagram of the study. (Figs 2 and 3).

Fig. 2. Baseline and end line values of IL-4, IL-10, IL12p70, and IFN-c in vitamin D and placebo groups. Independent
sample t-test showed no statistical differences between the two groups.

© 2019 APMIS. Published by John Wiley & Sons Ltd 683

 SHARIFI et al.

DISCUSSION

Vitamin D has been linked to a number of autoim-

Fig. 3. Baseline and end line values of TNF-a in vitamin
D and placebo groups. Independent sample t-test showed
no statistical differences between the two groups.
Afterward, analysis of covariance (ANCOVA)
was applied for adjusting of potential confounders
while comparing variables. In model 1 of
ANCOVA, only baseline values of each variable
was considered as the confounder (Table 1), while
in model 2 baseline values of each variable, baseline
BMI (body mass index), disease duration, age, gen-
der, and baseline vitamin D levels were adjusted
(Table 2). In either model, vitamin D had signifi-
cant decreasing effects on serum TNF-a, IFN-c,
and IL12p70 levels, but it had no significant effect
on serum levels of IL4 and IL10 (Tables 1 and 2).
mune diseases such as multiple sclerosis and diabetes
mellitus (23). Many observational and experimental
studies have implicated vitamin D in IBD (16). For
example, VDR proteins are considerably lower in
the gut mucosa of ulcerative UC patients compared
to healthy individuals (19). In addition, the lack of
vitamin D interrupts the T-cell-mediated immune
responses; which at high doses of vitamin D, the
immune responses would return (6). Activated T
cells, macrophages, and other immune cells express
VDR (24), and it has been shown that vitamin D
regulates the immune system via the VDR (25).
In this study, we showed that vitamin D supple-
mentation in mild-to-moderate UC patients
decreases the inflammatory cytokines IL-12p70,
IFN-c, and TNF-a, but it has no effect on the cir-
culatory levels of IL-4 and IL-10.
Previously, we showed that vitamin D decreases
ESR and hs-CRP, the non-specific markers of
inflammation, in these patients. Here, the possible
mechanisms have been shown, that seems to be the
Th1 pathway that is IL-12, IFN-c and eventually
the cascades which leads to the increase of TNF-a.
There is evidence that calcitriol, the active form of
vitamin D, directly inhibits T-cell proliferation (26)
and the expression of the inflammation stimulatory
markers (27). For example, some in vitro studies have
shown that calcitriol inhibits the development of Th1

Table 1. ANCOVA Model 1; to compare cytokines between vitamin D and placebo groups adjusting for each variable’s
baseline levels
Variable Vitamin D group (ng/mL) Placebo group (ng/mL) P (ANCOVA)
IL4 Baseline 10.74  3.54 11.20  5.28 0.08
End line 11.33  4.24 10.45  4.63
IL10 Baseline 5.97  3.72 5.58  4.43 0.34
End line 4.69  3.88 5.09  4.45
IL12p70 Baseline 3.58  2.61 3.40  2.95 0.003
End line 2.72  2.49 3.60  2.87
IFN-c Baseline 4.77  4.43 4.87  4.18 < 0.001
End line 3.74  3.52 5.14  4.51
TNF-a Baseline 8.75  8.46 8.01  7.14 < 0.001
End line 6.45  6.79 8.84  8.59

Table 2. ANCOVA Model 2; to compare cytokines between vitamin D and placebo groups adjusting for background
variables
Variable P (baseline BMIs) P (disease duration) P (age) P (gender) P (baseline vitamin D) P (allocation)
IL-4 0.49 0.64 0.064 0.006 0.74 0.18
IL-10 0.87 0.37 0.11 0.024 0.15 0.52
IL-12p70 0.046 0.68 0.33 0.42 0.28 0.001
IFN-c 0.25 0.97 0.47 0.41 0.87 <0.001
TNF-a 0.28 0.15 0.17 0.44 0.86 0.001
ANCOVA Model 2; Compare of immune cytokines adjusting for baseline BMIs, disease duration, age, gender, and base-
line vitamin D levels of the patients. Significant differences were seen in IL12p70, IFN-c and TNF-a (in bold).

684 © 2019 APMIS. Published by John Wiley & Sons Ltd

 VITAMIN D & IMMUNE CYTOKINES IN UC
cells and downregulates pro-inflammatory cytokines
including IFN-c, the indicator of Th1 cell develop-
ment (25, 28–30). Furthermore, evidence shows that
vitamin D cultured dendritic cells have tolerogenic
properties, which in the reaction mixture with lym-
phocyte demonstrated a limited IFN-c production
(27, 31, 32).
In another in vivo study, calcitriol alone and in
combination with dexamethasone was effective in
both preventing severe colitis and ameliorating clin-
ical severity if given in established model of colitis.
It downregulated Th1 and upregulated Th2
responses that is it reduced IL12, TNF-a, and IFN-
a, but increased IL4 which shifts the T-cell differen-
tiation toward Th2 (33).
Consistent with these observations, we showed
that vitamin D decreased IFN-c and TNF-a, which
reflects diminish in T-cells differentiation to Th1
and/or downregulation of inflammatory pathways
in the Th1 cells. In addition, our study showed that
vitamin D increases IL12, a potent stimulatory
cytokine which shifts the T-cell differentiation
toward IFN-c producing Th1 cells.
Calcitriol has been demonstrated to downregu-
late IL12 (34) while inhibiting Th1 pathways by
both downregulating IL-12 production and block-
ing IFN-gamma synthesis by Th1 T cells, and even-
tually decreasing the production of TNF-a (35).
The ability of vitamin D to diminish this pathway,
especially its crucial role in the reduction of TNF-a
is clinically important.
TNF-a has a key role in the pathogenesis and
clinical manifestations of IBD. Anti-TNF-a therapy
in most IBD patients in relapse phase induces the
remission and improves quality of life. It has been
suggested that vitamin D increase the chance of
response to anti-TNF-a therapy by suppressing the
expression of TNF-a-related genes in the gut (36).
KH 1060, an analog of vitamin D, decreased TNF-
a levels in PBMC culture drown from IBD patients
(37). This potential effect of vitamin D was
endorsed by Kuo YT et al. (38), which showed that
calcitriol suppressed TNF-a and Th1-related cytoki-
nes in LPS-stimulated THP-1 cells and human pri-
mary monocytes.
Conversely, we did not see significant alterations in
the IL4 and IL10 levels. Nevertheless, it has been
shown in vitro that interleukin 10, the regulatory cyto-
kine produced predominantly by regulatory T cells (T-
reg cells), along with vitamin D play an essential role
in the modulation of the immune system (39, 40).
For example, vitamin D deficient interleukin 10
knockout (IL10-KO) mice developed an accelerated
form of enterocolitis, while vitamin-D-deficient
wild-type mice did not develop enterocolitis. When
dietary vitamin D or calcitriol was given to the
© 2019 APMIS. Published by John Wiley & Sons Ltd
vitamin D deficient IL10-KO mice enterocolitis did
not develop (41). Furthermore, calcitriol has a stim-
ulatory role in the production of T-reg cells
expressing potent anti-inflammatory components
such as IL-10 (27, 30, 33, 42). In turn, IL-10
induces regulatory T cells and strongly inhibits pro-
duction of pro-inflammatory chemokines, such as
IFN-c, TNF-alpha, and NF kappa beta (43, 44).
There were some limitations in our study; first,
we did not screen patients for baseline vitamin D
that is the patients were included even they were
not vitamin D deficient. Second, only patients in
the remission phase were included, the condition
that is basically with considerably lower inflamma-
tory status compared to those in relapse phase.
Therefore, we suggest conducting a similar study in
vitamin D deficient patients in the relapse phase
using different doses of vitamin D.
Both CRP and ESR values reflect clinical disease
activity, however, CRP is more correlated with endo-
scopic appearance (45). Previously we showed that
vitamin D decreased both ESR and hs-CRP in these
patients (22). CRP is a marker of global inflamma-
tion, and its production by the liver is being induced
by many factors such as TNF-a (46). Therefore the
reduction in ESR and CRP in these patients seems to
be a response to the reduction of upstream pro-in-
flammatory cytokines in particular TNF-a.
As best as we know, this study is the first random-
ized placebo-controlled trial which has been con-
ducted to assess the effect of vitamin D on the
immune responses in ulcerative colitis patients. Also,
the only RCT with a good quality examined the effect
of vitamin D3 in the maintaining of remission in
Crohn’s disease for 12 months, in which, it was
reported a non-significant reduction of relapse rate in
the vitamin D group (13% vs 29%, p = 0.06) (47).
In conclusion, vitamin D appears to inhibit Th1
immune responses, and have no effect on Th2
responses. The findings of this study support sev-
eral in vitro studies, which demonstrate evidence of
the therapeutic immunomodulatory potential of
vitamin D.
This work was supported by Tehran University of Medi-
cal Sciences and Health Services grant (No. 27089).
CONFLICT OF INTEREST
None.
AUTHORS’ CONTRIBUTIONS
Amrollah Sharifi: literature search; the conception
and design of the study; carry out the study;
685
 SHARIFI et al.
acquisition, statistical analysis, and interpretation
of the data; drafting the manuscript; final approval
of the version to be submitted. Homayoon Vahedi:
acquisition of the data; revising the manuscript crit-
ically for important intellectual content; final
approval of the version to be submitted. Saharnaz
Nedjat: design of the study; interpretation of data;
revising the manuscript critically for important
intellectual content; final approval of the version to
be submitted; clinical supervision. Hossein Rafiei:
acquisition of the data; interpretation of data;
revising the manuscript critically for important
intellectual content; final approval of the version to
be submitted. Mohammad Javad Hosseinzadeh-
Attar: design of the study; interpretation of data;
revising the manuscript critically for important
intellectual content; final approval of the version to
be submitted.
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