Research J. Pharm. and Tech.

13(2): February 2020

ISSN 0974-3618 (Print) www.rjptonline.org

0974-360X (Online)

RESEARCH ARTICLE

Immunomodulatory effect of Standardized Polysaccharide Fraction syrup

from Noni fruit (Morinda citrifolia) on Cytokines level (IL-2 and IFN-γ) and
Its Histological Evaluation in rats Vaccinated with Hepatitis-B
Indra Yudhawan1, Ediati S2, Ika Puspitasari3
1
Student of Postgraduate Program, Master Program of Pharmaceutical Sciences and Technology, Faculty of
Pharmacy, Universitas Gadjah Mada, Sekip Utara, Yogyakarta 55281, Indonesia.
2
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universitas Gadjah Mada, Sekip Utara,
Yogyakarta 55281, Indonesia.
3
Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Gadjah Mada, Sekip
Utara, Yogyakarta 55281, Indonesia.
*Corresponding Author E-mail: ika.puspitasari@gmail.com
ABSTRACT:
Polysaccharide is widely distributed around the world and rapidly garnered attention in biotechnology. Noni fruit
(Morinda citrifolia) has been acknowledged for its usefulness in promoting health, and this natural
polysaccharide is relatively safe compared to another source like bacteria or synthesis1,2. In the previous study,
SPF syrup formula, which can increase the activity of macrophages and lymphocyte proliferation, had been
successfully developed3. Therefore, it is necessary to elucidate the molecular mechanism of Standardized
Polysaccharide Fraction (SPF) syrup on related cytokines (IL-2 and IFN-γ) and its safety by evaluating the
histology of spleen and skin allergy potency. The SPF syrup is prepared according to the previous research
method3,4. Wistar rats aged 9-10 weeks were used in this study. SPF syrup was given in 3 different dosages (25,
50 and 100 mg/kg body weight). Cytokines level was evaluated using FineTest® ELISA kit. Hematoxylin-eosin
stain was used for spleen histology, while toluidine blue stain was used to evaluate skin allergy potency
mediated by mast cell degranulation. Results indicated that SPF syrup dosage 100 mg/kg body weight can
modulate cytokines by increasing IFN-γ level. There is a decreasing tendency for IL-2 level, although not
statistically significant. Histological evaluation showed that SPF syrup was safe to use based on histology of rat
spleen organ and skin allergy potency mediated by mast cell degranulation.

KEYWORDS: SPF Syrup, Morinda citrifolia, IL-2, IFN-γ, Spleen Histology, Mast Cell Degranulation

INTRODUCTION: This pathophysiological state can be corrected by a

The immune system is a connection between cells,
tissues and organs that work together to protect the body
from outside attacks. This system is a complex
interaction of biochemical components and cellular
dynamics. The dynamics in the immune system
homeostasis are influenced by various exogenous and
endogenous factors which can cause pathophysiological
conditions.
Received on 28.08.2019 Modified on 11.10.2019
Accepted on 11.11.2019 © RJPT All right reserved
Research J. Pharm. and Tech 2020; 13(2):882-888.
DOI: 10.5958/0974-360X.2020.00167.5
882
substance called immunomodulator. The restorative and
rejuvenating nature of immunomodulators can overcome
the body's defense system in fighting diseases.
Immunomodulators can act as a stimulator by increasing
the immune response (immunostimulant), suppressing
an immune response (immunosuppressant), or increase
the efficacy of a vaccine (immunoadjuvant)1.
Polysaccharide is one example of compounds that can
affect the immune system. Polysaccharide is a polymer
of sugar units. It occurs as storage polysaccharides and
structural polysaccharides5. Polysaccharide, as a primary
metabolite, widely distributed around the world and can
 Research J. Pharm. and Tech. 13(2): February 2020
be collected from various plants and animals. Compared
to the amount of secondary metabolite in the plant, the
source of polysaccharide is abundant. For the past 20
years, polysaccharide rapidly garnered attention,
especially on the variety of its use in biotechnology1,2.
Various studies show that polysaccharides have the
activity in modifying the immune system.
Polysaccharides were able to modulate certain
components of the immune system, by both direct and
indirect effect. One theoretical concept that supports
polysaccharide activity in the immune system is its
ability to influence lymphocyte proliferation and the
activity of macrophages. Activity on macrophages and
lymphocytes is affected by cytokines. Previous research
has proven that polysaccharides contained in noni can
affect lymphocyte proliferation, activity of macrophages
and also cytokines3,6–8. Some examples of cytokines that
have a direct relationship with lymphocytes and
macrophages are IL-2 and IFN-γ. Several
polysaccharides have been known to influence the
activity of macrophages by several mechanisms and in
various signaling pathways, resulting in the modulation
of cytokines. However, few research has focused on the
structure/class of polysaccharides and their principles of
action9.
Many kinds of research have been conducted to evaluate
polysaccharide activity in the immune system. From all
of them, Ediati has been developing noni fruit
polysaccharide and obtain polysaccharide-rich syrup that
has been standardized and could enhance lymphocyte
proliferation3. Noni fruit (Morinda citrifolia) has been
acknowledged for its efficacy and usefulness in
promoting health. Noni fruit contains up to 90% water,
with solid components were formed by fibers, metal,
and protein/amino acids such as glutamic acid or
isoleucine10,11. Noni fruit also contains terpenoids, fat,
alkaloid, phenolic12,13, anthraquinone, scopoletin, α- and
β-glucopyranose, iridoid glycoside14–16, and of course
polysaccharide6,17,18.
Efficacy is an important aspect of a quality drug. Also,
an equally important aspect is safety or toxicity. Most of
the polysaccharides derived from plants are reported to
have much better safety compared to polysaccharides
from other sources (fungi, synthesis, etc.). In addition,
there are no known side effects/allergies that occurred as
a result of polysaccharides consumption. This is an
important factor to note in order to support the quality of
drugs affecting the immune system.
Ediati’s finding is a significant progress in getting a
standardized herbal syrup drug. Recently a Standardized
Polysaccharide Fraction (SPF) syrup formula that could
increase lymphocyte proliferation, has a stable physical
properties, stable under influence of extreme
883
temperature changes and fulfill microbial contamination
parameter has been successfully made and published3.
Therefore, evaluating its molecular mechanism is
necessary. This study aims to elucidate Standardized-
Polysaccharide Fraction (SPF) syrup
immunomodulatory mechanism by evaluating cytokines
affecting macrophages and lymphocytes (IL-2 and IFN-
γ) and its safety by evaluating the histology of spleen
and skin allergy potency mediated by mast cell
degranulation.
MATERIALS AND METHODS:
Samples:
The SPF syrup was a grant from Prof. Ediati from the
research in 2017. SPF syrup is a standardized noni fruit
syrup with various non-specific and specific
standardization parameter, with 5% glucose as a
marker4.
Experiment:
Wistar rats aged 9-10 weeks having a weight range of
150-200 g were used in this study. They were obtained
from local breeding in the Department of Pharmacology
and Clinical Pharmacy, Faculty of Pharmacy,
Universitas Gadjah Mada. Rats were divided into 5
groups consisting of 5 rats. Groups 1 (K1) as a negative
control (SPF vehicle), Group 2 (K2) as normal control
(SPF syrup vehicle + vaccination), group 3-5 (K3-5) as a
test group (SPF syrup + vaccination). Rats were placed
in the cage and adapted to the environment for 7 days.
Food and water were given ad libitum. At days 8 – 33
SPF syrup was given to rats in 3 different dosages
(group 3,4,5; 25, 50 and 100 mg/kg body weight). Rats
were vaccinated every 7 days (day 8, 15 and 22). Days
31 blood was taken from the eye vein and collected for
ELISA assay. Rat dissected in days 33, spleen and skin
were harvested and persevered in 10% formalin for
histological evaluation purpose.
ELISA Assay:
Blood was centrifugated at 3000 rpm for 30 minutes.
Supernatant isolated and used as assay samples or stored
at -20°C for 3 months or -80°C or 1 year until use.
Cytokines level (IL-2 and IFN-γ) was evaluated using
IL-2 and IFN-γ ELISA kit (Fine Test), using method as
described in the ELISA kit protocol19,20.
Histology of Spleen:
Spleen safety was evaluated by histology of spleen
organ with hematoxylin-eosin staining. The spleen was
dissected, deparaffinated with xylene, hydrated with
water, and nuclear staining with hematoxylin.
Differentiation with acid alcohol, bluing with ammonia
water and counterstaining with eosin, and dehydrated,
and also cleared with xylene. After fixation, the sample
was analyzed under the microscope with 400x
magnification.
 Research J. Pharm. and Tech. 13(2): February 2020

Histology of Skin Mast Cell: 48 hours of the infection phase and can decrease again
Skin allergy potency was evaluated by counting mas cell within a matter of hours25.
degranulation on the dermal layer zone with Toluidine
Blue staining. The skin was deparaffinized/dewaxed,
stained with toluidine blue for 30’ at 37 °C. The section
was differentiated until the background was clear,
dehydrated, and fixated for analysis. Samples were
analyzed under the microscope with 400x magnitude
and 5 fields of view. Intact mast cells in the dermal layer
were calculated for analysis.

RESULTS AND DISCUSSION:

Noni fruit is a well-known herb as a good herb for
promoting human health. It is also a good and potential
herb with immunomodulatory activity, especially its Figure 1. Effect of standardized polysaccharide fraction (SPF)
polysaccharide. This study aims to elucidate syrup from Morinda citrifolia on IL-2 levels. P-value was
immunomodulatory activity of Noni polysaccharide (as determined through ANOVA with α = 0.05.
SPF syrup) by evaluating its molecular mechanism in
cytokines affecting macrophages and lymphocytes (IL-2
and IFN-γ). A preliminary study about the safety of SPF
syrup on several organs needs to be conducted. In this
case, histological evaluation of spleen and evaluation of
skin allergy potency mediated by skin mast cell
degranulation were suitable.

Effect of SPF Syrup on Cytokines Level:

This study aims to evaluate the immunomodulatory
mechanism of SPF syrup in vivo on cytokines level (IL-
2 and IFN-γ). Rats were given a Hepatitis-B vaccine to
induce immune responses. Immunomodulatory
mechanism of SPF syrup evaluated based on the
increase or decrease of cytokines level compared to the
normal group (Vaccine + SPF Vehicle).
Hepatitis-B vaccine can induce immune responses by
increasing IL-2 level21 and indirectly modulate IFN-γ.
Changed on IFN-γ level caused by viruses mainly
mediated by type-I Interferon and NK (Natural Killer)
Cell. Normally, viral infection induces type-I Interferon
immune response and further induce NK cell to produce
IFN-γ22. For the record, IFN-γ level does not always
increase throughout the immune response period. The T
cell immune response caused by immunization is very
broad and complex, encompassing a much broader
spectrum instead of single cytokine measurements23.
There have been several reports in patients with acute
HBV infection who have decreased activity from NK
cells at the peak of viremia, as well as decreased IFN-γ
and TNF-α production in chronic HBV patients24.
Another factor is the dynamic homeostasis between IFN
(Interferons) type I and type II which work together
protecting the body and fight against pathogenic
infections over time. IFN types I and II levels will rise
and fall alternately according to their function in
defence. IFN-γ level, in particular, will increase before
884
Figure 2. Effect of standardized polysaccharide fraction (SPF)
syrup from Morinda citrifolia on IFN-γ levels. P-value was
determined through ANOVA and t-test with α = 0.05.
The results can be seen in Figure 1 (IL-2) and Figure 2
(IFN-γ). Administration of SPF syrup showed no
significant effect on IL-2 levels of the treatment group
(SPF syrup 25, 50 and 100 mg / kg body weight)
compared to the normal group. Although, there was a
tendency of decreasing IL-2 levels due to SPF syrup (the
levels of the treatment group were lower than the normal
group). There is a significant difference in IFN-γ levels
of the treatment group (SPF syrup dose 100 mg / kg
body weight) compared to the normal group. The graph
in Figure 2 shows a significant increase in IFN-γ levels
due to administration of 100 mg/kg body weight of SPF
syrup. Although, there were no significant differences in
IFN-γ levels in the administration of 25 and 50 mg / kg
body weight of SPF syrup. Further research can be
conducted in finding the optimal dose of SPF syrup that
can significantly modulate IL-2 levels.
Polysaccharides are complex combinations of various
saccharide compounds. Recent studies has shown a
better understanding of structural aspects of
polysaccharides, which is closely related to the
regulation of biological functions and regulation of
 Research J. Pharm. and Tech. 13(2): February 2020

cytokine systems/tissues therefore affecting the immune
system of certain organisms. Literature related to
polysaccharides are quite abundant and diverse, but it is
not enough to generalize the effects of polysaccharides
and the relationship between the composition/structure
of polysaccharides and the immune response9. Limited
information related to structural and mechanistic aspects
became a boundary on establishing further research of
polysaccharides, especially in their clinical use26,27.
Research related to the specific identity/marker
compounds from end products of polysaccharides that
are consumed orally is not widely known. Some
polysaccharide components such as arabinogalactan,
galactomannan, glucans (laminarin), glucomannan and a
mixture of polysaccharide products can be partially
degraded by human intestinal bacteria and further
interact with intestinal epithelium causing local effects,
as well as entering the blood vessels and causing
systemic effect. There were several recent studies on
finding of relationship between the bioconversion of a
polysaccharide/its bioavailability and the
downstream/further effects on host metabolism and
physiology using a metabolomic and metagenomic
approach26. Other research studying the function of
polysaccharides in the immune response related to the
microbes in human. The result indicates that other
factors can affect polysaccharides before they can
modulate the immune response. Mainly, they have
effects to the ecology of intestinal microbes, which can
further affect nutrition and the immune system 26. A
temporary conclusion that can be drawn is that the
mechanism essentially related to the complexity of the
digestive tract environment itself. Some studies also
show a relationship between the frequency of
polysaccharide consumption and loss of effect (the
effect of tolerance) or an increase in the effects of
polysaccharides on the immune system, either direct
effect to the immune system or indirect effect through
their activity on the body's probiotics.
Other research related to the connectivity architecture of
cytokines shows that immune cells do not work
individually / alone, but work collectively, integrated
and have a hierarchy. Connectivity between cytokines
and immune system cells is very rich and complex, not
only working in defence against pathogens but also
integrates maintaining the balance of the immune
system28.
Consistent with the previous findings, a deeper study of
the polysaccharides of noni fruit needs to be conducted.
Research about polysaccharides from various plants and
their effects on IL-2 and IFN-γ have been carried out.
Most studies show that polysaccharides from various
plants can increase of IL-2 and IFN-γ levels, while some
studies show varied results or a decrease in both
cytokines. Among them are summarized in Table 1.

Table 1. Various research related to polysaccharides from various plants and their effects on IL-2 and IFN-γ level.
Plant Source Result () Reference

Zizhypus jujuba  IL-2 Hsu et al., 2014

Astragalus membranaceus  IL-2 Yang et al., 2013
Artemisia argyi  IL-2 Bao et al., 2013

lhagi pseudalhagi Desv. Alhagi pseudalhagi Desv.  IFN-γ Wusiman et al., 2019
Ulva pertusa  IFN-γ Gao et al., 2019
Cordyceps ghunii  IFN-γ Zhu et al., 2012
Lycium barbarum  IFN-γ Bo et al., 2016

Codonopsis pilosula Nannf. Var. modesta  IL-2,  IFN-γ Fu et al., 2018

Caltha palustris  IL-2,  IFN-γ Suszko and Obmińska-Mrukowicz, 2013
Rehmania glutinosa  IL-2,  IFN-γ Huang et al., 2013
Tremella  IL-2,  IFN-γ Zhou et al., 2018
Camellia sinensis  IL-2,  IFN-γ Liu et al., 2018
Panax ginseng  IL-2,  IFN-γ Wang et al., 2015
Angelica sinensis  IL-2,  IFN-γ Wang et al., 2016

An increase in IFN-γ levels and decreasing tendency in
IL-2 are part of the body's immune system balance
mechanism. Within the scope of this study, the increase
in IFN-γ levels is consistent with predictions based on
the previous study, that these cytokines affect the
activity of macrophages and lymphocyte proliferation3,6.
The tendency of decreasing IL-2 levels may be related
with the potency of noni fruit polysaccharides in
reducing the level of proinflammatory cytokines, as
885
discussed in several previous studies29,40,43, and the
potency as an anti-inflammatory. The mechanism related
to the modulation these two cytokines cannot be
elucidated, bearing in mind that this research was
conducted in vivo.
Discussion related to the immunomodulatory
mechanism can be further elucidated by conducting in
vitro assay on certain signalling systems or pathways.
 Research J. Pharm. and Tech. 13(2): February 2020
Further research related to noni fruit polysaccharides,
especially SPF syrup, can be developed. For example;
evaluation of the composition of noni fruit
polysaccharides and their functional groups/structures,
studies of synergism/ antagonism effect between
polysaccharide components, their effects on intestinal
microbial, metabolism in certain body organs and
metabolite activities, studies of anti-inflammatory
activities, studies of antihistamine activities, and further
studies based on chemotaxonomy and metabolomics
aspect.
Effect of SPF Syrup on Spleen Histology:
Histological evaluation of spleen was carried out with
hematoxylin-eosin, general staining for histological
analysis. We evaluate histopathological changes or the
K1 K2
K4
Figure 3. Effect of standardized polysaccharide fraction (SPF) syrup from Morinda citrifolia on spleen organs histology. Effect of SPF
syrup evaluated with appearance of pathology or degenerative lesion. Sequence from top left to bottom right is: K1, K2, K3, K4, K5.
Effect of SPF Syrup on Mast Cell Degranulation
Skin histology preparations were evaluated by checking
the detailed aspect of the mast cell stained with toluidine
blue. Mast cells stained with toluidine blue are observed
as the dark blue to purple cells in the dermis layer. The
sizes of mast cells observed were various, from small to
large. Changes on mast cells can occur as mast cells
degranulated and spit out its content, which can be
observed as broken mast cells with small granules
around it. Normal mast cells, which is observed as intact
cells (not degranulated), were quantified and compared
to the normal group. Observation carried out in the
dermis layer of the skin because mast cells in skin
mostly distributed in this layer.
886
occurrence of any lesions/degeneration in the test group
compared with the control group. Changes/degeneration
can occur spontaneously because of aging, although
several lesion (like atrophy and fibrosis) can occur
because of direct or indirect treatment44. There was no
change or appearance of any degenerative lesions in the
test group compared with the control group. These
results indicate that administration of SPF syrup at doses
of 25, 50 and 100 mg / kg body weight does not induce
any changes or lesions of splenic organs, implying that
SPF syrup at these doses have no toxic effect to the
spleen. Previous study have been conducted to evaluate
the administration of polysaccharides from other plants
such as Devi et al., 2015. The result was consistent with
this study and several other studies on polysaccharides.
K3
K5
The result shows that the presence of intact mast cells in
the test group (SPF Syrup) is higher than the negative
control group (solvent / SPF carrier) or normal control
group (solvent / SPF + vaccine carrier). The number of
mast cells observed in the normal control group was less
than the control group, indicating a higher incidence of
mast cell degranulation. The presence of intact mast
cells in the test group (SPF Syrup) which is still high
indicates a small incidence of mast cell degranulation.
Less mast cell degranulation indicates less histamine
release due to mast cell degranulation. Conversely, few
mast cell presence in the control group might be because
of Hepatitis-B vaccine, which was noted to have side
effects on the skin46.
 Research J. Pharm. and Tech. 13(2): February 2020
The higher number of intact mast cells in the test group
compared to the normal group shows that SPF syrup
administration did not cause a significant effect on
allergic reactions. In contrast, SPF syrup actually has the
potency to reduce the incidence of histamine release
mediated by degranulation of skin mast cells.Several
studies related to polysaccharides show that
polysaccharides could reduce the incidence of
activation/degranulation of mast cells43,47, although in
K1 K2
K4
Figure 4. Effect of standardized polysaccharide fraction (SPF) syrup from Morinda citrifolia on skin mast cell degranulation. Mast cell
determined as quantitiy of whole/undamaged mast cell (red arrow). Sequence from top left to bottom right is: K1, K2, K3, K4, K5.
CONCLUSION:
Our study showed that SPF syrup in dosage 100 mg/kg
body weight could increase IFN-γ level. There is a
decreasing tendency in IL-2 level, although it is not
statistically significant on all dosages. Histological
evaluation showed that SPF syrup was safe to be
consumed because there are no toxic effect/lesion
between SPF and the control group in both spleen
histology and mast cell degranulation in the skin.
In future studies, further research can be conducted to
find the optimal dosage of SPF syrup that can
significantly modulate IL-2. Furthermore, more research
could be established, as well as finding the active
compound of polysaccharide, characterization of
polysaccharide component and their functional
groups/structures, studies of synergism/antagonism
effect between polysaccharide components, their effects
on intestinal microbial, metabolism in certain body
organs and metabolite activities, studies of anti-
inflammatory activities, studies of antihistamine
activities, further research based on chemotaxonomy and
metabolomics aspect, and histological evaluation of
887
other studies some polysaccharides otherwise activate
mast cells. Other studies also show that polysaccharides
could reduce pro-inflammatory cytokines level29,40,43.
Based on this finding and considering some of the
references mentioned before, further research can be
conducted to evaluate noni fruit polysaccharides potency
as antihistamine and anti-inflammatory.
K3
K5
other organs commonly affected by most drugs such as
liver and kidney.
ACKNOWLEDGEMENT:
The author acknowledges to Kementerian Riset dan
Pendidikan Tinggi (Kemenristek Dikti) through the
research scheme of Penelitian Unggulan Perguruan
Tinggi year 2017-2018 with contract number of
1804/UN1/DITLIT/DIT-LIT/LT/2018.
CONFLICT OF INTEREST:
The authors have declared “no conflicts of interest with
respect to the research, authorship, and/or publication of
this article”.
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