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354
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Review Article
J Ginseng Res Vol. 36, No. 4, 354-368 (2012)
http://dx.doi.org/10.5142/jgr.2012.36.4.354
E-mail: hymin@cau.ac.kr
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*
Corresponding author
INTRODUCTION
Ginseng (the root of Panax ginseng Meyer, Family
Araliaceae), one of the most well-known oriental medici-
nal herbs, has been widely used as an herbal remedy for
various disorders [1]. Natural-dried ginseng is known as
white ginseng, and red ginseng is prepared by steaming
fresh ginseng root prior to drying on the purpose of en-
hancing effi cacy, safety, and preservation [2].
Ginseng contains various pharmacological compo-
nents including a series of tetracyclic triterpenoid sapo-
nins (ginsenosides), polyacetylenes, polyphenolic com-
pounds, and acidic polysaccharides [3]. Ginsenosides
can be classifi ed into three groups based on the chemical
structure of aglycones: the protopanaxadiol group (e.g.,
Rb1, Rb2, Rb3, Rc, and Rd); the protopanaxatriol group
(e.g., Re, Rf, Rg1, and Rg2); and the oleanane group (e.g.,
Ro) (Fig. 1) [2,4]. Among these components, ginsen-
osides Rh2, Rs4, and Rg3 are found only in red ginseng
Ginseng, the 'Immunity Boost': The E ects of Panax ginseng on Immune
System
Soowon Kang and Hyeyoung Min*
College of Pharmacy, Chung-Ang University, Seoul 156-756, Korea
Thousands of literatures have described the diverse role of ginseng in physiological processes such as cancer, neurodegenera tive
disorders, insulin resistance, and hypertension. In particular, ginseng has been extensively reported to maintain homeostasis of the
immune system and to enhance resistance to illness or microbial attacks through the regulation of immune system. Immune system
comprises of different types of cells fulfi lling their own specialized functions, and each type of the immune cells is differentially
infl uenced and may be simultaneously controlled by ginseng treatment. This review summarizes the current knowledge on the
effects of ginseng on immune system. We discuss how ginseng regulates each type of immune cells including macrophages,
natural killer cells, dendritic cells, T cells, and B cells. We also describe how ginseng exhibits benefi cial effects on controlling
infl ammatory diseases and microbial infections.
Keywords: Panax ginseng, Innate immunity, Acquired immunity, Immunomodulation, Cytokine
This is an Open Access article distributed under the terms of the Cre-
ative Commons Attribution Non-Commercial License (http://creativecom-
mons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial
use, distribution, and reproduction in any medium, provided the original
work is properly cited.
Received 14 Jun. 2012, Revised 19 Jul. 2012, Accepted 19 Jul. 2012
and are derived from the hydrolysis of saponins by heat-
processing [5]. Fermentation of red ginseng by intestinal
microorganisms transforms saponins into readily absorb-
able forms such as compound K (20-O-D-glucopyrano-
syl-20[S]-protopanaxadiol) [6].
Ginseng has been well known as an immune modula-
tor [7-10]. Roots (mostly), stems, leaves of ginseng, and
their extracts have been used for maintaining immune
homeostasis and enhancing resistance to illness or micro-
bial attacks through effects on immune system. Im mune
system is composed of diverse types of cells with their
own specialized functions, and each type of the immune
cells differentially responds to ginseng treatment. This
review summarizes the current knowledge on the effects
of ginseng on immune system. Among the hundreds
of literatures on immune responses, we only embraced
the reports which used mice, rats, or humans as in vivo
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Kang et al. Ginseng and Immunity
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model organisms, murine or human-derived cell lines as
in vitro experimental models, and P. ginseng as a source
of ginseng.
INNATE IMMUNITY
Innate immunity is the fi rst barrier of defense against
various infections by foreign organisms or substances
(antigens), and is composed of four principal components.
They comprise 1) physical/chemical barriers such as skin,
mucous membranes, and the acidity of the stomach, 2)
cellular components including phagocytes and natural
killer cells, 3) blood proteins such as complements and
infl ammatory mediators, and 4) cytokines that regulating
the cells of innate immune system [11,12]. These com-
ponents of innate immunity recognize foreign microbes,
initiate rapid primary immune responses, and prevent
or eliminate infection of the host [13]. In addition to
defensive function, innate immune system also gener-
ates a signal alarming the presence of infection, and thus
stimulating a subsequent adaptive immune response [12].
Although an innate immunity comprises a variety of com-
ponents mediating diverse functions, we only assess the
effects of ginseng on cellular component in this review.
Macrophages
The mononuclear phagocytes are composed of mono-
cytes circulating in the blood and macrophages in the
tissues [14]. Macrophages exhibit different morphologic
forms in different tissues, and they include microglia of
the central nervous system, Kupffer cells in the liver, al-
veolar macrophages in the lung, and osteoclasts in bone
[14]. Macrophages are principal components of innate
defense against infections, and also play important roles
in adaptive immune responses [12]. When activated by
various stimuli, macrophages enhance phagocytic activ-
ity, increase the ability to kill ingested microbes, and
produce many cytokines and inflammatory mediators
such as nitric oxide and H2O2 [15]. They also express
high levels of class II major histocompatibility complex
(MHC) molecules to present antigens to helper T cells,
and thereby connect the innate and adaptive immune sys-
tems [12].
Through numerous experiments, it was confi rmed that
ginseng extract enhanced phagocytic activity of mac-
rophages [16]. Macrophages treated with ginseng poly-
saccharides stimulated the phagocytosis of zymosan, a
preparation of cell wall from Saccharomyces cerevisiae,
and peritoneal macrophages also showed an increase in
Fig. 1. Structures of saponins from Panax ginseng. (A) Protopanaxadiol- and protopanaxatriol-type saponins, (B) ginsenoside Ro, and (C) com-
pound K. Glc, β-D-glucose; Ara(p), arabinose (pyranose form); Ara(f), arabinose (furanose form); Rha, α-L-rhamnose.
http://dx.doi.org/10.5142/jgr.2012.36.4.354
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phagocytosis following treatment with red ginseng acidic
polysaccharides (RGAPs, ginsan) [16,17]. In a clinical
trial with 20 healthy adults, oral administration of gin-
seng extract improved phagocytic activity [8].
In addition to the effects on phagocytosis, ginseng
can stimulate the generation of infl ammatory mediators
such as nitric oxide (NO), a reactive nitrogen intermedi-
ate, through up-regulation of inducible nitric oxide syn-
thase (iNOS) [18]. Macrophages produce NO in order
to destroy phagocytized microbes, and ginseng aqueous
extract and ginsan have shown to up-regulate NO pro-
duction in activated RAW 264.7 cells and primary peri-
toneal macrophages, respectively [16,18,19]. In addition,
treatment of macrophages with a combination of RGAPs
and IFN-γ has shown to potentiate the activation of mac-
rophages, and NO production is greatly improved [18].
Upon activation by microbial products such as lipo-
polysaccharide (LPS) and IFN-γ derived from natural
killer (NK) cells, macrophages secrete IL-1β and TNF-α
to induce infl ammatory reactions, and IL-12 to stimulate
NK cells and T cells to produce IFN-γ [17,18]. Isolated
polysaccharides from P. ginseng augmented the secre-
tion of IL-1β and TNF-α from peritoneal macrophages in
vitro [17]. Treatment of macrophages with RGAPs and
IFN-γ signifi cantly increased the production of IL-1β and
TNF-α as well as NO as previously described [18]. IL-
12 release was also boosted up by treatment of murine
J774A.1 macrophage cells with ginseng extract and its
isolated components [20].
Dendritic cells
Dendritic cells (DC) play important roles in innate im-
mune responses to infections and in linking innate and
adaptive immune responses [21]. DCs recognize antigens
at the fi rst sites of defense, migrate into lymphoid organs,
and present antigenic molecules to lymphocytes to initi-
ate lymphocytes activation [21]. In addition, activated
DCs release cytokines such as IL-12, IL-4, IFN-γ, and
TNF-α to stimulate adaptive as well as innate immune
responses [22].
In general, ginseng exhibits immunostimulatory ef-
fects on DCs [23,24]. Takei et al. [24] have reported that
M1 and M4, end products of steroidal ginseng saponins
metabolized in digestive tracts were able to drive the
maturation of DC from human monocytes manifested by
the increased expression of DC maturation markers such
as MHC class II, CD80, CD83, and CD86. These surface
molecules are associated with antigen-presenting capa-
bilities of DCs implying that the increased expression of
MHC class II and co-stimulatory molecules may enhance
the differentiation and proliferation of lymphocytes. In
fact, M4-primed mature DCs displayed enhanced T cells
stimulatory capacity as measured by T cell proliferation,
and the production of IFN-γ and 51Cr release on M4-
primed mature DCs were more augmented than those of
control DCs. Similarly, ginsan also markedly increased
the production of IL-1 and TNF-α as well as the expres-
sion of maturation markers such as MHC class II and
CD86 on DCs [23]. Subsequent experiment demonstrat-
ed that ginsan-treated DCs improved the proliferation of
allogeneic T cells, corroborating the constructive role of
ginseng on DC function.
However, some ginseng saponins have inhibitory effect
on immune maturation of DCs. According to Su et al.
[25], treatment of DCs with total saponins of P. ginseng
followed by oxidized-low density lipoprotein diminished
the secretion of cytokines such as IL-12 and TNF-α, and
the expression of maturation markers including CD40,
CD86, CD1a, and HLA-DR. In other experiments using
steamed ginseng-leaves and flowers, ginsenosides Rg6
and F4 exhibited inhibitory effects on bone marrow-
derived dendritic cells and decrease in the production
of IL-12 p40, a subunit component of IL-12 upon LPS
stimulation [26]. Although it remains unclear why gin-
seng showed such opposite effects, researchers suspect
that ginseng may cause pro-maturation or anti-maturation
of DCs and stimulate different signaling pathways [25].
Natural killer cells
NK cells are a type of cytotoxic lymphocytes of innate
immune system that are involved in the fi rst line of de-
fense against newly arising malignant cells and infected
cells [27]. Distinguished from cytotoxic T lymphocytes,
they can recognize target cells in the absence of antibod-
ies and MHC, and do not require activation to kill target
cells thereby enabling a fast immune response [27]. In
addition to killing target cells non-specifi cally, NK cells
release pro-infl ammatory cytokines such as IFN-γ which
activates macrophages to destroy phagocytized microbes
[27].
Many literatures have reported that total ginseng ex-
tract enhances NK cell functions. Oral administration of
aqueous extract of P. ginseng increased natural killing
activity in mice [7], and ginsenoside Rg1-treated mice
also showed an enhanced natural killing activity of the
splenocytes [28]. Interestingly, the stimulatory effects of
ginseng on NK cells were observed regardless of disease
condition of the host. Therefore, the functions of NK
cells stimulated by ginseng were comparable between
immunosuppressed mice and immunocompetent mice
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[29]. The trial using blood sample of human patients
who had chronic fatigue syndrome and acquired im-
munodeficiency syndrome (AIDS) showed functional
enhancement of NK cells isolated from peripheral blood
mononuclear cells [30]. In vivo test conducted by Sca-
glione et al. [8] also demonstrated that NK cell function
in individuals taking ginseng was promoted compared
to placebo group. Collectively, these results suggest that
ginseng may improve NK cell activity irrespective of
host immune conditions.
ACQUIRED IMMUNITY
Acquired (or adaptive) immunity is an antigen-specifi c
immune response which occurs in response to the stimu-
lation by specific antigens [31]. The major players of
acquired immunity are lymphocytes such as T cells and
B cells and their secreted antibodies. B lymphocytes play
a role in the humoral immune response, whereas T lym-
phocytes are primarily involved in cell-mediated immune
response [31]. The key feature of the adaptive immune
response is its specifi city and the ability to generate and
maintain immunological memory [32]. Upon antigenic
stimulation, antigen-specifi c lymphocytes proliferate and
differentiate into effector cells whose function is to elimi-
nate the antigen, and into memory cells which possess
an enhanced response to subsequent encounters with the
same antigen [31,32].
Humoral immune response
The humoral immune response is an immunity medi-
ated by antibodies [33]. In this response, the immune
system triggers specifi c B cells (mostly, plasma cells) to
proliferate and secrete large amounts of specifi c antibod-
ies which then fi ght invading microorganisms or patho-
genic antigens [33]. Antibodies can bind to the antigens
such as toxin and virus, and keep them from contacting
and harming normal cells of the body [33,34]. In addi-
tion, antigens coated with antibodies can be easily rec-
ognized, phagocytized, and destroyed by phagocytes or
macrophages [35]. Antibodies are also able to stimulate
complement system to form membrane attack complex
on the membrane of invading microbes and kill them
[36].
Although numerous studies describe the role of gin-
seng on antibody production, most of them evaluate its
adjuvant potential on the secretion of specifi c antibodies.
In general, ginseng extract successfully induced antigen-
specifi c IgM, IgG, and IgA antibody responses when ad-
ministered orally or intraperitoneally [37,38]. When mice
were pre-treated with ginsan before oral-immunization
of Salmonella for 2 wk, higher amounts of serum IgG1
and IgG2 as well as secretory IgA against Salmonella
were produced [39]. In addition, subcutaneous injection
of ginsenoside Rg1 developed a high level of specific
antibody responses against Toxoplasma gondii and gin-
senoside Re also significantly enhanced serum specific
IgG, IgG1, IgG2a and IgG2b responses to H3N2 infl uenza
virus [40,41]. Collectively, ginseng extract or its purifi ed
components appear to elicit improved humoral responses
against microbial invasion irrespective of administration
methods or types of microbes, suggesting the critical
roles of ginseng as an adjuvant in vaccines. More details
on the adjuvant effects of ginseng are well described in
‘GINSENG AS ADJUVANTS’ section in this review.
While many studies have reported the enhanced hu-
moral immune responses by ginseng treatment, ginseng
also reduces antibody production in certain conditions.
For example, long-term (30 consecutive days) oral ad-
ministration of ginseng extract suppressed spleen cell
function and considerably reduced IgG and IgA produc-
tions [38]. In addition, oral administration of ginseng
extract also inhibited an increase in ovalbumin (OVA)-
specifi c IgG1 in the serum of OVA-sensitized mice with-
out changing IgG2a, IgA, and IgE levels [42].
Cell-mediated immune response
Cellular immune response is principally mediated by
T cells and NK cells, and is most effective in destroying
virus-infected cells, cells with intracellular bacteria, and
cancer cells presenting tumor antigens [43,44]. It can also
stimulate cells to release various cytokines in response to
antigenic challenge and infl uence the function of numer-
ous cells in the immune system [43]. Many reports have
described that ginseng extract significantly enhances
antibody-dependent cellular cytotoxicity and NK cell ac-
tivity derived from human peripheral blood mononuclear
cells (PBMC) or mice [7,29,30]. In addition, ginsenoside
Rc, Rd, Rg1, and ginsan all stimulated T cell prolifera-
tion as well as NK cell activity suggesting a critical im-
munomodulatory effect of ginseng on cellular immune
responses [28,45-47].
In case of autoimmune diseases, immunosuppressive
responses can exert benefi cial effects on disease progres-
sion. Hwang et al. [46] has reported that ginsan promotes
the generation of immunosuppressive regulatory T cells
(Tregs) through the activation of transcription factor,
FoxP3, indicating a favorable effect of ginsan on experi-
mental autoimmune encephalomyelitis (EAE), a mouse
model of multiple sclerosis (MS).
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CYTOKINE RELEASE
Cytokines are small signaling molecules that are se-
creted by a variety of cells mediating immune responses
[31,48]. Cytokines are synthesized in response to micro-
organisms and other antigenic stimuli, and the binding of
cytokines to their specifi c receptors triggers subsequent
cascades of intracellular signaling and infl uences the de-
velopment, differentiation, and function of immune cells
[48]. Cytokines are often classifi ed, based on their func-
tional properties, into three categories, and they include
modulators of innate immunity, modulators of adaptive
immunity, and regulators of hematopoiesis [48]. How-
ever, this functional classifi cation is not always distinct,
and many cytokines play multiple roles in hematopoiesis
and innate and adaptive immunity.
Many literatures have reported that ginseng regulates
immune responses through the modulation of cytokine
secretion. The affected cytokines are mostly proinfl am-
matory cytokines via the activation or inhibition of Toll-
like receptors (TLRs), but ginseng also changes cytokine
production to control Th1/Th2 lineage differentiation.
Detailed information on the role of ginseng on cytokine
release is described below.
Cytokines of innate immunity
Different cytokines play critical roles in innate im-
munity against microbial invasion, and these mediators
of innate immunity include TNFs, IL-1, IL-6, IL-10, IL-
12, type I interferons, and so on [49]. They are mainly
secreted by macrophages and NK cells while some are
produced by T cells, dendritic cells, and endothelial cells
[49]. In order to detect microbial infection, the innate im-
mune system uses pattern recognition receptors (PRRs),
and TLRs are an important category of PRRs [50,51].
TLR detects the invasion of viruses, bacteria, fungi, and
protozoa, and initiates signaling events which enable
cells to control and clear infections.
Many literatures have shown that ginseng controls
proinflammatory cytokine responses. TNF-α, IL-1β,
IL-6, and IFN-γ are produced by macrophages treated
with ginseng radix extract (GRE) in vitro as well as in
vivo [52]. Spleen cells cultured with ginsan induced an
increase in IL-2, IFN-γ, IL-1α, and granulocyte-macro-
phage colony-stimulating factor production in vitro [53].
However, ginseng can also show opposite effects on
cytokine production. The production of TNF-α, IL-1β,
IL-6, IFN-γ, IL-12, and IL-18, was markedly down-regu-
lated in ginsan-treated mice upon Staphylococcus aureus
challenge, compared with those of control-infected mice
[54]. Ginseng saponin metabolite, compound K inhibited
the expression of inducible nitric-oxide synthase and
proinflammatory cytokines such as TNF-α and IL-1β,
and exerted anti-infl ammatory effects in LPS-stimulated
BV2 microglial cells and primary cultured microglia [55].
Similarly, Rg5, a major constituent of steamed ginseng
reduced the expression of IL-1β and TNF-α, as well as
infl ammatory enzymes, COX-2 and iNOS in LPS-stim-
ulated alveolar macrophages [56]. In addition, the secre-
tion of infl ammatory cytokines such as IFN-γ, IL-1β and
IL-17 were also reduced by ginsan treatment which is
accompanied by a decrease in encephalitogenic response
in EAE, an animal model of MS [46]. TNF-α production
is signifi cantly reduced by ginseng and ginsenoside Rb1,
which leads to an anti-arthritic effect on collagen induced
arthritis in mice [57].
The generation of proinfl ammatory cytokines is main-
ly through the activation of TLRs, and ginseng has been
shown to modulate TLR activation by itself. While the
production of TNF-α and IFN-γ was induced by GRE
in spleen cells and peritoneal macrophages from control
mice, it was impaired in C3H/HeJ mice carrying a defec-
tive TLR-4 gene suggesting that GRE activates TLR-
4 signaling for cytokine release [58]. However, it seems
that GRE does not contain LPS but have a non-LPS
agent that can stimulate TLR-4 according to the endo-
toxin test with the threshold level of 1 ng/mL. In contrast,
some studies have demonstrated that ginseng down-
regulates TLRs and suppresses inflammatory response
[54,59]. Ahn et al. [54] and Ahn et al. [59] reported the
signifi cant reduction of TLR-2 and its adaptor molecule
MyD88 expression by ginsan treatment in vitro. In addi-
tion, expression of TLR-2, TLR-4, TLR-9, and MyD88
was considerably reduced in peritoneal macrophages
treated with ginsan, and thereby mice were protected
from S. aureus-induced sepsis [54].
These results indicate that ginseng modulates innate
immunity through TLR expression, and ginseng or gin-
san possesses an antiseptic activity by reducing proin-
fl ammatory cytokines via TLR signaling and prevents S.
aureus-induced sepsis [54].
Cytokines of acquired immunity
The cytokines of acquired immunity are critical for the
development and activation of effector cells [60]. The ef-
fector cells are further divided into Th1 cells which pro-
duce IL-2, IL-12, IFN-γ, and TNF-β, and Th2 cells which
secrete IL-4, IL-5, IL-10, and IL-13 [60]. The differences
in the cytokines secreted by Th1 and Th2 cells determine
their own differentiation and distinct biological functions
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Kang et al. Ginseng and Immunity
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[47,60,61].
In addition to the effects on cytokines of innate im-
munity, ginseng also regulates the secretion of cytokines
mediating adaptive immunity. Many literatures have
reported that ginseng itself or various forms of puri-
fi ed ginsenoside control Th1 and Th2 immune response
differentially [62-66]. The study by Larsen et al. [62]
indicated that ginseng enhanced IL-2 production induc-
ing a stronger Th1 response through the modulation of
stimulated PBMC. Upon challenge with live Candida
albicans, ginsenoside Rg1 helps the infected mice to re-
sist candidiasis by developing Th1-dominant production
of IFN-γ and IL-2 [63]. Similarly, ginseng treatment in
mice inoculated with Pseudomonas aeruginosa stimu-
lated Th1 cytokine response resulting in a faster bacterial
clearance from the lung and significantly milder lung
pathology compared with control group [64]. In addition,
ginsan induced the endogenous production of cytokines
such as IL-1, IL-6, IFN-γ, and IL-12 which are required
for hematopoietic recovery, and was able to enhance Th1
function while interfering with the Th2 response in irra-
diated mice [61]. However, according to the study by Lee
et al. [47], Rg1 enhances Th2 lineage development from
the naïve CD4+T cells both by increasing Th2 specific
cytokine secretion such as IL-4 and by repressing Th1
specifi c cytokine production such as IFN-γ. Furthermore,
when ginseng was used as an adjuvant for vaccination,
it seemed to stimulate Th1 and Th2 cytokine responses
equally. For example, when mice were immunized with
vaccines containing ginsenoside Rb1 as adjuvant, aug-
mented productions of IFN-γ, IL-2, IL-4, IL-10, and
TNF-α were reported with no sign of polarization of the
immune response [65]. Similarly, Rd also significantly
promoted the production of the Th1 and Th2 cytokines
in OVA-immunized mice [66]. Such disparities in con-
trolling Th1/Th2 lineage differentiation may have arisen
from differences in dosage, duration of exposure, route
of administration, composition of the extract or the types
of ginsenoside between the studies. Collectively, these
results suggest that ginseng controls Th1/Th2 lineage dif-
ferentiation by changing the balanced production of Th1
and Th2 cytokines. Moreover, the Th1/Th2 fate decision
process is not a unidirectional but bidirectional event
which can change with different experimental conditions.
EFFECTS OF GINSENG ON INFLAMMATORY
DISEASE
Inflammation is a physiological response to various
stimuli such as invading pathogens, irritants, and tissue
injury, and can be classified as acute or chronic [67].
In general, an acute inflammatory response has a rapid
onset with short duration time, and is characterized by
a rapid movement of plasma proteins and leukocytes to
the injured tissues [67]. Although the acute response is
a protective attempt to remove stimuli and to initiate the
healing process, sustained inflammation may lead to a
detrimental, pathologic consequences on host [68]. Such
chronic infl ammatory responses may result in signifi cant
tissue damages and develop to autoimmune diseases [69].
Ginseng has been shown to reduce the production of
pro-inflammatory cytokines and thus, ameliorate the
symptoms and the progression of infl ammatory diseases
[54,70,71]. In an ovalbumin-sensitized murine asthma
model, ginseng effectively suppresses airway hyper-
responsiveness by decreasing inflammatory cell infil-
tration, CD40 engagement of lymphocytes, eosinophil
major basic protein production, and cytokine secretion
[70]. This anti-asthmatic effect of ginseng was confi rmed
by Babayigit et al. [72] who have reported the improved
histopathological changes of the lung in asthmatic mice
with ginseng treatment. Additionally, Lim et al. [73]
demonstrated that ginsan administration reduced air-
way hyperresponsiveness, remodeling and eosinophilia,
which was equivalent to the effect of dexamethasone.
Ginseng can also protect host from bacterial septic
responses through the suppression of robust acute in-
fl ammation. Sepsis is a dangerous and systemic disease
caused by fatal and aberrant inflammatory response to
infections [54]. As previously described in the ‘Cytokines
of innate immunity’ section, ginsan and total polysaccha-
ride have shown to suppress acute infl ammation and pro-
tect host mice from sepsis-induced death upon bacterial
challenge [17,54,59]. Interestingly, although the studies
demonstrated the same anti-septic effects upon S. aureus
challenge, the mechanisms behind showed discrepancy
in cytokine production. For example, ginsan down-regu-
lated the secretion of infl ammatory cytokines such as IL-
1β, IL-6, IFN-γ, IL-12, and IL-18, but total polysaccha-
ride increased the level of IL-1 and IL-6. Collectively, the
primary anti-septic protective effects given by ginsan or
total polysaccharide seemed to be attributed to enhanced
bacterial clearance through the augmented phagocytic
activity of monocytes and macrophages rather than the
reduced synthesis of sepsis-inducing infl ammatory cyto-
kines.
In addition, ginseng exerts beneficial effects on ce-
rebral ischemia by modulating central nervous system
inflammation [55,74]. Ginsenoside Rb1 depressed the
activation of microglia and its conversion to phagocytic
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microglia as well as TNF-α and IL-6 production [74].
Compound K inhibited the expressions of inducible
nitric-oxide synthase, proinflammatory cytokines such
as TNF-α and IL-1β, monocyte chemotactic protein-1,
and matrix metalloproteinase-3 and -9 in LPS-stimulated
BV2 microglial cells and primary cultured microglia [55].
These results propose the application of ginseng as a
neuroprotective agent for prevention and/or treatment of
neuroinfl ammatory diseases such as cerebral ischemia.
In the murine model of collagen-induced arthritis, red
ginseng saponin extract including ginsenosides Rg3,
Rk1 and Rg5, n-butanol extract, and ginsenoside Rb1 all
showed anti-arthritic effects [57,75,76]. They presented
reduced infl ammatory cell infi ltration, cytokine produc-
tion, and cartilage destruction, and thereby ameliorated
the clinical arthritis score significantly. Taken together,
the results suggest that various forms of ginseng could
be beneficial supplements or alternatives to the current
anti-TNF-α therapeutics for rheumatoid arthritis or other
infl ammatory diseases characterized by TNF-α up-regu-
lation.
Lastly, numerous literatures have described the ef-
fects of ginseng on contact and atopic dermatitis [77-82].
Korean red ginseng (KRG) extracts have been shown
to suppress the production of TNF-α and IL-8 in human
keratinocytes [78]. Furthermore, in a mouse model of
atopic dermatitis, topical application of ginseng extract
or ginsenoside Rb1 signifi cantly improved the atopic der-
matitis-like skin lesion and scratching behavior as well
as the decrease of serum IgE, IL-4, and IL-10 [5,79,81].
This anti-atopic dermatitis effect was also observed in
mice when KRG was given orally [80], and further con-
fi rmed in the human study with 30 atopic patients. Lee
and Son [82] reported that 16-week oral ingestion of
KRG decreased serum IgE level and the severity of scor-
ing of the atopic dermatitis index, suggesting a role of
KRG as a functional food for atopic dermatitis.
ANTIMICROBIAL ACTIVITY OF GINSENG
Plants are continuously in contact with different mi-
croorganisms such as viruses, bacteria and fungi. The in-
teractions between plants and microbes may be benefi cial
for the plants, but many plant-associated microbes are
pathogens which affect development, reproduction, and
growth of the plants [83]. Therefore, plants produce anti-
microbial compounds as a defense mechanism against
microbial attacks, and these plant-derived compounds
have been reported to prevent bacterial or viral infection
also in humans. Especially, ginseng is one of the best-
known medicinal herbs improving microbial clearance
from the body [8,84,85]. Total ginseng extracts as well
as single or multiple components derived from ginseng
have shown anti-microbial activities, and clinical trials
have also been performed to evaluate the anti-bacterial or
anti-viral activities of ginseng.
Anti-bacterial activity
For successful establishment of bacterial infections, it
is necessary to have adhesion to host cells, colonization
of tissues, and in certain cases, cellular invasion followed
by intracellular multiplication, dissemination to other tis-
sues, or persistence [86]. In general, bacterial adhesion is
mediated by certain interactions between adhesin from
bacteria and carbohydrates on the surface of host cells.
Studies have shown that ginseng polysaccharides could
interact with microbes, interrupt microbial adhesion to
host cells, and block the initiation of infectious disease
[87,88]. For example, PG-F2 and PG-HMW, pectin-
type polysaccharides from P. ginseng, had anti-adhesive
activity against various microbes such as Porphyromo-
nas gingivalis, Actinobacillus actinomycetemcomitans,
Propionibacterium acnes, and S. aureus [87]. These two
polysaccharides did not directly affect microbial growth
but decreased the percentages of attached microbe, sug-
gesting that ginseng polysaccharides have potential roles
in anti-adhesive activity. In addition, polyacetylenes
isolated from P. ginseng hairy root culture exerts direct
bactericidal effects [89]. Four different polyacetylene
compounds were treated to various microorganisms
such as Gram-positive bacteria (methicillin-resistant S.
aureus and Bacillus subtilis) and Gram-negative bacteria
(Escherichia coli and Serratia marcescens), and their
minimum inhibitory concentrations were measured. The
results show that polyacetylene compounds were ef-
fective against bacterial infections and the level of anti-
bacterial activity was dependent on structural features of
the polyacetylene.
Additionally, ginsan had bactericidal activity against
S. aureus [54]. Although ginsan treatment had no direct
effects on bacterial killing in vitro, pretreatment of mice
with ginsan showed enhanced anti-Staphylococcal ac-
tivity by decreasing the numbers of bacteria present in
the spleens, kidney, and blood. The phagocytic activity
against S. aureus was also enhanced considerably in
ginsan-treated mice. In addition to bactericidal activity,
ginseng polysaccharide and ginsan showed anti-septi-
caemic effects against S. aureus infection and protected
mice from septic death during early acute infl ammation
as previously discussed [17,54].
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Microorganisms have their own specifi c mode of ac-
tion by which they survive or exert pathogenic effects in
the host. Ginseng can inhibit those survival or pathogenic
mechanisms and thereby exhibit anti-bacterial ability.
For example, acidic saccharides from P. ginseng and red
ginseng extract (RGE) have shown to possess the protec-
tive effects against Helicobacter pylori causing gastric
infl ammation, ulceration, and DNA damage [88,90,91].
Through the treatment of acidic saccharides from P. gin-
seng, H. pylori could not attach to gastric cells and initi-
ate infl ammatory responses [88,90,91]. Moreover, RGE
was identified to significantly weaken both H. pylori-
induced DNA damage and gastric cell apoptosis by in-
activating ERK1/2 signaling and attenuating caspase-3
activation and poly ADP ribose polymerase cleavage [91].
Furthermore, literatures have described the anti-
Pseudomonal activity of ginseng. Ginseng treatment
signifi cantly decreased the lung pathology and enhanced
bacterial clearance from the lung in a rat model of
chronic P. aeruginosa lung infection mimicking cystic fi -
brosis [64,84,85,92]. During infectious process by P. ae-
ruginosa, cell-to-cell communication mechanism called
quorum sensing (QS) plays a critical role in the patho-
genesis of the bacteria. The QS of P. aeruginosa uses N-
acetylated homoserine lactone as a signal molecule and
coordinates the formation of biofi lms, swarming motil-
ity, exopolysaccharide production, and cell aggregation.
Song et al. [93] have shown that hot water extracts from
ginseng compromises the generation of P. aeruginosa
QS. Although hot water ginseng extracts did not inhibit
the growth of P. aeruginosa directly and enhanced the
production of capsule-like polysaccharides and alginates,
ginseng extracts suppressed the synthesis of virulence
factors such as LasA protease, LasB elastase, and AHL
molecules, and strongly inhibited QS system of P. aeru-
ginosa [93].
Anti-viral activity
Infl uenza virus, commonly referred to as the fl u, can
be influenced by RGE [94-97]. After intranasal admin-
istration of ginseng extract with infl uenza virus A/PR8,
significant increases in IgA as well as total IgG were
observed in blood, lung, vaginal lavage, and fecal extract
in mice [98]. The increase in total IgG was comparable
to that observed in the aluminium hydroxide or cholera
toxin-adjuvant group. In addition, all serum IgG subtypes
such as IgG1, IgG2a, IgG2b, and IgG3 antibodies were all
augmented [98]. Simultaneously, virus neutralization
activity, cytokine production, body weight changes, and
survival rates were all improved by ginseng treatment
indicating that ginseng extract well-executes immuno-
regulatory function as an adjuvant.
Avian influenza H9N2 is generally related to major
mortality of human endothelial cells and causes serious
infl ammation and apoptosis on host cells [95,96]. H9N2
may induce the generation of reactive oxygen species
(ROS), stimulate inflammatory response by produc-
ing IP-10 chemokine, and cause cellular apoptosis and
DNA damages. Two ginsenosides have shown to possess
different protective functions against H9N2 and medi-
ate dual roles in infectious situations [95]. Ginsenoside
protopanaxatriol reduced ROS stress and decreased IP-
10 expression stimulated by ROS, whereas ginsenoside
Re reduced the infl uenza-induced DNA damage and cell
death.
Infection of infl uenza A (H1N1) virus is also regulated
by red ginseng extracts [97]. RGE treatment inhibited
plaque formation occurred by infl uenza A virus in cell-
based system, and oral administration of RGE improved
body weight loss and decreased influenza A titer in
mouse lung.
Human immunodeficiency virus type 1 (HIV-1) is a
virus that causes AIDS, a condition in which the immune
system fails due to the destruction of CD4+ helper T
cells (mostly), macrophages, and dendritic cells [99,100].
Owing to the introduction of highly active anti-retroviral
therapy (HAART) and the development of many anti-ret-
roviral drugs, the rates of mortality and morbidity related
to HIV-1 disease have reduced meaningfully [101]. How-
ever, anti-retroviral drug-resistant mutants are incessantly
occurring and limit the availability of effective drugs. In-
terestingly, KRG has been shown to exert positive effects
on HAART by maintaining CD4+ T cell counts and de-
laying the development of resistance mutations in HIV-1
patients treated with HAART [102]. Negative factor (Nef)
is a virulence factor securing T cell activation and the
establishment of a persistent state of infection early in the
HIV life cycle. Nef proteins derived from the long-term
non/slow progressors were found to be defective or far
less capable of enhancing viral replication and infectiv-
ity [103]. Interestingly, KRG increases the frequency of
gross deletion in the nef gene resulting in the delay in dis-
ease progression in HIV-1 patients [104-107]. Similarly,
increased frequency of deletion in the HIV-1 5’ LTR/gag
was found in HIV-1 infected long-term survivors treated
with KRG, suggesting the association of gross deletion
in HIV-1 5’ LTR/gag regions with KRG intake [107-109].
Therefore, combinational treatment or pre-treatment of
KRG with HAART is very valuable for the treatment of
HIV infections.
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J Ginseng Res Vol. 36, No. 4, 354-368 (2012)
Ginseng also had inhibitory effects on the growth of
other viruses such as rotavirus, murine norovirus (MNV),
and feline calicivirus (FCV) [110,111]. Pre-treatment but
not post-treatment of mice with RGE exhibited antiviral
effects on MNV and FCV, surrogates for human norovi-
rus. In addition, ginseng polysaccharide fractions showed
anti-rotaviral activity with the inhibitory potency compa-
rable to that of hesperidin, one of the most potent agent
for rotaviral infection [111].
Although the eradication of viral infection mainly
relies on the immune responses of the host, anti-viral
properties of ginseng have been rarely assessed from an
immunological perspective. Instead of examining the ac-
tivities of cytotoxic T cells and NK cells and the produc-
tion of interferon and neutralizing antibody, body weight
loss, survival rate, virus titer, and genetic mutation of
virulence factors have been employed to prove anti-viral
activities of ginseng. Future studies should include the
immunological methods described above to assess anti-
viral activity of ginseng more thoroughly.
GINSENG AS ADJUVANTS
Adjuvants play an important role in vaccine formula-
tions by increasing the immunogenicity of co-adminis-
tered antigens [112,113]. When appropriate adjuvants are
administrated with a supplied antigen, they can enhance
immunization effects while keeping the injected antigen
to a minimum and protect their recipients from deadly
infectious diseases. Adjuvants can act in various ways
to increase antigen presentation and to stimulate the im-
mune system [114]. For example, adjuvants may act as a
depot for the antigen and present the antigen over a long
period of time to maximize the immune responses. They
can also induce mucosal immunity, regulate antibody
avidity, specifi city, or isotype, and stimulate cytotoxic T
lymphocytes. Many substances have been developed as
adjuvants [112]. Inorganic aluminium salts such as alu-
minium phosphate and aluminium hydroxide are one of
the most common adjuvants in human vaccine. In addi-
tion, oil emulsions, polymers, carbohydrates, liposomes,
LPSs and other bacterial toxins are also used to augment
immune responses.
Ginseng extract has been applied as an immunologic
adjuvant and ginsenosides are believed to be the key
molecules that have adjuvanticity among the whole gin-
seng extract [115]. There are about 30 ginsenosides pres-
ent in P. ginseng and their ability as an adjuvant is depen-
dent on their characteristic structural features [116,117].
In general, ginseng has no immunogenicity by itself [118].
However, their combinations with antigens or other
adjuvants can promote and enhance immune responses
against immunized antigens.
Antibody production could be regulated by ginseng
extract and specifi c ginsenoside. It has been reported that
ginseng extract increases IgM and IgG antibody responses
in immunized mice [7], and ginsenosides Rd, Re and Rg1
also augment specific-antibody responses [41,66,118-
121]. Similarly, a novel adjuvant of ginsenoside-based
nanoparticles (ginsomes) containing ginsenosides Rb2,
Rc, Rb1, and Rd signifi cantly increased the levels of spe-
cifi c IgG1, IgG2a, IgG2b and IgG3 in mice [119].
Recent studies of ginseng also emphasize the adjuvant
effects of ginseng on the Th1 and Th2 immune responses
as well as antibody responses. In addition to increase in
lymphocyte proliferation, ginseng promotes the produc-
tion of cytokines which stimulate both Th1 and Th2
immune responses. The productions of IFN-γ and IL-5
were increased by administration of ginsenoside Re and
Rg1 in mice [118,119,121]. Ginsenoside Rd and Re also
improved the productions of Th1 and Th2 cytokines
including IFN-γ, IL-2, IL-4, IL-10, IL-12, and TNF-α
[41,66,120], and consequently, up-regulated Th1 and Th2
responses leading to a balanced immunity.
For these reasons, ginseng has been suggested as a po-
tent adjuvant for vaccine. For example, in the vaccine of
T. gondii, ginseng was regarded as a promising vaccine
adjuvant against toxoplasmosis by enhancing antibody
response against T. gondii antigen [41]. In infl uenza vi-
rus vaccine, ginsenoside Re is expected to improve the
quality of vaccine that may activate mixed Th1/Th2 im-
mune responses [118]. Overall, these results indicate that
ginseng functions well as an immunologic adjuvant, and
its combination with antigens would bring enhanced im-
mune responses during immunization.
CONCLUDING REMARKS
Here we discussed the current knowledge on the ef-
fects of ginseng on immune system (Table 1). Although
ample studies have examined the immunomodulatory
properties of ginseng in vitro and in animals, most of
them are limited to assess the phenotypic changes at
the cellular level, and only a few studies have looked
at the alterations by ginseng at the molecular level. For
example, cytokine secretion, antibody production, sur-
face marker expression, and cellular functions such as
phagocytosis and cytotoxicity were common criteria to
evaluate immunoregulatory properties, while molecular
components involved in signaling pathway were rarely
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Table 1. Summary of the ginseng effects on immune system
Effects References
Innate immunity
Macrophages Enhance phagocytosis [8,16,17]
Stimulate the generation of nitric oxide [16,18,19]
Induce infl ammatory reactions by IL-1β and TNF-α[17,18]
Stimulate NK cells and T cells by IL-12 [20]
DCs Increase DC maturation markers (MHC class II, CD80, CD83, CD86) [23,24]
Increase the production of IL-1 and TNF-α [23]
Reduce DC maturation markers (CD40, CD86, CD1a, HLA-DR) [25]
Diminish the secretion of TNF-α, IL-12 and IL-12 p40 [25,26]
NK cells Improve natural killing activity [7,8,28-30]
Acquired immunity
Humoral immunity Induce responses and production of IgA, IgM, IgG and IgG subunits [37-41]
Inhibit the OVA-sensitized decrease in IgA level in the small intestine [42]
Cell-mediated immunity Enhance antibody-dependent cellular cytotoxicity [7,29,30]
Stimulate T cell proliferation [28,45-47]
Promote the generation of immunosuppressive regulatory T cells (Tregs) [46]
Cytokine release
Of innate immunity Produce TNF-α, IL-1β, IL-6, and IFN-γ by macrophages [52]
Increase IL-2, IFN-γ, IL-1α, and GM-CSF production [53]
Decrease TNF-α, IL-1β, IL-6, IFN-γ, IL-12, and IL-18 by TLR reduction [54]
Reduce nitric oxide synthesis and production of TNF-α and IL-1β[55-57]
Inhibit secretion of IL-1β, IL-17 and IFN-γ[46]
Of acquired immunity Enhance production of IFN-γ and IL-2 [62,63]
Increase generation of IL-1, IL-6, IFN-γ, and IL-12 [61]
Increase Th2 cytokine (e.g., IL-4) and repress Th1 cytokine (e.g., IFN-γ) [47]
Stimulate Th1 and Th2 cytokine equally (IFN-γ, IL-2, IL-4, IL-10, and TNF-α) [65,66]
Infl ammatory disease regulation
Mitigate asthma symptoms suppressing airway hyperresponsiveness [70,72,73]
Protect host from bacterial septic responses [17,54,59]
Modulate CNS infl ammation and improve cerebral ischemia [55,74]
Ameliorate arthritis by reducing infl ammatory cell infi ltration, cytokine production, and cartilage destruction [57,75,76]
Alleviate atopic dermatitis by decreasing infl ammatory cytokines [77-82]
Anti-microbial activity
Bacteria Interrupt microbial adhesion to host cells [87,88]
Kill Gram positive and Gram nagative bacteria directly [89]
Inhibit survival or pathogenic mechanism of specifi c pathogen [88,90,91]
Enhance bacterial clearance and decrease pathology [64,84,85,92]
Interrupt quorum sensing system [93]
Infl uenza virus Increase antibody production and response with infl uenza virus A/PR8 infection [98]
Reduced ROS stress, IP-10, infl uenza-induced DNA damage and apoptosis in H9N2 infection [95]
Inhibit proliferation of infl uenza virus A (H1N1) [97]
HIV-1 Increase the frequency of gross deletion in the nef gene [104-107]
Increases the frequency of gross deletion in HIV-1 5’ LTR/ gag regions [107-109]
Others Inhibit viral growth of rotavirus, MNV and FCV [110,111]
Adjuvant
Improve antibody production and responsiveness (IgM, IgG, and IgG subunits) [7,41,66,118-121]
Activate mixed Th1 and Th2 immune responses [41,66,118-121]
NK, natural killer; DC, dendritic cells; MHC, major histocompatibility complex; OVA, ovalbumin; GM-CSF, granulocyte-macrophage colony-stimu-
lating factor; CNS, central nervous system; ROS, reactive oxygen species; HIV-1, human immunodeficiency virus type 1; MNV, murine norovirus;
FCV, feline calicivirus.
http://dx.doi.org/10.5142/jgr.2012.36.4.354
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J Ginseng Res Vol. 36, No. 4, 354-368 (2012)
investigated. In order to reveal the underlying molecular
mechanisms for the immunomodulating effects of gin-
seng in more detail, further in-depth studies need to be
provided.
As a well-known herbal immune stimulant, hundreds
of studies have extensively reported the anti-cancer or
chemopreventive effects of ginseng. The anti-cancer ef-
fects of ginseng are mainly through the improvements in
cell-mediated immunity consisting of cytotoxic T cells
and NK cells, while other mechanisms such as oxidative
stress, apoptosis, and angiogenesis are also involved. A
comprehensive review dealing with anti-cancer effects
from the immunological point of view would be impera-
tive in the near future.
ACKNOWLEDGEMENTS
This research was supported by the Public welfare &
Safety research program through the National Research
Foundation of Korea funded by the Ministry of Educa-
tion, Science and Technology (2010-0020842).
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