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We discuss current information on the ability of extracts and isolated metabolites from mushrooms to modulate immune responses. This can result in a more enhanced innate and acquired disease resistance. The major immunomodulating effects of these active substances derived from mushrooms include mitogenicity and activation of immune effector cells, such as lymphocytes, macrophages, and natural killer cells, resulting in the production of cytokines, including interleukins (ILs), tumor necrosis factor alpha (TNF)-α, and interferon gamma (INF)-γ. In particular, the ability of selective mushroom extracts to modulate the differentiation capacity of CD4+ T cells to mature into TH1 and/or TH2 subsets will be discussed. As a consequence these extracts will have profound effects in particular diseases, like chronic autoimmune TH1-mediated or allergic TH2-mediated diseases. Immunosuppressive effects by mushroom components have also been observed. The therapeutic effects of mushrooms, such as anticancer activity, suppression of autoimmune diseases, and allergy have been associated with their immunomodulating effects. However, further studies are needed to determine the molecular mechanisms of the immunomodulating effects of mushrooms metabolites both individually and in complex mixtures, for example, extracts.
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©2005 Hindawi Publishing Corporation
Mediators of Inflammation 2005:2 (2005) 63–80 PII: S0962935105412223 DOI: 10.1155/MI.2005.63
INVITED REVIEW
Antiinflammatory and Immunomodulating
Properties of Fungal Metabolites
Cristina Lull,1Harry J. Wichers,1and Huub F. J. Savelkoul2
1Agrotechnology and Food Innovations, Wageningen University and Research Center,
Bornsesteeg 59, 6708 PD Wageningen, The Netherlands
2Cell Biology and Immunology Group, Wageningen University and Research Center,
Marijkeweg 40, 6709 PG Wageningen, The Netherlands
Received 22 December 2004; accepted 25 January 2005
We discuss current information on the ability of extracts and isolated metabolites from mushrooms to modulate immune responses.
This can result in a more enhanced innate and acquired disease resistance. The major immunomodulating eectsoftheseactivesub-
stances derived from mushrooms include mitogenicity and activation of immune eector cells, such as lymphocytes, macrophages,
and natural killer cells, resulting in the production of cytokines, including interleukins (ILs), tumor necrosis factor alpha (TNF)-α,
and interferon gamma (INF)-γ. In particular, the ability of selective mushroom extracts to modulate the dierentiation capacity of
CD4+T cells to mature into TH1 and/or TH2 subsets will be discussed. As a consequence these extracts will have profound eects
in particular diseases, like chronic autoimmune TH1-mediated or allergic TH2-mediated diseases. Immunosuppressive eects by
mushroom components have also been observed. The therapeutic eects of mushrooms, such as anticancer activity, suppression of
autoimmune diseases, and allergy have been associated with their immunomodulating eects. However, further studies are needed
to determine the molecular mechanisms of the immunomodulating eects of mushrooms metabolites both individually and in
complex mixtures, for example, extracts.
INTRODUCTION
The number of dierent mushroom species on earth
is estimated at 140 000, of which may be only 10% are
known. Meanwhile, of those approximately 14 000 species
that we know today, about 50% are considered to possess
varying degrees of edibility, more than 2000 are safe, and
about 700 species are known to possess significant phar-
macological properties [1,2,3,4]. Mushrooms have long
been attracting a great deal of interest in many areas of
foods and biopharmaceuticals. They are well known for
their nutritional and medicinal values [1,4,5,6,7,8,9].
In accordance to Breene [10] the gross composition of
mushrooms is water (90%), and from the dry matter: pro-
tein (10%–40%), fat (2%–8%), carbohydrates (3%–28%),
fiber (3%–32%), and ash (8%–10%) (the ash percentage
Correspondence and reprint requests to Huub F. J. Savelkoul,
Cell Biology and Immunology Group, Wageningen University
and Research Center, Marijkeweg 40, 6709 PG Wageningen, The
Netherlands; huub.savelkoul@wur.nl
This is an open access article distributed under the Creative
Commons Attribution License which permits unrestricted use,
distribution, and reproduction in any medium, provided the
original work is properly cited.
is the fraction of dry matter that remains after inciner-
ation of the organic material in a sample, and is mainly
composed of salts, metals, and so forth). Many species
of mushrooms are cultivated worldwide. Global produc-
tion increased to about 6.2 million tons in 1997, with a
more than 12% increase annually from 1981 to 1997 [11].
Mushroom extracts have been increasingly sold as dietary
supplements. The market value of mushroom dietary sup-
plement products worldwide is about US$5–6 billion per
year [12].
Medicinal mushrooms have an established history of
use in traditional oriental therapies. Historically, hot-
water-soluble fractions (decoctions and essences) from
medicinal mushrooms were used as medicine in the Far
East, where knowledge and practice of mushroom use pri-
marily originated [4,13,14]. Mushrooms such as Gano-
derma lucidum (Reishi), Lentinus edodes (Shiitake), Inono-
tus obliquus (Chaga), and many others have been collected
and used for hundreds of years in Korea, China, Japan,
and eastern Russia [4].
Mushroom metabolites are increasingly being utilized
to treat a wide variety of diseases, particularly as they
can be added to the diet and used orally, without the
need to go through phase-I/II/III trials as an ordinary
medicine, and they are considered as a safe and use-
ful approach for disease treatment. A lot of scientific
64 Cristina Lull et al 2005:2 (2005)
Spore germination
Mycelium
Mating of compatible hyphae
Primordia formation
Fruit body development
Fruiting body
Vegetative mycelium
Cap
Stem
Gills
Spore liberation
Figure 1. Diagrammatic representation of mushroom life cycle.
investigations have been performed to discover possible
functional properties, which could be ecient in possi-
ble treatments of diseases like allergic asthma [15,16,17],
food allergy [18,19], atopic dermatitis [20], inflamma-
tion [21,22], autoimmune joint inflammation such as
rheumatoid arthritis [23], atherosclerosis [24,25], hy-
perglycemia [26], thrombosis [27], human immunodefi-
ciency virus (HIV) infection [28,29], listeriosis [30], tu-
berculosis [31], septic shock [32], and cancer [33,34,35,
36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,
52,53,54,55].
In the last years many researchers have studied the
possibility that extracts and isolated metabolites from
mushrooms stimulate or suppress specific components of
the immune system. Immunomodulators can be eective
agents for treating and preventing diseases and illnesses
that stem from certain immunodeficiencies and other de-
pressed states of immunity [56]. Synonymous terms for
immunomodulators include biological response modi-
fiers, immunoaugmentors, or immunorestoratives [57].
Those metabolites which appear to stimulate the human
immune response are being sought for the treatment of
cancer, immunodeficiency diseases, or for generalized im-
munosuppression following drug treatment, for combi-
nation therapy with antibiotics, and as adjuvants for vac-
cines [58]. Those metabolites that suppress immune re-
actions are potentially useful to mitigate autoimmune or
certain gastrointestinal tract diseases (eg, Crohn’s) [59].
At least 651 species and 7 infraspecific taxa repre-
senting 182 genera of hetero- and homobasidiomycetes
mushrooms contain antitumor or immunostimulating
metabolites [4]. Bioactive metabolites can be isolated
from fruiting bodies (Figure 1), pure culture mycelia,
and culture filtrate (culture broth). Nowadays many at-
tempts are being made to obtain bioactive metabolites
from mycelia through submerged fermentation culture.
The cultivation of mushrooms to produce fruiting bod-
ies is a long-term process requiring from one to several
months for the first fruiting bodies to appear. The growth
of mushroom cell cultures in submerged conditions in a
liquid culture medium accelerates the process, resulting in
biomass yield within a few days and allows to obtain stan-
dardized nutriceutical substances.
Several major substances with immunomodulatory
and/or antitumor activity have been isolated from mush-
rooms. These include mainly polysaccharides (in particu-
lar β-D-glucans (Figure 2)), polysaccharopeptides (PSP),
polysaccharide proteins, and proteins. Furthermore, other
bioactive substances, including triterpenes, lipids, and
phenols, have been identified and characterized in mush-
rooms with proven medicinal properties. The major im-
munomodulating eects of these active substances de-
rived from mushrooms include mitogenicity and activa-
tion of immune cells, such as hematopoietic stem cells,
lymphocytes, macrophages, dendritic cells (DCs) and nat-
ural killer (NK) cells, resulting in the production of cy-
tokines. The therapeutic eects of mushrooms, such as
anticancer activity, suppression of autoimmune diseases,
and allergy have been associated in many cases with their
immunomodulating eects.
Whilst it is known that mushroom extracts have im-
munomodulatory and/or antitumor activity, the standard
approach has been to isolate, characterize, and administer
the pure active constituents. However, dierent compo-
nents in a mushroom extract may have synergistic activi-
ties [49,60]. There are several reports of mushrooms con-
taining more than one polysaccharide with antitumor ac-
tivity. The responses to dierent polysaccharides are likely
to be mediated by dierent cell surface receptors, which
may be present only on specific subsets of cells and may
2005:2 (2005) Immunomodulating Eects of Fungal Metabolites 65
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(a)
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Figure 2. Repeating unit of immunomodulatory β-glucans (a) from Grifola frondosa (D-fraction, MW: 1000 kD) and (b) from L
edodes (lentinan, MW: 500 kD).
Tab l e 1. Immunomodulatory activities of mushroom compounds on hematopoietic stem cells.
Species Compound Immune eects Reference
Grifola frondosa MD-fraction BMCs growth and dierentiation into CFU-GM [61]
recovery of CFU-GM response after DOX induced hematopoietic suppression
Lentinus lepideus PG101 CFU-GM, BFU-E, IL-1β, IL-6, GM-CSF [63]
TNF-αin irradiated mice
Sparassis crispa SCG granulocytes, monocytes, γδT cells and NK1.1 cells in the peripheral cells in [64]
CY-induced leukopenia
trigger distinct downstream responses. A combination of
such responses involving dierent cell subsets could con-
ceivably provide greater tumor inhibition than could be
induced by a single polysaccharide [49].
EFFECTS OF MUSHROOM METABOLITES
ON HEMATOPOIETIC STEM CELLS
Various metabolites, especially carbohydrates isolated
from mushrooms, were reported to aect bone mar-
row cells (BMCs), and to induce hematopoiesis (Ta-
ble 1). Recently, Lin et al [61] reported that Maitake
MD-fraction (obtained by further purification of D-
fraction), an extract isolated from the fruit body of
Grifola frondosa whose active component is an isolated
β-glucan, a protein-bound polysaccharide compound,
caused direct enhancement of the colony-forming units-
granulocytes/macrophages (CFU-GM) response of BMCs
progenitors and enhanced recovery of the CFU-GM re-
sponse after doxorubicin (DOX) induced hematopoietic
suppression. These studies suggest that MD-fraction has
the potential to reduce hematopoietic suppression in-
duced by chemotherapy.
PG101, a water-soluble extract that consists of
protein-bound polysaccharides, isolated from cultured
mycelia of Lentinus lepideus [62], is a potent immune
modulator that recovers the radiation-damaged bone
marrow system very eciently. In PG101-treated mice,
the number of CFU-GM and erythroid burst-forming
units (BFU-E) were increased to almost the levels seen
in nonirradiated control as early as 8 days after irradi-
ation. Radiation is known to result in serious dysregu-
lation of cytokine expression. PG101 increased the lev-
els of IL-1β, IL-6, and granulocyte macrophage-colony-
stimulating factor (GM-CSF) over the 24-day period.
PG101 significantly reduced the level of TNF-α.TNF-α,
which is increased as a consequence of tissue injury and
anemia due to radiation, is thought to be a key mediator
for the pathogenesis of radiation damage. Thus, PG101
showed great potential as a supplement or a major ther-
apeutics in immunocompromised or immunosuppressed
individuals whose bone marrow system is damaged [63].
SCG, a β-(13)-D-glucan with β-(16) branches
isolated from fruit bodies of Sparassis crispa,enhanced
the hematopoietic response in cyclophosphamide- (CY-
) induced leukopenic mice by intraperitoneal routes over
a wide range of concentrations. Monocytes and granulo-
cytes in the peritoneal cavity, liver, spleen, and bone mar-
row recovered faster than in the control group. The ratio
of NK cells and γδT cells in the liver, spleen, and peri-
toneal cavity was also increased. These results suggest the
usefulness of Scrispain cancer immunotherapy [64].
EFFECTS OF MUSHROOM METABOLITES
ON THE INNATE IMMUNE SYSTEM
Macrophages
The recognition of microbes by macrophages and
neurophilic granulocytes leads to phagocytosis of the mi-
crobes and activation of the phagocytes to kill the ingested
microbes. Recognition is mediated by toll-like receptors
(TLR) that are specific for dierent components of mi-
crobes. TLR-2 binds lipogycans, TLR-4 binds bacterial
66 Cristina Lull et al 2005:2 (2005)
lipopolysaccharide (LPS), TLR-5 binds flagellin, and TLR-
9 binds unmethylated CpG nucleotides present in bac-
teria. As a consequence of recognition and phagocyto-
sis several enzymes are activated, including oxidases and
inducible nitric oxide synthase (iNOS), resulting in the
production of bacteriocidal reactive oxygen intermediates
(ROI) and nitric oxide (NO).
The eects of mushroom extracts and metabolites on
macrophages have been extensively studied in vitro and in
vivo. Some mushroom metabolites activate macrophages
to produce various mediators, even in normal mice. Ac-
tivities are summarized in Tab l e 2 .
Water extracts of the mycelial culture and fruiting
bodies of Agaricus blazei Murill induced TNF-αsecretion
by macrophages derived from rat bone marrow. Fractions
B-4 and B-5 obtained from ethanol precipitation of fruit-
ing bodies markedly induced TNF-αsecretion. Similar ef-
fects were observed in IL-8 secretion by macrophages. Re-
garding NO, fraction B-5 induced a significant increase
in NO secretion and fractions B-4 and B-6 slightly in-
duced NO secretion. Northern blot analysis showed that
the increases in cytokine and NO secretion were due to
an increase in cytokine mRNAs or NO synthase mRNA
[65]. Thus AblazeiMurill contains certain components
which activate macrophages contributing to the immune
response in vitro.
Wang e t a l [ 66] reported that after treatment of
macrophage cultures with a polysaccharide from fresh
fruiting bodies of G lucidum, the levels of IL-1β,TNF-α,
and IL-6 were 5.1-, 9.8-, and 29-fold higher than in cul-
tures of untreated cells. In addition, the release of INF-
γfrom T lymphocytes was also greatly enhanced in the
presence of this polysaccharide. This proinflammatory cy-
tokine response is suggested to facilitate the antitumor ac-
tivity of this extract.
Grifolan (GRN), an antitumor β-glucan isolated from
Gfrondosainduced the release of IL-1, IL-6 and TNF-α
from macrophages [67,68]. Ishibashi et al [69]reported
that an insoluble as well as a high-molecular-mass solu-
ble form of GRN are required for TNF-αproduction by
macrophages.
The eect of Maitake D-fraction was studied by
Sanzen et al [70] on the iNOS-mediated NO production
in RAW264.7 macrophages with special reference to anti-
tumor activity of MD-fraction against human hepatoma-
derived huH-1 cells and the data suggested that MD-
fraction is a novel inducer for iNOS which contributes at
least in part to antitumor activity of MD-fraction.
Kodama et al [30] examined the eects of Maitake
D-fraction on the treatment of Listeria-infected mice in
combination with vancomycine (VCM). In mice admin-
istered with both D-fraction and VCM, macrophages pro-
duced2.7timesasmuchIL-1βas that of nontreated con-
trol mice. The bactericidal activity of splenic T cells was
also enhanced by 2.6 times of that of nontreated control
mice. These results suggest a clinical benefit of D-fraction
in the case of antibacterial treatment for patients with
high risks.
Monocytes/macrophages seem to be the major tar-
get cell type responsive to PG101. Jin et al [62] proposed
that PG101 interacts with macrophages or related cells
and results in the activation of the transcription factor
nuclearfactorkappaB(NF-κB), which sets oaseries
of reactions producing a variety of proinflammatory and
antiinflammatory cytokines (TNF-α,IL-1β, IL-10, IL-12,
GM-CSF, IL-18) in a sequential manner. Inflammatory-
cytokine-induced phosphorylation of a degradative mo-
tif in IκBtriggersIκB proteolysis, liberating NF-κBfrom
the inactive heterodimer and NF-κB transcription which
in turn prevents cytokine-induced death of inflamma-
tory cells. Despite its significant biological eect on vari-
ous cytokines, PG101 remained nontoxic in both rats and
human peripheral blood mononuclear cells (hPBMCs)
even at a biological concentration approximately 20 times
greater. PG101 demonstrates great potential as a thera-
peutic immune modulator.
A galactomannan isolated from a polar extract of
Morchella esculenta carpophores enhanced macrophage
activation. At 3.0 µg/mL the galactomannan polysaccha-
ride (about 2.4% protein) increased NF-κB-directed lu-
ciferase expression in THP-1 human monocytic cells to
levels of 50% of those achieved by maximal activating
concentration (10.0 µg/mL)ofLPS[71].
By administering PL, an acidic polysaccharide iso-
lated from Phellinus linteus, the production of NO and
tumoricidal activity were increased in murine peritoneal
macrophages in vivo and in vitro. PL has been claimed to
cause the inhibition of tumor growth and metastasis of
murine B16F10 melanoma cells [72]. Such properties of
PL may be related to its ability to induce the production
of the tumoricidal eector molecule NO through protein
tyrosine kinase (PTK) and protein kinase C (PKC) [73].
Considering the main role that proinflammatory cytokine
production plays in the pathogenesis of septic shock, Kim
et al [32] examined how the in vivo administration of
PL can modulate circulating cytokine responses in LPS-
treated mice. Administration of PL in vivo decreased IL-
2, IFN-γ,andTNF-αproduction in splenocytes and en-
hanced spontaneous cell apoptosis in macrophages and
lymphocytes stimulated with LPS in vitro. Thus, part of
the antiinflammatory eects of PL treatment in vivo may
result from the enhanced apoptosis of a portion of the ac-
tivated macrophages and lymphocytes. The ability of PL
to significantly reduce TNF-αproduction indicates the
potential of the polysaccharides in possible therapeutic
strategies that are based on down regulation of TNF-α
[32].
The methanol extract of fruit bodies of Cordyceps
pruinosa inhibited IL-1β,TNF-α, NO, and prostaglandin
E2(PGE2) in vitro and in vivo. The extract inhib-
ited these inflammatory mediators in LPS-stimulated
murine macrophage cell line RAW264.7 and primary
macrophages, by suppressing gene expression of IL-1β,
TNF-α, iNOS, and cyclooxygenase-2 (COX-2) through
the inhibition of NF-κB activation. Administration of the
extract significantly decreased the plasma level of these
2005:2 (2005) Immunomodulating Eects of Fungal Metabolites 67
Tab l e 2. Immunomodulatory activities of mushroom products on macrophages.
Species Product Immune eects Reference
Gfrondosa D-fraction IL-1β[30]
L lepideus PG101 TNF-α,IL-1β, IL-10, IL-12, GM-CSF, IL-18 [62]
Ablazei Water extracts mycelia and fruit bodies TNF-α[65]
Fractions B-4 and B-5 TNF-α, IL-8, NO
G lucidum Polysacchar ide IL-1β,TNF-α,IL-6 [66]
Gfrondosa GRN IL-1, IL-6, TNF-α[67,68,69]
Gfrondosa MD-fraction iNOS [70]
Mesculenta Galactomannan macrophage activity [71]
P linteus PL
NO
[72,73]
IL-2, IFN-γ,andTNF-αproduction in splenocytes
apoptosis of a portion of the activated
macrophages and lymphocytes in LPS-treated mice
C pruinosa Methanol extract Inhibit IL-1β,TNF-α,NO,PGE
2[74]
Saspratus Fucogalactan TNF-α,NO [75]
A cylindracea Ubiquitin-like peptide NO [77]
Tmongolicum Lectins (TML-1, TML-2) TNF-α, Nitrite ions [78]
inflammatory mediators in LPS-injected mice. These re-
sults suggest that the Cpruinosamethanol extract sup-
presses inflammation through suppression of NF-κB-
dependent inflammatory gene expression, suggesting that
the Cpruinosaextract may be beneficial for treatment
of endotoxin shock or sepsis [74]. Also, the methanol
extract of fruit bodies of Pleurotus florida showed anti-
inflammatory and antiplatelet-aggregating activities but
the exact mechanism for these activities is unknown
[21].
A fucogalactan, isolated from Sarcodon aspratus,
elicited the release of TNF-αand NO in macrophages of
mice in vitro. TNF-αproduction induced with 50 µg/mL
of fucogalactan was significantly higher than that in-
duced by lentinan (500 µg/mL)byapproximately4.3-fold.
Mizuno et al [75] suggested that the immunomodulat-
ing activity of this fucogalactan on TNF-αand NO pro-
ductions might contribute to antituor activity in tumor-
bearing hosts as well as various immunomodulating ef-
fects.
In mice treated with an immunosuppressive carcino-
gen, administration of a mushroom-enriched diet con-
taining L edodes,Gfrondosa,andPleurotus ostreatus re-
stored the normal level of the chemotactic activity of
macrophages and the capability of lymphocytes to pro-
liferate in response to mitogen [76].
Proteins and peptides from mushrooms are also
known to activate macrophages. A ubiquitin-like pep-
tide isolated from fruiting bodies of the mushroom Agro-
cybe cylindracea enhanced NO production in murine peri-
toneal macrophages with a potency comparable to that of
LPS [77]. Two lectins isolated from the mushroom Tri -
choloma mongolicum (TML-1 and TML-2) stimulated the
production of nitrite ions and TNF-αby macrophages in
normal and tumor-bearing mice [78].
Natural killer cells
Natural killer cells are a class of lymphocytes that
rapidly respond to intracellular infections with viruses or
bacteria, by killling the infected cells and by producing the
macrophage-activating cytokine, IFN-γ.
Some mushroom metabolites exhibit stimulating ef-
fects on NK cells (Tab l e 3). Innate immunity is in the
critical arms of immune surveillance against tumor de-
velopment. Moreover, in the innate immune system, NK
cells, which do not express T-cell receptors that recognize
specific peptides presented on the major histocompatibil-
ity complex (MHC), rather than T cells, seem well suited
for this role. NK cells can recognize the surface changes
that occur on a variety of tumor cells and virally infected
cells [79]. NK cells have two relevant functions, related
to the natural immune response against pathogens [80].
One is cytotoxicity, mediated by the recognition and lysis
of target cells such as virus- and bacteria-infected cells.
The second NK cells function is to produce cytokines
such as IFN-γ,TNF-α, and GM-CSF, that can modulate
natural and specific immune responses. Additionally, in-
fected or activated DCs and macrophages produce cy-
tokines and chemokines such as IFN-α/β, IL-12, IL-15,
and IL-18 that stimulate NK cells to rapidly produce other
cytokines (including IFN-γ,TNF-α, and GM-CSF) and
chemokines (such as ATAC/lymphotactin, mig, and MIP-
1α)[81].
Kodama et al [41,82] monitored levels of NK cell cy-
totoxic activity in cancer patients receiving D-fraction. El-
evated levels of cytotoxic activity were maintained for one
year. To elucidate the mechanisms underlying long-term
activation of NK cells during treatment with D-fraction,
the authors examined tumor volume and levels of IFN-γ
and TNF-αin MM46-bearing C3H/HeN mice to which
D-fraction was administered for 19 days. D-fraction
68 Cristina Lull et al 2005:2 (2005)
Tab l e 3. Immunomodulatory activities of mushroom products on NK cells.
Species Compound Immune eects Reference
Gfrondosa D-fraction
TNF-α,IFN-γreleased from spleen cells; TNF-αexpressed
[41,82,83,84]
in NK cells in tumor-bearing mice
NK cells activity (INF-γ) indirectly through IL-12 produced by
macrophages and DCs in normal mice
Ablazei Hot-water extract NK activity of spleen cells in na¨
ıve BALB/c mice [85]
Ablazei
n-hexane
Maintain NK activity of spleen cells in tumor-bearing mice [87]
Dichloromethane
Methanol
Ablazei ABMK NK activity on cancer patients [88]
markedly suppressed tumor growth, corresponding with
increases in TNF-αand IFN-γreleased from spleen cells
and a significant increase in TNF-αexpressed in NK cells.
Furthermore, D-fraction increased macrophage-derived
IL-12, which serves to activate NK cells. Thus, NK cells
are not only responsible for the early eects of D-fraction
on tumor growth, but also for the long-term tumor-
suppressive eects of D-fraction through increased IL-12
released from macrophages. D-fraction was capable of en-
hancing and maintaining peripheral blood NK cell activ-
ity in patients with lung and breast cancer [41]. In ad-
dition, Maitake D-fraction, stimulated the natural immu-
nity related to the activation of NK cells indirectly through
IL-12 produced by macrophages and DCs in normal mice
[83]. IFN-γproduction by splenic NK cells increased sig-
nificantly 3 days after D-fraction administration. In a re-
cent study, Kodama et al [84] reported the activation of
macrophages and DCs in normal mice as well. Therefore,
administration of D-fraction to healthy individuals may
serve to prevent infection by microorganisms.
Treatment with hot-water extracts of Ablazeifruit-
ing bodies increased NK activity of spleen cells in na¨
ıve
BALB/c mice [85]. In meth A-bearing BALB/c mice, the
same extracts enhanced the induction of antigen-specific
cytotoxic T lymphocytes (TC)andIFN-γproduction. Up
regulation of NK and TCactivity is triggered by IL-12-
dependent activation [86]. It is not yet clear whether oral
administration of Agaricus extracts enhances IL-12 pro-
duction in vivo [85].
Ehrlich-carcinoma-bearing mice treated with the n-
hexane, dichloromethane, or methanol extracts from A
blazei fruiting bodies were able to maintain the NK ac-
tivity of spleen cells during the first 10 days after tumor
implantation. The NK activity of these groups was sim-
ilar to that of normal controls and higher than that of
tumor-bearing mice treated with water. The results of NK
activity on the 30th day after the injection of tumor cells
suggest that none of the three extracts was able to main-
tain the lytic activity against Yac-1 target cells. It is pos-
sible that after 30 days the production of soluble factors
like prostaglandins, TGF-β, or IL-10 by Ehrlich carcinoma
cells was enough to prevent the increase of NK activity by
the n-hexane extract [87].
Ahn et al [88] investigated the beneficial eects of
the consumption of an extract of AblazeiMur ill Kyowa
(ABMK) on immunological status and qualities of life
in cancer patients undergoing chemotherapy. They ob-
served that NK cell activity was significantly higher in
the ABMK-treated group and suggested that ABMK treat-
ment might be beneficial for gyneacological cancer pa-
tients undergoing chemotherapy.
The medicinal fungus water extract (FWE) consists
of equal amounts of Coriolus versicolor,Cordyceps sinen-
sis,L edodes,Ablazei,andG lucidum. Zhang et al [89]
reported that FWE enhanced the phagocytosis of peri-
toneal macrophages, promoted NK activity in mice, and
suppressed the growth of B-16 melanoma. FWE had sig-
nificantly promoted mouse NK activity at the dose of
400 mg/kg, which suggests that FWE may possess the abil-
ity to activate NK to directly kill tumor cells, induce NK
to secrete cytotoxic agents to elicit the apoptosis of tumor
cells, or remove tumor cells by other pathways.
Dendritic cells
DCs are antigen-presenting cells (APC) with a unique
ability to induce primary immune response of both helper
(TH)andT
C[90]. Beside activating naive T cells, DCs can
directly activate naive and memory B cells. DCs at dier-
ent stages of dierentiation can regulate eectors of innate
immunity such as NK cells and NK T cells. The induction
of tumor immunity can be initiated by the eectors of in-
nate immunity and further developed by cells of adaptive
immunity, with DCs playing a central regulatory role.
Cao and Lin [91] studied the regulatory eects of Gl-
PS, G lucidum polysaccharides (GLPS), on maturation
and function of cultured murine bone-marrow-derived
DCs in vitro. Gl-PS could promote not only the matura-
tion of cultured murine bone-marrow-derived DCs, but
also the immune response initiation induced by DCs.
PL induced maturation of bone-marrow-derived DCs
and readies them for T-cell-mediated immune responses.
PL significantly increased membrane molecules, includ-
ing MHC class I, II, CD80, and CD86, and IL-12p70
in DCs. Also, PL markedly reduced the endocytic activ-
ity of DCs and augmented their capacity to promote the
proliferation of na¨
ıve allogeneic T cells [92]. PL enhanced
2005:2 (2005) Immunomodulating Eects of Fungal Metabolites 69
the phenotypic and functional maturation of DCs via
TLR-2- and/or TLR-4-mediated NF-κB, ERK, and p38
MAPK signal pathways. It is the first article reporting
that a polysaccharide from mushrooms can activate a TLR
signaling [93]. Kim et al [94] reported that the admin-
istration of PL induced antitumor and immunomodu-
lating activities via maturation of CD11c+CD8+DCs in
tumor-bearing mice. The inhibitory eect of PL on the
growth of MCA-102 tumor cells was associated with its
immunoregulatory properties, including the induction of
IL-12 and IFN-γproduction leading to a TH1 dominant
state. Therefore, PL would be useful in preventing tumor
growth, and it also has the advantage of having no side
eects.
The existence of a strongly immunosuppressive state
in cancer-bearing individuals inhibits DCs maturation.
Kanazawa et al [95] reported that a protein-bound
polysaccharide K (PSK) isolated from the cultured
mycelium of C versicolor promoted both the phenotypic
and functional maturation of DCs derived from human
CD14+mononuclear cells. PSK has also been reported to
resolve the immunosuppressive state of a cancer-bearing
host and might be associated with DCs maturation di-
rectly [95]. Activities of mushroom metabolites on DCs
are summarized in Tab l e 4 .
Complement
Activation of complement by either the classical or al-
ternative pathway results in the generation of a wide spec-
trum of biological activities with the potential to modify
immune responses [96,97]. Particularly, the activation of
complement via the alternative pathway is important in
natural immunity to bacterial infections [98,99].
Although there are a few reports concerning the re-
lationship between complement-activating and tumor-
regressing activity of glucan including lentinan, the pos-
itive correlation between the two activities was found by
Okuda et al [100]. They observed a correlation between
the ability to activate complement via the alternative path-
way in vitro and inhibition of tumor growth in vivo.
However, the opposite result, no correlation, was found
by Hamuro et al [101]. Thus there is no consistent view
on the correlation between the two antagonozing activi-
ties.
ABP-F and ABP-M, fine particles of AblazeiMurill
fruiting body and mycelium, respectively, prepared by
mechanical disruption, activated the human complement
system via the alternative pathway in human serum (Tab l e
5). When particles from fruiting bodies of AblazeiMurill
(ABP-F) were reacted with human serum, the formation
of complement-opsonized ABP, iC3b-ABP-F complexes,
and binding of the complexes to human peripheral blood
monocytes, were demonstrated in vitro by immunofluo-
rescence. Further, the resident human peripheral nucle-
ated cells incubated in the presence of iC3b-ABP-F com-
plexes inhibited the proliferation of the human tumor cell
line TPC-1 in vitro [102].
An alkali extract from cultured mycelium of Glu-
cidum activated both classical and alternative pathways of
complement [103]. Min et al [104] reported that triter-
penoids such as ganoderiol F, ganodermanondiol, and
ganodermanontriol from G lucidum had a potent anti-
complement activity against the classical pathway with
IC50 values of 4.8–4.17 µM. A clinical study in elderly pa-
tients with insomnia and palpitation has shown that tak-
ing G lucidum essence for 4–6 weeks increased their serum
C3 levels [105].
Also, LELFD, a β-(13)-glucan, obtained from liq-
uid-cultured mycelium of Gfrondosa, could activate the
alternative complement pathway [106].
Anticomplementary activity of 61 strains of higher
fungi from Korea was screened for immunostimulation
[107]. Extracts from 11 of 61 strains, including 5 of G
lucidum,3ofL edodes,2ofCordyceps sp,and1ofAgari-
cus campestris, showed higher anticomplementary activity
than Krestin from C versicolor. The most potent anticom-
plementary activity was found with an extract from Ledo-
des IY105, that reduced complement capacity by 31.7%.
EFFECTS OF MUSHROOM METABOLITES
ON ADAPTIVE IMMUNE SYSTEM
T lymphocytes
T lymphocytes include T-helper (TH)cellsandcyto-
toxic T (TC) cells. THcells interact with B cells and help
them to divide, dierentiate, and make antibody or inter-
act with mononuclear phagocytes and help them destroy
intracellular pathogens. THcells generate their eects by
releasing soluble cytokines and/or by direct cell-cell in-
teractions. The TCcells destroy target host cells that have
been infected by pathogens.
THcells
CD4+cells secrete a number of cytokines that are im-
portant in the activation of B and other T cells, as well
as cells of the innate immune system. Based on the types
of cytokines these CD4+cells produce, they are classified
into a number of THtypes (0, 1, 2, or 3). TH1cellspro-
duce IL-2, IFN-γ,andTNF-β(LT), and introduce cel-
lular immunity to mainly intracellular infections organ-
isms. TH2 cells produce IL-4, IL-5, IL-6, IL-10, and IL-13,
and activate humoral immunity, mainly directed against
extracellular infections. Precursor or TH0 cells produce
IL-4 and IFN-γconcomitantly. Less is known about the
physiologicalroleofT
H0 type cells. Thymus-derived reg-
ulatory T-cell populations, including naturally occur-
ring CD4+CD25+T cells and inducible IL-10 or TGF-β-
producing TR/TH3 cells, develop in the periphery from
THcells depending on the tolerance-inducing micro-
environment in which these T cells reside. By blocking ac-
tivation of other lymphocytes and APC either directly (by
CTLA4-CD28 interaction) or indirectly (by cytokines like
IL-10 and TGF-β), these cells ensure self-tolerance mech-
anisms. In diseased states, however, the presence and/or
70 Cristina Lull et al 2005:2 (2005)
Tab l e 4. Immunomodulatory activities of mushroom compounds on DCs.
Species Compound Immune eects Reference
G lucidum Gl-PS proliferation of one-way MLC induced by DC [91]
P linteus PL
phenotypic and functional maturation of DC
[92]
membrane molecules, including MHC I, II, CD80, and CD86, and IL-12p70 in DC
endocytic activity of DC
capacity of DC to promote the proliferation of na¨
ıve allogenic T cells and
readies them for T-cell-mediated immune responses
Cversicolor PSK Promoted both the phenotypic and functional maturation of DC derived from [95]
human CD14+mononuclear cells
Tab l e 5. Immunomodulatory activities of mushroom compounds on complement.
Species Compound Immune eects Reference
Ablazei Fine particles of fruiting body: ABP-F, Activation of the human complement system via the [102]
and mycelium: ABP-M alternative pathway in human serum
G lucidum Alkali extract Activation of both classical and alternative pathways of [103]
complement
G lucidum Triterpenoids Anticomplement activity [104]
Gfrondosa LELFD Activation of the alternative complement pathway [106]
activity of these cells is often reduced leading to enhanced
immunopathology, characteristic of chronic inflamma-
tory diseases, like auto-immune and allergic diseases.
The downstream immune response is chosen depend-
ing on which subtype of T cell is activated, which means
that the proportion of the activated sub-types influences
phylaxis immunity and antitumor immunity. This control
system is also aected by the production of IL-1β, IL-12,
and IL-18 by APC [108,109]. The development of TH1
or TH2typesfromna
¨
ıve cells to eector cells is regulated
by the presence of specific cytokines in the microenviron-
ment at the time of T cell priming. For the TH1 type, IL-
12 is a necessary cytokine of dierentiation [110], whereas
for the TH2 type, IL-4 and IL-10 are critical [111]. Recent
study shows that many immune disorders are attributable
to the collapse of the system controlling the proportion
of TH1toT
H2 cells [112]. Many diseases such as leprosy,
allergy, multiple sclerosis, and responses to immunotoxic
agents have pathology associated with aberrant TH1and
TH2 polarization. TH1 cells may cause immunopathol-
ogy and organ-specific autoimmune disease if dysregu-
lated [113,114,115,116]. Because cytokines produced by
TH2 cells, such as IL-4 and IL-5, can activate mast cells and
eosinophils and in addition can result in elevated levels of
IgE, they have been strongly implicated in atopy and aller-
gic inflammation [117]. Restoration of the proper balance
between TH1andT
H2 cells is generally considered essen-
tial in the treatment of tumors, which are generated when
cellular immunity is aected by immunosuppressing fac-
tors.
Some mushroom polysaccharides might induce a type
1 immune response, whereas others favor a type 2 polar-
ization [49,118]. Borchers et al [49] reported that the lim-
ited data available to date do not allow one to determine
whether mushroom polysaccharides do so independently
of the animal strain or species and disease state investi-
gated or whether the nature of their immunomodulatory
eects depends on the model to a greater extent than has
been appreciated to date.
Lentinan has been described as a T-cell-oriented ad-
juvant [119]. The skewing of TH1/TH1 balance to TH1
by lentinan (Tab l e 6 ) is directed through the distinc-
tive production of IL-12 versus IL-6, IL-10, and PGE2
by peritoneal macrophages, depending on intracellular
glutathione redox status [120]. Based on the intracellu-
lar content of glutathione, two classes of macrophages
have been proposed with diverse functional conse-
quences: reductive macrophages with high, and oxidative
macrophages with low glutathione levels.
Sclerotinia sclerotiorum glucan (SSG) from Sclero-
tinia sclerotiorum IFO 9395 induced the development of
TH1 cells via the IL-12 pathway [118].
Inoueetal[121] investigated the antitumor func-
tions of D-fraction in relation to its control of the bal-
ance between T lymphocyte subsets TH1andT
H2. D-
fraction decreased the activation of B cells and potenti-
ated the activation of THcells, resulting in enhanced cel-
lular immunity. It also induced the production of IFN-
γ, IL-12p70, and IL-18 by whole spleen cells and lymph
node cells, but suppressed that of IL-4. These results sug-
gest that D-fraction establishes TH1 dominance which in-
duces cellular immunity in the population that was TH2
dominated due to the presence of this particular car-
cinoma [121]. In a later study, Harada et al [122]re-
ported that D-fraction induces the dierentiation into
TH1 cells of CD4+T cells in tumor-bearing BALB/c mice
2005:2 (2005) Immunomodulating Eects of Fungal Metabolites 71
Tab l e 6. Immunomodulatory activities of mushroom compounds on T cells.
Species Compound Immune eects Reference
F velutipes Fve TH1response [18]
S sclerotiorum IFO
9395 SSG TH1 response [118]
L edodes Lentinan TH1response [120]
Gfrondosa D-fraction Enhances TH1 dominant response through enhancement of [121,122]
IL-12p70 and IFN-γproduced by activated DCs
Vvolvacea Vvo TH1-specific cytokines (IL-2, IFN-γ,LT),T
H2-specific [123,124]
cytokine (IL-4), TNF-α, and IL-2R
in which the TH2 response was dominant through en-
hancement of IL-12p70 production by DCs, when the ra-
tio of CD8α+DCs to CD8αDCs increased. In addition,
examination of the tumor rejection eect of D-fraction-
stimulated DCs loaded with tumor antigen revealed that
tumor growth is inhibited completely by activating CD4+
T cells and CD8+T cells. Furthermore, the level of TNF-α,
whichisproducedbyactivatedmacrophagesandNKcells
and is cytotoxic for tumor cells, increased by D-fraction-
DCs injection, indicating that D-fraction enhanced the
protective immunity by DCs loaded with tumor anti-
gen through activating macrophages and NK cells. Al-
though the action of D-fraction on DCs and its intra-
cellular signal transduction pathway remain unclear, D-
fraction may be a useful stimulator of DCs, which in-
duce the dierentiation of CD4+T cells to TH1cells
[122].
Vvo, a fungal immunomodulatory protein (FIP) pu-
rified from the edible mushroom, Vol v a r i e ll a v o l va c e a , in-
duced most TH1-specific cytokines (IL-2, IFN-γ,andLT)
and one TH2-specific cytokine (IL-4) within 4 hours in
mouse spleen cells. This result indicates that Vvo princi-
pally acts on TH1 cells and to a lesser extent on TH2cells
in the early event of activation. It is known that IL-4 acts
on B cells to induce activation and dierentiation, lead-
ing in particular to the production of IgE. The lower ef-
fect of Vvo compared with other FIPs on the prevention
of systemic anaphylaxis may be attributed to the elevated
expression of IL-4 [123,124].
Fve, a FIP isolated from the fruiting body of Flam-
mulina velutipes, selectively stimulates a TH1response
in hPBMCs [18]. Recently Hsieh et al [18]havechar-
acterized the immunomodulatory eects of Fve in more
detail and investigated the prophylactic use of Fve via
the oral route in a murine model of food allergy. They
have demonstrated that oral administration of Fve during
allergen sensitization could induce a TH1-predominant
allergen-specific immune response in mice and protect
the mice from systemic anaphylaxis-like symptoms af-
ter subsequent oral challenge with the same allergen. It
is worth noting that Fve could be administered orally
and retain its activity, while most protein drugs cannot.
This characteristic greatly promotes the potential of im-
munoprophylactic use of Fve [18]. Liu et al [16,17]have
demonstrated the ecacy of local nasal immunother-
apy (LNIT) for group 2 allergen of house dust mite
Dermatophagoides-pteronyssinus- (Dp2-) induced airway
inflammation in mice, using Dp2 peptide and Fve or LZ-
8, a FIP isolated from G lucidum.
B cells
Three polysaccharides isolated from G lucidum,two
heteroglycans (PL-1 and PL-4) and one glucan (PL-3) en-
hanced the proliferation of T and B lymphocytes in vitro
to varying contents and PL-1 exhibited an immune stim-
ulating activity in mice [125].
PGL, a complex β-D-glucan, has a strong eect on
suppressing the antibody production [126].
GLIS, a proteoglycan isolated from the fruiting body
of G lucidum, is a B-cell stimulating factor. This com-
pound stimulated B lymphocyte activation, proliferation,
dierentiation and production of immunoglobulins. The
activation of B cells by GLIS may be associated with the
expression of PKC αand PKC γin B cells [127]. GLIS
stimulated the proliferation of mouse spleen lympho-
cytes, resulting in a threefold to fourfold increase in the
percentage of B cells. GLIS also activated mouse spleen
lymphocytes, and most of the activated cells were B cells
[127].
PL selectively activates murine B cells but not T cells
[128]. Since PL cannot penetrate cells due to its large
molecular mass (approximately 15 kD), this selectivity
may be caused by the surface binding of this molecule
to receptors specifically expressed on B-cells but not on
T cells. The B-cell receptor, BCR, consists of surface im-
munoglobulin and CD79a-CD79b. Upon BCR ligation,
the BCR-associated kinase Lyn phosphorylates CD79a-
CD79b. In addition, coreceptors such as CD19 and CD38
positively regulate BCR signaling. Complement receptor
CD11b-CR3, or Mac-1, is expressed on the surface of
macrophages and NK cells and has been identified as the
receptor of β-glucans [129]. Although PL and β-glucans
show dierent specificities on B and T cells, they may use
the same receptor on B cells. A further complete investi-
gation of the membrane receptors of PL should shed light
on its selectivity for B cells.
72 Cristina Lull et al 2005:2 (2005)
Tab l e 7. Immunomodulatory activities of mushroom compounds on B cells.
Species Compound Immune eects Reference
G lucidum PL-1, PL-3, PL-4 T and B lymphocytes proliferation [125]
antibodies
G lucidum PGL antibody production [126]
G lucidum GLIS
proteoglycan
proliferation of mouse spleen lymphocytes
[127]
B lymphocyte activation, proliferation, and dierentiation
and production of immunoglobulins
P linteus PL murine splenic lymphocytes and activation of B cells [128]
G lucidum LZ-8 antibody production [130]
F velutipes Fve antibody production [131]
Evidence that FIPs suppress antibody production
came from the result that the proportion of Arthus
reaction-positive mice was reduced to 40% by LZ-8 [130].
Fve also suppressed antibody production as demonstrated
by its eect in the hind paw edema test but the inhibition
was not complete [131]. Activities are summarized in Ta-
ble 7.
Figure 3 summarizes the targets for interaction be-
tween mushroom ingredients and various components of
the adaptive immune system.
RECOGNITION AND RECEPTORS
Evidence for β-glucan receptor
binding of immune cells
The innate immune system is the first line of defense
against microbial invasion, and must immediately recog-
nize and counter infections while the slower, more spe-
cific, adaptive response is mounted. The innate cellular
response is comprised principally of phagocytic cells and
is dependent on germline encoded receptors which rec-
ognize conserved microbial structures. The innate im-
mune system identifies infectious agents or compounds
by means of pattern-recognition receptors (PRR). These
receptors recognize pathogen-specific macromolecules
called pathogen-associated molecular patterns (PAMP).
Polysacharides cannot penetrate cells due to their
large molecular mass, so the first step in the modulation
of cellular activity is binding to immune cell receptors.
Among all the immunomodulatory metabolites isolated
from mushrooms, glucans and in particular β-glucans
have been studied profoundly to identify its target recep-
tor in immune cells. It has been postulated that glucans
are fungal pattern-recognition molecules for the innate
immune system [132,133]. The mechanisms by which the
innate immune system recognizes and responds to fungal
cell wall carbohydrate is a very complex and multifacto-
rial process [134]. The various activities of β-glucans may
reflect the presence of multiple cellular targets or recep-
tors [135]. To date several β-glucan receptors have been
identified as candidates mediating these activities [136],
namely, complement receptor 3 (CR3, αMβ2integrin, or
CD11b/CD18) [137], lactosylceramide [138], scavengers
receptors [139], dectin-1 [140], and toll-like receptors
TLR-2 and TLR-4 [141].
Dectin-1 is broadly expressed, with highest sur-
face expression on populations of myeloid cells (mono-
cyte/macrophage and neutrophil lineages) in the blood,
bone marrow and spleen. DCs, and a sub-population of
T cells , also expressed dectin-1 but at lower levels [142].
It is plausible that the expression of dectin-1, as a T-cell
binding receptor, on a subset of T-cells may be part of a
novel mechanism for the regulation of the T cell response
by specific subsets of T cells as well as by APC [143].
Recently, Kim et al [93] have shown that PL, proteo-
glycan isolated from Plinteus, could induce the pheno-
typic and functional maturation of DCs via TLR-2 and/or
TLR-4. Shao et al [141] suggested that TLR-4 is also in-
volved in GLPS-mediated macrophage activation. Rat an-
timouse TLR-4 monoclonal antibody (AB) inhibited the
proliferation of BALB/c mouse B cells under GLPS stim-
ulation. Combination of Abs against mouse TLR-4 and
immunoglobulin achieved almost complete inhibition of
GLPS-induced B-cell proliferation, implying that both
membrane Ig abd TLR-4 are required for GLPS-mediated
B cell activation.
Lowe et al [134] reported that a β-D-(13)- linked
glucan polymer composed of seven glucose subunits is
the minimum binding ligand for glucan PRR on a hu-
man monocyte cell line and indicated that all available
monocyte glucan receptors will recognize the basic β-
D-(13)-glucan structure with approximately the same
anity. However, as the glucan polymer becomes more
complex it appears to be preferentially recognized by one
glucan receptor versus another.
Additional studies are required to determine which
receptor(s) are essential to the expression of the various
immunobiological eects ascribed to β-glucans. The in-
tracellular events that occur after glucan-receptor bind-
ing have not been fully determined. As long as it remains
unclear what receptors are involved in and what down-
stream events are triggered by the binding of these glu-
cans to their target cells, it will be dicult to make further
progress in understanding their biological activities.
2005:2 (2005) Immunomodulating Eects of Fungal Metabolites 73
FcR
TLR
C’
CR1
No
CD80/86
APC
NF-κB
GSH
MHC II
Tc
Cytokines
CD28
Cytokine
receptor
TCR
TH0
B
cell
IL-4R
IL-4
Modulation of
APC-TH0 interaction:
Grifola,Phellinus,Morchella,Lentinus
Modulation of
immunoglobulin production:
Ganoderma,Phellinus
Modulation of TH-cell
dierentiation and function:
Ganoderma,Cordyceps,Flammulina,Lentinus
TH1
TH2
TR/TH3
Figure 3. Schematic representation of the possible targets of the adaptive immune system for mushroom ingredients with im-
munomodulatory properties. APC: antigen-presenting cell; FcR: Fc receptor; TLR: Toll-like receptor; CR1: complement receptor
type 1; C’: activated complement; GSH: glutathione; MHC II: major histocompatibility complex class II; TCR: T-cell receptor; TH:
helper T cells; TC: cytotoxic T lymphocytes; TR: regulatory T cells; NO: nitric oxide; IL-4: interleukin-4; IL-4R: interleukin-4 receptor;
CD: cluster designation.
CONCLUSIONS
The information presented here illustrates the distinct
immunomodulatory properties associated with mush-
room constituents. The discovery and identification of
new safe drugs, without severe side eects, has become
an important goal of research in the biomedical science.
Medicinal eects have been demonstrated for many tra-
ditionally used mushrooms, with large dierences in im-
munomodulatory properties. The species studied so far
represent a vast source of immunomodulating and an-
titumor extracts and metabolites. Thus, the biochemi-
cal mechanisms that mediate the biological activity are
still not clearly understood. Mushroom metabolites are
known to stimulate dierent cells of the immune sys-
tem. The major immunopotentiation eects of these
active substances include mitogenicity, stimulation of
hematopoietic stem cells, activation of alternative comple-
ment pathway, and activation of immune cells, such as TH
cells, Tc cells, B cells, macrophages, DCs, and NK cells.
Dierent profiles have been observed in relation to
the activated immune cells, for example, GLPS activate
mouseBcellsandmacrophagesbutnotTcells[141],
polysaccharides from Plinteuscan stimulate B cells, T
cells, and macrophages [144], while lentinan is a stimu-
lator of T cells and macrophages, but not B cells [145].
Some of them might promote a TH1 response and oth-
ers a TH2response[49]. In the particular case of glu-
cans, despite the structural and functional similarities of
some of them, they dier in their ability to elicit various
cellular responses, particularly cytokine expression and
production and in their eectiveness against specific tu-
mors [5]. The relationship between polysaccharide origin,
structure, and their immunomodulation activity remains
to be further characterized [125,146].
Mushroom products are obvious immunoenhancers
that potentiate the immune system in multiple ways.
Mushroom polysaccharides are among the emerging new
agents that could directly support or enhance functional
autologous hematopoietic stem cell recovery [61]. In pre-
ventive medicine, defense against invasion by foreign bod-
ies is dependent on enhancing the natural immune sys-
tem, including activation of macrophages and NK cells.
Macrophages stimulated by mushroom products release
several inflammatory cytokines, IL-1, IL-6, IL-8, TNF-
α, and NO, all of which directly induce tumoricidal ac-
tivity in macrophages. Macrophages produce also IL-1β,
IL-10, IL-12, GM-CSF, and IL-18. In other cases mush-
room extracts inhibit the production of NO, PGE2,IL-
1β,andTNF-αin LPS-stimulated macrophages and LPS-
administer mice. This antiinflammatory eect occurs by
down regulation of iNOS, COX-2, IL-1β,andTNF-α
gene expression via the suppression of NF-κB activation.
Thus, these mushroom extracts might be relevant for clin-
ical use for inflammatory diseases, including endotoxemia
or sepsis. Some mushroom metabolites like D-fraction
74 Cristina Lull et al 2005:2 (2005)
represent an important biological response modifier
(BRM) due to the enhancement of NK cells activity in
cancer patients. Mushroom polysaccharides induce reg-
ulatory eects on maturation and function of DCs and
consequently enhance the capacity of DCs to promote the
proliferation of na¨
ıve allogenic T cells and readies them
for T-cell-mediated immune responses. Both classical and
alternative pathways of complement have been activated
by mushrooms and also anticomplementary activity has
been detected in dierent mushrooms. T and B lympho-
cytes are also activated by mushrooms. Some mushroom
polysaccharides stimulate the production of antibodies
but others as PGL have a strong eect on suppressing the
antibody production [126].
The immunomodulating action of mushroom
metabolites is specially valuable as a means of pro-
phylaxis, a mild and noninvasive form of treatment,
prevention of metastatic tumors, and as a cotreatment
with chemotherapy [4]. The enhancement or potenti-
ation of host defense mechanisms has been recognized
as a possible means of inhibiting tumor growth without
harming the host, but other alternative mechanisms
are possible, like targeting the ras-mediated signaling
pathway [147]. Whether certain metabolites enhance or
suppress immune responses can depend on a number
of factors, including dose, route of administration, and
timing of administrations of the compound in question.
The type of activity these metabolites exhibit can also
depend on their mechanism of action or the site of
activity. Taken together, the present data suggest that
mushroom extracts or metabolites should be selected
and used properly for modulation of immune responses.
Due to the dierences in activities among various
extracts and isolated metabolites, it is imperative to
evaluate its biological properties before any suggestions
for use of a particular product in clinical practice. For
example, D-fraction enhanced rather than suppressed
the development of collagen-induced arthritis (CIA)
[148]. Administration of D-fraction stimulates immune
function of normal and tumor-bearing mice [84]. GLIS
from G lucidum has an eect on lymphocytes or purified
B cells from tumor-bearing mice markedly stronger than
on lymphocytes or purified B cells from normal mice
[127]. It has also been reported that an extract from the
deep layer of cultivated mycelia of the Cov-1 strain of C
versicolor enhances the immune functions in old mice but
not in young mice [149].
For some of the mushroom metabolites described,
further research is needed to determine whether there are
any in vivo benefits comparable to the in vitro eects re-
ported. Although it is unlikely that high molecular weight
polysaccharidse would be absorbed after oral administra-
tion, it is possible that it could exert a therapeutic eect
by direct interaction with the mucosal immune system of
the gastrointestinal tract. Thus, they could be developed
as a preparation for use as a dietary supplement or phar-
maceutical.
Some mushroom metabolites, such as the glucans
lentinan and schizophyllan, or the polysaccharide-protein
PSK, and the PSP, are used clinically for immune therapy
[150,151,152,153] and have been developed as phar-
maceuticals in Japan and are now commercially available
worldwide. PSK was commercialized by Kureha Chem-
icals, Japan. After extensive clinical trials, PSK was ap-
proved for use in Japan in 1977, and by 1985, it ranked
19th on the list of the world’s commercially most suc-
cessful drugs [154]. Annual Japanese sales of PSK in 1987
were worth US$357 million [154]. About 10 years af-
ter PSK, PSP appeared on the market. Both compounds
have been isolated from C versicolor. In addition to
clinically tested PSK and PSP, numerous other extract
preparations of C versicolor are on the market as neu-
traceuticals and traditional medicines. Neutraceutical PSP
preparations are sold worldwide in the form of capsules,
ground biomass tablets, syrups, food additives, and teas
[153].
Quality control of mushrooms poses significant chal-
lenges: small dierences in genetics, soil, temperature,
moisture, and time of harvesting can lead to signifi-
cant dierences in the concentration of important con-
stituents. The cultivation of mushrooms to produce fruit-
ing bodies is a long-term process requiring from one to
several months for the first fruiting bodies to appear.
Nowadays, more research is carried out in relation to sub-
merged culture. Submerged culture has potential advan-
tages for higher mycelial production in a compact space
and for a shorter incubation time with a lesser chance
of contamination. Further optimization of the culture
medium composition and physicochemical conditions of
growth allows regulation of fungal metabolism in order
to obtain standardized nutriceutical substances in higher
yield. Mycelia formed by growing pure cultures in sub-
merged culture is the best technique for obtaining con-
sistent and safe mushroom products [3,12,155]. Mush-
rooms are still far from being thoroughly studied.
ACKNOWLEDGMENT
The authors acknowledge the financial support
of the Valencian authorities (Generalitat Valenciana;
CTBPDC/2003/014) for Cristina Lull.
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... Fungi produce a diversity of bioactive compounds, making them ideal for natural goods. About 130 therapeutic functions are believed to be formed by medicinal mushrooms and fungi, including antitumor (Deshmukh et al., 2018;Uzma et al., 2018) immunomodulating (Lull et al., 2005;Kanazawa et al., 2013)antioxidant (Sugiharto et al., 2016;Hameed et al., 2017), cardiovascular, anti parasitic, antiviral, antifungal, antibacterial, radical scavenging, hepato protective, detoxification, anti diabetic (Murugan et al., 2017, anti hypercholesterolemia as well as protection against tumor development and inflammation are exhibited by fungi. Polysaccharides, alkaloids, proteins, fats, minerals, carotenoids, glycosides, terpenoids, folates, tocopherols, flavonoids, phenolics, volatile oils, ascorbic acid, lectins, enzymes, and organic acids, are bioactive molecules synthesized by different fungal organisms. ...
... Several fascinating research on the benefits of curative mushrooms in cancer patients has been conducted. Many of the benefits reported in oncology can be due to mechanisms such as modification of cellular and humoral immunity, meanwhile, others can be attributed to an unbroken antitumor effect (Lucius, 2020). Patients with breast, prostate, colorectal, hepatic, and lung malignancies, among others, have participated in mushroom clinical trials (Lucius, 2020). ...
... Many of the benefits reported in oncology can be due to mechanisms such as modification of cellular and humoral immunity, meanwhile, others can be attributed to an unbroken antitumor effect (Lucius, 2020). Patients with breast, prostate, colorectal, hepatic, and lung malignancies, among others, have participated in mushroom clinical trials (Lucius, 2020). The immunomodulatory effective nature formed on immune cells may be determined by the manner of extraction of medicinal mushrooms, resulting in the varied solubility of inhibitory mediators and stimulatory (Hetland et al., 2021). ...
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... Immunomodulators can be effective agents for treating and preventing diseases and illnesses that stem from certain immunodeficiencies and other depressed states of immunity. Those metabolites which appear to stimulate the human immune response are being sought for the treatment of cancer, immunodeficiency diseases, or for generalized immunosuppression following drug treatment, for combination therapy with antibiotics, and as adjuvants for vaccines (Jong and Birmingham, 1992;Lull et al., 2005;Thompson et al., 2010). alcohol dehydrogenase (ADH), which is used in alcoholic beverage brewing (Okamura-Matsui et al., 2003). ...
... Immunomodulators, including β-glucans, may form part of prophylaxis and/or therapeutic strategy following exposure to pathogen challenge by non-specifically stimulating components of the innate immune system, such as macrophages, monocytes, and neutrophils, dendritic cells, or natural killer cells. The activation of these cells is associated with increased phagocytosis, increased synthesis of lysozyme, reactive oxygen species, reactive nitrogen intermediates, free radicals, proinflammatory cytokine and chemokine activation of the classical and alternative complement pathways, and increased antibody production (Lull et al., 2005). β-glucans have also been identified in extracts of the cell walls of many mushroom species. ...
Chapter
Most mushroom farming has been carried out using classical farming practices, giving one of the main reasons for low mushroom yield; in traditional mushroom farms routine practices are more labor intensive. Moreover, controlling insects, pests, and diseases is much more challenging and needs more vigilance. However, adapting innovative agricultural techniques can improve overall efficiency and productivity at a mushroom farm. One of the most advanced technologies is the application of the Internet of Things (IoT), which provides remote access to daily farm operations, and insect and pest control to the farmers. This sensor-based technique can be used to monitor crucial environmental factors including humidity, light, moisture, and temperature at a mushroom farm. The long-term benefits of semi- or fully automated farms result in high productivity, less labor, and reduced cost of production. Aside from the surrounding environmental conditions, controlling biotic stresses is also a challenging task at a mushroom farm. These may include insect pests, fungi, bacteria, nematodes, and some viral diseases. The use of synthetic chemical products at a mushroom farm can be hazardous to mushroom cultivation; thus, integrated pest management (IPM) and use of modern molecular approaches to confer natural resistance to biotic stresses can be effective control measures.
... Several bioactive constituents, including triterpenes, lipids, phenols, polysaccharides, and polysaccharopeptides with immense biological properties such as immunomodulatory and antitumor drugs, were isolated from mushrooms [137,138]. Albatrellus confluens (Alb. & Schwein.) ...
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... Mushrooms are not only a cuisine containing rich nutrients including vitamins and minerals [8], but they are also a medicinal resource with a variety of pharmacological functions [9,10], such as modulating immunity [11], being anticancer [12,13] and even preventing dementia [14]. Indeed, a recent meta-analysis on cohort studies indicates that mushroom consumption will reduce the risk of several diseases including cancer, and will therefore reduce the risk of mortality [15]. ...
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... Polysaccharides from Morchella esculenta exhibit anticancerous activities against colon cancer cells (HT-29) and polysaccharide MIPW 50-1 isolated from M. importuna stimulates macrophages and increases phagocytosis of RAW 264.7 cells as well as secretion of IL-6, TNF-α, and NO (Liu et al. 2016;Wen et al. 2019). Through MAPK and p38 signaling pathway, polysaccharides extracted from Phellinus linteus help in dendritic cell maturation by activating TLR receptors (Lull et al. 2005). Galactoglucan isolated from Pleurotus djamor demonstrated antioxidant properties by exhibiting DPPH hydroxyl scavenging activity (Maity et al. 2020). ...
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Mushrooms are among the few natural products that have been relied upon for prophylactic and therapeutic applications in human diseases. They have been referred to as forest gems since they can be picked in the wild or better domesticated for appropriate use. Several scientific studies have been conducted to establish claimed potentials or further probe new areas into which mushrooms can find application. Many disciplines, including mycology, microbiology, physiology, chemistry, genetics, and medicine, among others, conduct research on mushrooms. These enable broad and in-depth studies of mushrooms, to include in vitro and in vivo demonstrations of their bioactivity, structural characterization, and isolation of bioactive components. This chapter highlights the bioactive composition of mushrooms by relating structure to bioactivity and demonstrating therapeutic effects on some human diseases using existing literature. The potentials of mushrooms or their products for the treatment or management of diseases, such as tropical illnesses and COVID-19 pandemic, among other issues, have been discussed. Chemistry of bioactive compounds, structure–activity relationships, patents, and analyses of data obtained have been reported and studied for interpretation of results.
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2nd edition of the first book on the topic published in North America. The first edition was self-published in October, 1986. An exploration of tradition, healing, and culture. Covers the history of the uses of fungi for healing, including nutritional value, summary of cultural uses, history, and science on over 100 species. Shamanistic uses of hallucinogenic fungi. Botanica Press Imprint, published by The Book Publishing Co., Summertown, TN. 251 pp. with illustrations.
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Glucans are cell wall constituents of fungi and bacteria that bind to pattern recognition receptors and modulate innate immunity, in part, by macrophage activation. We used surface plasmon resonance to examine the binding of glucans, differing in fine structure and charge density, to scavenger receptors on membranes isolated from human monocyte U937 cells. Experiments were performed at 25degreesC using a biosensor surface with immobilized acetylated low density lipoprotein (AcLDL). Inhibition of the binding by polyinosinic acid, but not polycytidylic acid, confirmed the interaction of scavenger receptors. Competition studies showed that there are at least two AcLDL binding sites on human U937 cells. Glucan phosphate interacts with all sites, and the CM-glucans and laminarin interact with a subset of sites. Polymer charge has a dramatic effect on the affinity of glucans with macrophage scavenger receptors. However, it is also clear that human monocyte scavenger receptors recognize the basic glucan structure independent of charge.
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The weight of recent experimental evidence strongly supports the conclusion that lymphokines of Th2-like cells, which are released in response to allergens, determine both IgE antibody production - via IL-4- and eosinophila - via IL05 - which are hallmarks of human allergic disorders. The reason why allergens preferentially activate Th2 cells is still unclear, but evidence is accumulating to suggest that the cytokine profile of the 'natural' immunity plays an important role in determining the Th2 profile of the subsequent allergen-specific immune response. These results provide a point of depature for the development of novel and specific immunotherapeutic procedures aimed towards successful transformation of Th2-like cells into Th0/Th1-like allergen-specific responses.
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Anticomplementary activity of 61 strains of Korean higher fungi was screened for immunostimulation. Extracts from 11 of 61 strains including 5 of Ganoderma lucidum, 3 of Lentinus edodes, 2 of Cordyceps sp. and 1 of Agaricus campestris, showed higher anticomplementary activity than krestin which was immunopotent extract from Japanese Coriolus versicolor. The most potent anticomplementary activity was found with extract from Lentinus edodes IY105 whose complement consumption was 31.7%.
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To examine effects on complement and reticuloendothelial system, alkali extract was isolated from cultured mycelium of Ganoderma lucidum IY107. It was shown to strongly activate both classical and alternative pathways of complement as compared with krestin. Activated complement C3, 3rd peak, was observed by crossed immunoelectrophoresis. It was also shown to activate reticuloendotherial system of ICR mice in the carbon clearance test and to increase hemolytic plaque forming cells of the spleen. Carbohydrate and protein contents of the alkali extract were 10% and 49%, respectively. The carbohydrate consisted of four monosaccharides and the protein contained 16 amino acids.