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Copyright , Japan Poultry Science Association.

http://www.jstage.jst.go.jp/browse/jpsa

doi: . /jpsa. .

,

Received: July , , Accepted: November ,

Correspondence: Dr. H.S. Lillehoj, Animal and Natural Resources

Institute, U.S. Department of Agriculture, Agricultural Research Ser-

vice, Building , BARC-East Beltsville, MD USA.

(E-mail: sunghyen.lee@ars.usda.gov)

Animal and Natural Resources Institute, Beltsville Agricultural Research Center, Agricultural Research Service,

United States Department of Agriculture, Beltsville, MD USA

Department of Korean Food Research for Globalization, National Academy of Agricultural Science,

Rural Development Administration, Suwon, South Korea

Department of Pediatrics University of Maryland School of Medicine, Baltimore, MD USA

A variety of fruits have traditionally been used in Asian cultures to enhance resistance to diseases and treat cancers.

However, limited information exists on the underlying mechanisms responsible for these e ects. The present investigation was

conducted to examine the ability of three Korean indigenous fruits (persimmon, raspberry and tomato) to stimulate

lymphocyte proliferation and macrophage nitric oxide production as parameters of innate immunity, and to inhibit tumor cell

growth. co-culture of chicken spleen lymphocytes with methanol extracts of persimmon ( ) or tomato

( ) induced greater cell proliferation compared with cells treated with the vehicle control. Stimulation

of chicken macrophages with extracts of persimmon or raspberry ( ), but not tomato, stimulated robust

nitric oxide production to levels similar to that produced by interferon- . All fruit extracts uniformly inhibited the growth

chicken tumor cells These results provide a rational basis for future studies investigating the e ects of medicinal fruits

on innate immunity and carcinogenesis in humans and animals.

: fruit, immunomodulation, macrophage, splenocyte, tumor

studies (Lee ). Additionally, persimmon reduced

body weight gain in rats fed a high-fat diet (Ahn

) and inhibited development of dermatitis and

Various fruits have been used in Asian cultures to blocked spontaneous increase in serum IgE levels in NC/

enhance resistance to diseases, including infections and Nga atopic dermatitis-model mice (Kotani ).

cancers. For example, persimmon ( ), rasp- Lyophilized raspberry showed a strong chemopreventive

berry ( ) and tomato ( e ect on esophageal tumorigenesis (Kresty )

) have traditionally been used as health-pro- and modulated -nitrosomethylbenzylamine metabolism

moting medicinal foods in Korean society. While the in the esophagus and liver of Fischer rats (Reen

active ingredients and mechanisms of action have not been ). Tomato consumption has been positively cor-

completely characterized, multiple reports have provided related with reduced incidence of respiratory infections in

a scientific basis for their e ects. For example, extracts of humans (Fawzi ). Similarly, inhabitants of the

persimmon peels showed protective e ects against high Mediterranean region, in general, showed lower incidence

glucose-induced oxidative stress in porcine renal epithelial of several important chronic diseases, including coronary

LLC-PK cells (Yokozawa ) and altered lipid heart disease and cancers, compared with other geograph-

profiles and anti-oxidative activity in and ic regions, which was attributed to the higher than average

consumption of lycopene and other tomato products

(Weisburger, ). These examples of dietary enhance-

ment of disease resistance provide a rational basis to

further explore the immunostimulating properties of food

substances in human and veterinary clinical medicine. In

this regard, recent progress has been reported in the

commercial application of plant phytonutrients to enhance

Sung-Hyen Lee , Hyun S. Lillehoj , Hye-Kyung Chun , Hong-Ju Park ,

Soo-Muk Cho and Erik P. Lillehoj

In vitro Diospyros kaki

Lycopersicon esculentum

Rubus crataegifolius

in vitro.

et al.,

J. Poult. Sci., : ,

et al.,

et al.,

Diospyros kaki

Rubus crataegifolius Lycopersicon et al.,

esculentum N

et al.,

et al.,

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in vitro in vivo

Key words

Introduction

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innate immunity against infectious diseases and tumors and the results for each treatment group were expressed as

(Masihi, ; Sampedro ; Okamura the stimulation index (SI) (SI mean cpm of the fruit

; Lee ; Usuki ). The present extract-treated cultures mean cpm of PBS-treated cul-

investigation was conducted to examine the e ects of tures) (Lee c).

organic extracts of persimmon, raspberry, and tomato on

various parameters of chicken innate immunity and tumor HD chicken macrophages were cultured in triplicate

cell growth. The chicken model was used since avians are at cells/m in -well plates ( /well) at

economically important food animals with well-charac- and CO for hr with fruit extracts or positive ( .

terized innate immune systems (Tsurushita ; g/m of recombinant chicken interferon- [IFN- ])

Nishibori ; Usuki ; ) as well as to (Song ) or negative (PBS) controls (Lillehoj

further extend our previous studies on phytonutrients and ). Culture supernatants ( ) were transferred

in this species (Lee ; Lee ; Lee to clean -well plates, mixed with of Griess reagent

c; Lee a; Lee b). (Sigma), incubated for min at room temperature, opti-

cal density at nm (OD ) was measured, and the

nitrite concentration was determined using a standard

curve generated with known concentrations of sodium

Methanol extracts of persimmon, raspberry, and tomato nitrite.

were obtained from the National Rural Resources Devel-

opment Institute of the Rural Development Administra- RP chicken B-cell lymphoma cells (Sharma and

tion (Suwon, Korea). Extraction was carried out by Okazaki, ) were cultured in triplicate at cells/

adding m of methanol to g of fresh fruit m in -well plates ( /well) at and CO for

samples with vigorous shaking for hr at room temper- hr with fruit extracts or positive (lipopolysaccharide-

ature. The process was repeated three times, the extracts induced TNF- factor [LITAF]) (Hong ) or

were pooled and dried using a rotary evaporator (Eyela, negative (PBS) controls. Tumor cell viability was meas-

Irvine, CA), and the residues were freeze-dried and stored ured using the WST- reagent (Cell-Counting Kit- ,

at . Prior to testing, the residues were Dojindo Molecular Technologies, Gaithersburg, MD).

dissolved in PBS at , and g/m and sterilized OD values were measured as an indicator of cell num-

by membrane filtration through a . m filter (Nalgene, bers as described (Miyamoto ).

Rochester, NY).

Statistical analyses were performed using SPSS software

All experiments were approved by the Beltsville Agri- (SPSS . K for Windows, Chicago, IL). All data were

cultural Research Center Animal Care and Use Commit- expressed as mean SEM values. The ANOVA test was

tee. Specific Pathogen-Free White Leghorn SC inbred used to test for di erences between the di erent treatment

chickens (Hy-Vac, Adel, IA) were maintained at the groups. To analyze di erences between the mean values,

Beltsville Agricultural Research Center Animal Facility the Duncan’s multiple range test was used. Di eren

and were fed with a standard diet that was

formulated to meet the recommended nutrient require-

ments (National Research Council, ). At weeks of

age, the animals were euthanized by cervical dislocation

and spleens were placed in m of Hanks’ balanced salt

solution supplemented with U/m penicillin and

g/m streptomycin (Sigma, St. Louis, MO). Single cell

suspensions were prepared as described (Okamura

; Lee a), adjusted to cells/m in

enriched RPMI- medium without phenol red (Sigma)

supplemented with fetal bovine serum, U/m

penicillin and g/m streptomycin, and /well

were cultured in -well flat bottom plates at and

CO for hr with the fruit extracts or positive ( . g/m

of concanavalin A, Sigma) or negative (PBS) controls.

Following incubation, the cells were radiolabeled for hr

with . Ci/well of [ H]-thymidine (Perkin Elmer Life

Science, Boston, MA), harvested using a semi-automated

cell harvester (Tomtec, Orange, CT), and the incorporat-

ed radioactivity was determined by liquid scintillation

counting ( Microbeta Wallac Trilux, Perkin Elmer

Life Sciences). All cultures were performed in triplicate

et al., et al.,

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Nitric oxide (NO) production

Preparation of methanol extracts

Inhibition of tumor cell growth

Statistical analyses

Spleen lymphocyte proliferation

Materials and Methods

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J. Poult. Sci., ( )

ces

were considered statistically significant at . (Sokal

and Rohlf, ).

Persimmon and tomato extracts at g/m signifi-

cantly enhanced splenocyte proliferation compared with

the PBS control (Fig. A). The proliferation induced by

the persimmon extract was . of that produced by .

g/m of concanavalin A. Increased proliferation also

was observed at g/m of persimmon (Fig. B) and at

g/m of tomato extracts (Fig. C). In contrast,

methanol extracts of raspberry did not stimulate spleno-

cyte proliferation.

Persimmon and raspberry extracts significantly in-

creased NO production by HD macrophages at g/

m compared with PBS-treated cells (Fig. A). Increased

NO production also was observed at g/m of persim-

mon (Fig. B) and at and g/m of raspberry

extracts (Figs. B-C). In contrast, methanol extracts of

tomato did not stimulate NO production.

P

l

l

l

l

l

l

l

Spleen lymphocyte proliferation

NO production

150

Results

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Fig. . Fig. .

Lee : Immunomodulating E ect of Medicinal Fruits

nificantly di erent ( . ) according to the Duncan’s

Chicken Chicken HDsplenocytes ( cells/well) were cultured for hr macrophages ( cells/well) were cultured for hrin -well plates with /well of the indicated fruit with of the indicated fruit extracts at (A)extracts at (A) g/m (B) g/m or (C) g/m (B) g/m and (C) g/m . g/m

g/m . g/m of concanavalin A (positive control), of IFN- (positive control), or PBS (negative control),or PBS (negative control). Following incubation, cell of cell culture supernatants were mixed withproliferation was determined by [ H]-thymidine in- of Griess reagent, and sodium nitrite levels werecorporation as described in the Material and Methods determined as described in the Materials and Methods.and expressed as the stimulation index (SI) (SI mean Each bar represents the mean SEM. Bars not sharingcpm of the fruit extract-treated cultures mean cpm of the indicated letters are significantly di erent ( . )PBS-treated cultures). Each bar represents the mean according to Duncan’s multiple range test.SEM. Bars not sharing the indicated letters are sig-

multiple range test.

A-C). The levels of growth inhibition observed in all cases

Extracts of persimmon, raspberry, and tomato signifi- were comparable to that produced by the LITAF positive

cantly reduced the growth of RP tumor cells compared control.

with the PBS control at all concentrations tested (Figs.

et al.

P

l ll, l, l, l, l, l

l, ll

l

P

E ect of methanol extracts of persimmon, rasp- E ects of methanol extracts of persimmon, rasp-

berry and tomato on splenocyte proliferation. berry and tomato on NO production.

Tumor cell growth

151

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Fig. .

J. Poult. Sci., ( )

Chicken RPtumor cells ( cells/well) were cultured for hrwith of the indicated fruit extracts at (A)

g/m (B) g/m and (C) g/m . g/mof LITAF (positive control) or PBS (negative control).Tumor cell viability was determined with WST- rea-gent as described in the Materials and Methods. Eachbar represents the mean SEM. Bars not sharing theindicated letters are significantly di erent ( . )according to the Duncan’s multiple range test.

tional medicinal plants on lymphocyte proliferation (Lee

; Pandey ; Sun ). How-

ever, little is known about the biological e ects of most

long-established medicinal Korean fruits, particularly

those evaluated in this study, and no reports have

described their e ects on innate immunity in terms of the

parameters examined in this paper. Our results provided

clear evidence that methanol extracts of persimmon, rasp-

berry, and/or tomato enhanced splenocyte pro-

liferation and macrophage NO production, and reduced

tumor cell growth, compared with PBS-treated cells. In

general, our results corroborate previous studies that

documented the beneficial properties of these fruits and

others. For example, feeding of persimmon leaves to rats

on a high-fat diet suppressed body weight gain and

lowered plasma and hepatic lipid concentrations com-

pared with animals given the high lipid diet alone (Lee

). Extracts of persimmon leaves also were shown

to inhibit the development of dermatitis in NC/Nga mice

(Kotani ). Finally, treatment of experimental

mice with oligonol, a compound produced by the oligo-

merization of polyphenols such as proanthocyanidin from

persimmon, grape, and apple, decreased the severity of

infection-induced inflammation (Tomobe ).

Macrophages play a significant role in host defense

against infectious agents and tumors mediated, in part, by

the elaboration of soluble inflammatory molecules such as

NO (Stuehr and Nathan, ). In this study, raspberry

extracts significantly increased NO production by HD

macrophages compared with the vehicle control and this

e ect was comparable to that of IFN- , a potent cytokine

involved in the di erentiation, maturation and prolifera-

tion of hematopoietic cells that enhances nonspecific im-

munity to tumors, as well as to microbial, viral and

parasitic pathogens (Lillehoj and Choi, ; Lee

b). Interestingly, tomato extract did not stimulate

NO production in spite of previously reported studies

demonstrating that dietary supplementation with tomato-

derived lycopene or carotenoids reduced the activity of

-hydroxy- -methyl glutaryl coenzyme A (HMGCoA)

reductase, the rate limiting enzyme in cholesterol synthesis

(Fuhrman ; Gorinstein ). Neverthe-

less, given the involvement of NO during innate immune

response, macrophage-mediated killing, and direct growth

inhibition of microorganisms and tumor cells as formerly

documented (Engel ; Stuehr ), our

results clearly imply an important role for dietary fruits in

the enhancement of innate immunity.

Host immune function is critically essential in the re-

sponse to tumorigenesis (Lee ). In our previ-

cell culture systems have provided a wealth of ous study, we demonstrated that traditional Asian medic-

information on the biological e ects of phytochemicals inal plants such as dandelion and sa ower inhibited tumor

and phytonutrients derived from fruits and vegetables, cell growth (Lee ; Lee c; Lee

and on the mechanisms through which diets high in these b). This e ect can now be extended to medic-

foods reduce the risk of chronic diseases (Steinmetz inal fruits. The anti-tumor activities of these foods were

; Lee c). Previous studies have demon- comparable to that mediated by LITAF, a transcription

strated the stimulatory e ects of natural foods and tradi- factor originally cloned from the LPS-stimulated THP-

ll, l, l, l

P

et al., et al., et al.,

in vitro

et

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et al.,

et al.,

et al., et al.,

et al., et al.,

et al.,

In vitro

in vitro et al., et al.,

et al.,

et al.,

et al.,

E ects of methanol extracts of persimmon, rasp-

berry and tomato on tumor cell growth.

152

Discussion

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�and -based probiotic (MitoMax )

ophageal tumorigenesis by dietary administration of lyo-

philized black raspberries. Cancer Research, : .

.

Lee JS, Lee MK, Ha TY, Bok SH, Park HM, Jeong KS, Woo

MN, Do GM, Yeo JY and Choi MS. Supplementation of

whole persimmon leaf improves lipid profiles and suppresses

body weight gain in rats fed high-fat diet. Food and Chem-

ical Toxicology, : . .

Lee SH, Park JB, Park HJ, Park YJ and Sin JI. Biological

properties of di erent types and parts of the dandelions:

comparisons of anti-oxidative, immune cell proliferative and

tumor cell growth inhibitory activities. Korean Journal of

Food Science and Nutrition, : . .

Lee SH, Lillehoj HS, Dalloul RA, Park DW, Hong YH and Lin

JJ. Influence of -based probiotic on coccidiosis in

broiler chickens. Poultry Science, : . a.

Lee SH, Lillehoj HS, Park DW, Hong YH and Lin JJ. E ect of

on coccidiosis in broiler chickens. Comparative Immunolo-

gy, Microbiology and Infectious Diseases, : .

b.

Lee SH, Lillehoj HS, Chun HK, Tuo W, Park HJ, Cho SM, Lee

YM and Lillehoj EP. treatment of chicken peripher-

al blood lymphocytes, macrophages, and tumor cells with

extracts of Korean medicinal plants. Nutrition Research, :

. c.

Lee SH, Lillehoj HS, Cho SM, Park DW, Hong YH, Chun HK,

Park HJ and Lillehoj HJ. Immunomodulatory properties of

dietary plum on coccidiosis. Comparative Immunology, Mi-

crobiology and Infectious Diseases. : . a.

Lee SH, Lillehoj HS, Heckert RA, Chun HK, Cho SM, Tuo W,Ahn HS, Jeon TI, Lee JY, Hwang SG, Lim YH and Park DK.

Lillehoj EP and Park HJ. Immune enhancing properties ofAntioxidative activity of persimmon and grape seed extract:

Sa ower leaf ( ) on chicken lympho-and Nutrition Research, : .

cytes and macrophages. Journal of Poultry Science, :.

, b.Engel LW and Straus SE. Development of therapeutics:

Lillehoj HS and Li G. Nitric oxide production by macrophaOpportunities within complementary and alternative medi-

cine. Nature Reviews. Drug Discovery, : . .

Fawzi W, Herrera MG and Nestel P. Tomato intake in relation

to mortality and morbidity among Sudanese children. Jour-

nal of Nutrition, : . .

Fuhrman B, Elis A and Aviram M. Hypocholesterolemic e ect

of lycopene and -carotene is related to suppression of

cholesterol synthesis and augmentation of LDL receptor

activity in macrophages. Biochemical and Biophysical Re-

search Communications, : . .

Gorinstein S, Kulasek GW, Bartnikowska E, Leontowicz M,

Zemser M, Morawiec M and Trakhtenberg S. The e ects of

diets, supplemented with either whole persimmon or phenol-

free persimmon, on rats fed cholesterol. Food Chemistry,

: . .

Hong YH, Lillehoj HS, Lee SH, Park DW and Lillehoj EP.

Molecular cloning and characterization of chicken lipo-

polysaccharide-induced TNF- factor (LITAF). Develop-

mental and Comparative Immunology, : . .

Kotani M, Matsumoto M, Fujita A, Higa S, Wang W, Suemura

M, Kishimoto T and Tanaka T. Persimmon leaf extract and

astragalin inhibit development of dermatitis and IgE eleva-

tion in NC/Nga mice. Journal of Allergy and Clinical

Immunology, : . .

Kresty LA, Morse MA, Morgan C, Carlton PS, Lu J, Gupta A,

Blackwood M and Stoner GD. Chemoprevention of es-

human macrophage cell line. Treatment of cells with

LITAF induces the expression of TNF- , one of the most

potent anti-tumor molecules known (Hong ).

The ability of persimmon and tomato to inhibit the growth

of tumor cells may be related to the stimulation of cancer-

specific cytotoxic T cell stimulation (Takii ),

while the high anti-tumor activity of raspberry may be

explained by macrophages NO production (Lee

c; Stuehr ).

In conclusion, we demonstrate for the first time that the

methanol extracts of three common Korean medicinal

fruits are capable of stimulating parameters of

innate immunity, as well as mediating the suppression of

tumor cell growth. Further studies to elucidate the nature

of the immunomodulating activities of these and other

phytonutrients from fruits and vegetables will facilitate

the development of novel dietary strategies against infec-

tious diseases and tumors in both humans and domestic

food animals.

This project was partially supported by a Trust agree-

ment established between ARS-USDA and the Rural De-

velopment Administration of South Korea and an o shore

grant from USDA-ARS. The authors thank Ms. Margie

Nichols for her contribution to this research.

Pediococcus Saccharomyces

Pediococcus

In vitro

Carthamus tinctoriusin vitro in vivo.

et al.,

et al.,

et al.,

et al.,

in vitro

Acknowledgments

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./ +313 +321 ,**130 +*,1 +*-3 +330

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