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,,2
*
Graduate Program in Nutritional Sciences,
Department of Internal Medicine, and
**
Department of Pathology, University of Kentucky, Lexington, KY 40536;
Veterans Administration Medical Center, Louisville, KY 40206-1499; and
Department of Internal Medicine and
Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40292
2To whom correspondence should be addressed. E-mail: craig.mcclain{at}louisville.edu.
 |
ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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production and
lethality in mice. Our present studies demonstrate that GrTP inhibit
inflammatory responses and may be useful in treating chronic
inflammatory states, such as inflammatory bowel disease. In this
preliminary study, we examined whether GrTP decrease disease activity
in interleukin-2–deficient (IL-2-/- mice. Eight-week
old IL-2-/- C57BL/6J mice who were fed nonpurified diet
were randomly assigned to receive water with GrTP (5 g/L) or water
alone (control) for up to 6 wk. After 1 wk, explant colon and lamina
propria lymphocyte (LPL) cultures were established from a subgroup of
mice and supernatants collected. Culture supernatants from
GrTP-treated mice showed decreased spontaneous interferon-
and
tumor necrosis factor- secretion compared with that of controls. At
6 wk, the GrTP group had less severe colitis as demonstrated by lower
histologic scores and wet colon weights. This was associated with lower
plasma levels of serum amyloid A, increased weight gain and improved
hematocrits. These results show that GrTP attenuated inflammation in
IL-2-/- mice and suggest a role for GrTP in
treating chronic inflammatory diseases such as inflammatory bowel
disease.
KEY WORDS: • green tea • inflammation • colitis • alternative medicine • mice
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. In Austria, Moser et al. (2)
found that
34% of IBD patients admitted using CAM. Similarly, Hilsden et al.
(3)
reported that 51% of surveyed IBD patients living in
Calgary, Canada had used CAM, and 33% admitted to current use.
Patients tended to use CAM in addition to traditional therapy. The most
commonly used agents were vitamins and herbal products. There are a
myriad of CAM treatments that may prove beneficial for patients with
IBD. These include therapies that have anti-inflammatory
properties, alter gut flora, or minimize or reduce responses to
psychosocial stresses. Unfortunately, the scientific basis for the use
of these modalities frequently is lacking, and safety has not been
assessed.
Of the various herbal and botanical agents used, tea (Camellia
sinensis) has drawn a great deal of interest. Tea is one of the
most popular beverages worldwide. Some epidemiologic studies suggest
that regular tea consumption reduces cancer risk in humans
(4)
, and animal studies show a reduction in
carcinogen-induced malignancies (5)
. Although tea
consists of >2000 components, interest has focused on the polyphenols
found in green tea. The green tea polyphenols include
(-)-epigallocatechin gallate (EGCG),
(-)-epigallocatechin (EGC), (-)-epicatechin gallate (ECG) and
(-)-epicatechin (EC). They have potent antioxidant properties
(6)
. Our laboratory recently showed that green tea
polyphenols inhibited tumor necrosis factor- (TNF-) induction in
macrophages by attenuating nuclear factor-
B (NF-B) activation
(7)
. Similarly, Lin and Lin (8)
showed that
EGCG inhibits lipopolysaccharide (LPS)-stimulated nitric oxide
production and inducible nitric oxide synthase gene expression in
peritoneal macrophages by decreasing NF-B. In addition, orally
ingested green tea polyphenols blocked LPS-induced death in BALB/c
mice (7)
. These studies provide proof that green tea
polyphenols have anti-inflammatory effects.
In this study, we evaluated whether extracted green tea polyphenols
(GrTP) decrease the inflammatory response in an animal model of IBD,
interleukin-2–deficient (IL-2-/- C57BL/6 mice
(9)
. IL-2-/- C57BL/6 mice have an
autoimmune-mediated disease characterized by a wasting syndrome,
colitis, and hemolytic anemia (9)
. Our results indicate
that IL-2-/- mice fed GrTP in the drinking
water for 6 wk have less severe disease than mice not receiving GrTP.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Breeding pairs of C57BL/6J mice heterozygous for the
IL-2tm1Hor mutation (9)
were
purchased from Jackson Laboratory (Bar Harbor, ME). The breeding colony
was housed in conventional conditions with free access to water and
food (Harlan Teklad Laboratory diet #8604, Madison, WI). Offspring were
weaned at 3 wk and genotyped using a 3-primer polymerase chain reaction
protocol provided by Jackson Laboratory. This study was approved and
performed in accordance with the guidelines for the care and use of
laboratory animals at the Veterans Administration Medical Center in
Lexington, Kentucky.
GrTP consumption in water supply.
Initially, we tested whether C57BL/6J mice would voluntarily drink water supplemented with GrTP. Wild type (IL-2+/+) mice were fed drinking water supplemented with 10 g/L sucrose and various concentrations of GrTP (0–10 g/L) for 1 wk. Mice tolerated concentrations up to 5 g/L, but concentrations above 5 g/L decreased fluid intake (data not shown). On the basis of these findings, the study was designed to examine whether orally ingested GrTP at a dose of 5 g/L in drinking water decreased inflammation in IL-2-/- mice.
Study groups.
Eight-week old mice homozygous for the IL-2tm1Hor mutation were randomized to either water supplemented with 10 g/L sucrose and 5 g/L of extracted green tea polyphenols (GrTP, >95% pure, LKT Laboratories, St. Paul, MN) or water with 10 g/L sucrose (placebo). Twenty-two mice (15 males, 7 females) were assigned to each group. In addition, eight IL-2+/+ littermates (4 male, 4 female) were treated with GrTP. Mice were individually housed under conventional conditions with free access to food and conditioned water. Body weight was monitored weekly. Serum concentrations of serum amyloid A (SAA) and hematocrit were obtained at entry and at the end of the study. Daily consumption of food and liquid was monitored. At the end of the study, mice were humanely killed after sedation with methoxyfurane. Blood was collected. The colon was excised, flushed with ice-old PBS and weighed.
Baseline demographics of the GrTP-treated and placebo-treated IL-2-/- mice.
Disease development in IL-2-/- mice is somewhat variable
and results may be biased by mouse selection. The following entry
criteria were established to limit the potential for selection bias and
provide a relatively homogeneous population for study. We chose male
mice weighing 
17 g and female mice weighing 16 g for this study. In
our mouse colony, low body weight predicts severity of disease. At 8 wk
of age, male mice weighing <14 g and female mice weighing <13 g have
more aggressive disease and frequently die before reaching 12 wk. A
second criterion for entry was a baseline serum SAA level 60 mg/L,
but 
150 mg/L. Healthy mice typically have values <20 mg/L. Serum SAA
levels correlate well with the severity of the colitis in
IL-2-/- mice (10)
. No differences in
baseline body weight, serum SAA concentrations or hematocrits were
observed between GrTP-treated IL-2-/- mice and
control IL-2-/- mice.
Colon explant cultures.
Explant cultures of colon fragments were performed following a
published method (11)
. Briefly, distal sections (1 cm) of
cleansed colons from 1-wk treatment groups were cut, opened lengthwise
and attached to pieces of sterile silicon paper with the mucosa
exposed. The remaining fragments of colons were used for isolation of
lamina propria lymphocytes (LPL) as described below. The distal
sections of colon were then washed twice with RPMI (GIBCO BRL, Grand
Island, NY) supplemented with 5% (v/v) endotoxin-free fetal calf
serum, 2 mmol/L glutamine and 1 x 105
U/mL of penicillin/streptomycin. Samples of the same weight
were then plated in wells of a 24-well cell culture plate and cultured
in 0.5 mL of complete RPMI as described above. The cultures were
incubated for 24 h at 37°C in an atmosphere of 10%
CO2 and 95% relative humidity. Culture supernatants were
collected and stored at -70°C.
Isolation and culture of lamina propria lymphocytes.
LPL were isolated using a previously described method
(12)
. Briefly, each cleansed colon was cut into 5-mm
pieces and then incubated in 50 mL of PBS containing 0.1mol/L EDTA, 5
mmol/L dietythritol in a shaking water bath at 37°C for 30 min. The
cultures were filtered and washed with PBS over a 100-mm sterile nylon
mesh (Sefar America, Kansas City, MO). The tissue fragments were then
transferred to another flask and digested with 25 mL of complete RPMI
supplemented with 1% collagenase Type IV (Sigma Chemical, St. Louis,
MO) at 37°C with agitation for 2 h. The resulting suspensions
were filtered through a 100-µm sterile nylon cell
strainer (Becton, Dickinson Labs, Franklin Lakes, NJ). The cells were
collected by centrifugation, and washed once with medium. The cells
were resuspended in 5 mL of 45% Percoll (Pharmacia LKB, Piscataway,
NJ), layered onto 65% Percoll and centrifuged at 600 x g for 20min at 20°C. Lymphocytes were removed from the
interface of 45–65%, washed and counted. The resulting LPL (2 x 105) were cultured in 1.0 mL of complete RPMI for 24 h
under the conditions described above. Culture supernatants were
collected and stored at -70°C.
Histology.
At the time of dissection, a small cuff of the distal colon (within 1
cm from rectum) was fixed in 10% formalin (pH 7.1). The tissue samples
were embedded in paraffin, cut into 5-µm thick
sections and stained with hematoxylin and eosin. Grading on the
severity of the colitis was based on a scoring system with a numeric
value (0–4) assigned to the specimen on the basis of histologic
features (13)
. Dr. Eun Lee, a pathologist specializing in
gastrointestinal diseases scored the specimens in a random fashion
without knowledge of their origin.
Immunoassays.
Protein concentrations of interferon- (IFN-) and TNF- were
measured in culture supernatants from colonic explant and LPL cultures
using an ELISA kit (Quantikine M mouse, R&D Systems, Minneapolis, MN).
Serum concentrations of SAA also were determined by ELISA (Cytoscreen
mSAA, Biosource, Camarillo, CA).
Statistical analysis.
All results are expressed as means ± SEM. Unless otherwise stated, mean responses were compared by using the Kruskal-Wallis test, a nonparametric ANOVA with a Dunn multiple comparison test using GraphPad Instat version 3.01 for Windows 95, GraphPad Software, San Diego, CA. Other nonparametric tests were employed as noted.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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At the end of 1 wk, male mice from each group (n = 8)
were humanely killed and colon explant and LPL cultures established.
The remaining 14 (7 male, 7 female) mice in each group continued to
receive treatment for 6 wk. As shown in Table 1
, both the colon explants and LPL from placebo-treated
IL-2-/- mice spontaneously secreted IFN-. In
contrast, LPL isolated from wild-type mice did not secrete
detectable amounts of IFN- (data not shown). Compared with
sucrose-treated mice, GrTP-treated mice demonstrated a
significant reduction in the spontaneous release of IFN- from colon
explants and LPL (72 and 85%, respectively; Table 1
). TNF- release
in explant cultures from mice treated with GrTP was also significantly
diminished in the explant cultures, but there was no noted difference
in the LPL cultures. The lack of a difference in the LPL cultures
probably reflected the low concentrations measured and suggests that
lymphocytes may not be the major source of TNF- in the lamina
propria. These data show that after 1 wk of ingestion of GrTP, there
was a reduction in IFN- and TNF- production by the inflamed
mucosa.
|
Throughout the study, water and food consumption was monitored daily.
There were no significant differences in food or water consumption
between the GrTP- and control-treated
lL-2-/- mice (Fig. 1
). Similarly, IL-2+/+ mice fed GrTP for 6 wk did
not alter their water or food intake (data not shown). However,
IL-2+/+ mice generally consumed greater amounts
of food and liquid, with control IL-2+/+ being
significantly higher than control IL-2-/-
(P < 0.001)
|
The severity of colitis was assessed by histologic grading of the
colitis in the distal colon and by comparing wet colon weights.
Histological scoring was based on a scoring system ranging from 0
(normal) to 4 (severe) (13)
. Scoring was limited to the
distal colon, within 1 cm of the rectum. The severity of the colitis in
the distal colon varied within each group (Fig. 2A
). Overall, the GrTP group had lower mean scores than the placebo group
(1.5 ± 0.9 vs. 2.3 ± 0.8, P < 0.04,
Wilcoxan signed rank test; Fig. 2B
). Consistent with the
histologic data (Fig. 2C
), the GrTP-treated
group had lower wet colon weights (Fig. 3
). These data showed that oral ingestion of GrTP decreased the severity
of colitis in IL-2-/- mice, but the effect
appears to be modest.
|
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IL-2-/- mice in the placebo-treated group
did not gain weight during the 6-wk study period (Fig. 4
). In contrast, oral ingestion of GrTP resulted in a mean increase in
body weight, and the average weight gain approached that of
IL-2+/+ mice (Fig. 4)
. Although GrTP-treated
mice gained weight, overall food consumption did not change (Fig. 1)
.
|
In an earlier study, we showed that serum levels of SAA closely
correlated with the severity of colitis in IL-2-/-
mice and colon tissue levels of the proinflammatory cytokine,
IL-1ß (10)
. At initiation of the study, serum SAA
concentrations were elevated in both treatment groups with an average
value of nearly 100 mg/L (Fig. 5
). At the end of 6 wk, serum SAA concentrations in the GrTP group did
not rise over baseline values. In contrast, serum levels of SAA
increased nearly twofold in the control group (Fig. 5)
. These data
showed that GrTP modulates the acute phase response and suggested that
disease progression was suppressed by ingestion of GrTP.
|
We measured the hematocrit at the beginning and at the end of study. At
8 wk of age, all IL-2-/- mice had lower
hematocrits than those observed in IL-2+/+ mice
(Fig. 6
). After 6 wk of treatment, the hematocrit in the GrTP group improved
from an average of 26 to 36%, whereas no improvement was noted in the
placebo group (Fig. 6)
.
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|
DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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recently showed
that oral GrTP given before and continued after the insult reduced the
incidence and severity of collagen-induced arthritis in mice. One
of the major differences in our study was the introduction of GrTP into
the diet at a point at which the disease was well established. This is
more in keeping with the use of therapies during the active phase of
disease. Taken together, these data support the potential use of green
tea polyphenols in the treatment of inflammatory diseases.
IL-2-/- C57BL/6 mice develop a colitis that has
striking clinical and histologic similarity to ulcerative colitis
(9)
. The colitis is T-cell mediated (15)
.
In the absence of IL-2, thymocyte maturation is abnormally directed by
IL-12 toward the generation of mature, activated Th1-type thymocytes,
which are responsible for the autoimmunity and mediation of colitis
(16)
. IL-2 is an important permissive cytokine for
activation-induced programmed cell death and, not surprising,
IL-2-/- mice have a defect in T-cell
apoptosis resulting in sustained activation of T cells
(17)
. The cytokine profile of the colitis is consistent
with a Th1-type immune response with increased mRNA expression of
INF- and TNF (10
,18)
. Further extending these
observations, we demonstrated increased spontaneous production of
INF- from colon explants and LPL cultures isolated from
IL-2-/- mice. After 1 wk of GrTP ingestion, we
found a marked reduction in spontaneous INF- production. These data
suggest that GrTP can modulate Th-1–mediated responses in the gut and
may have clinical relevance in the treatment of Crohn’s disease, a
Th-1 process. In support of this, the collagen-induced arthritis
model discussed above also evokes a Th-1 response, and GrTP reduced the
incidence and severity of injury (14)
.
After ingestion, GrTP are widely distributed throughout the body; one
of the highest tissue concentrations is found in the intestine
(19)
. This distribution favors its use in gastrointestinal
diseases such as IBD. The mechanism(s) of action for the
anti-inflammatory effects of green tea have not been clearly
elucidated. The anti-inflammatory and anticarcinogenic effects of
green tea have been attributed to the polyphenol fraction, which is
rich in antioxidants (16)
. Oxidant-mediated injury
plays an important role in the pathogenesis of IBD. Activated
inflammatory cells within the lamina propria produce toxic oxidants
(20
,21)
; this process occurs in the setting of depleted
antioxidant defenses (22)
. This establishes an imbalance,
promoting oxidative stress. In animal models of IBD
(23
,24)
and in humans with Crohn’s disease
(25)
, antioxidants have been shown to ameliorate
inflammation.
The effects of GrTP may not be limited to the scavenging of toxic
oxidants. GrTP and specifically the polyphenol, EGCG, block the
activation of the transcription factor, NF-B (7
,8)
,
which plays a central role in numerous immunologic processes. NF-B
controls the expression of a wide variety of genes active in
inflammation, including cytokines (e.g., IL-1, TNF-, IL-8), enzymes
(inducible nitric oxide synthase), adhesion molecules and acute phase
proteins (SAA, IL-6) (26
27)
. NF-B plays a critical
role in the pathogenesis of chronic inflammatory diseases
(28)
. Increased NF-B activation has been reported in
IBD patients (29
30)
, as well as in animal models of IBD
(10
,31)
. Inhibitors of NF-B have been shown to decrease
inflammation in an animal model of IBD, confirming its pivotal role
(31)
. These observations suggest that NF-B is a
suitable target to prevent or reduce an inflammatory response. The
ability of GrTP to inhibit NF-B activation may be responsible in
part for its anti-inflammatory effects.
In summary, our results show that GrTP reduced disease activity in IL-2-/- mice. The concentration (0.5% solution) used in this study is higher than that readily available in food sources (tea). Assuming that a cup (100 mL) of green tea contains 200–500 mg of GrTP, a 70-kg human would have to consume 100–200 cups of green tea to achieve an equivalent daily dose. We do not know whether lower doses of GrTP are as effective in this model. In the collagen-induced arthritis study, a lower concentration of GrTP (2 g/L solution) was used and found effective. However, concentrated forms of green tea extracts are now being sold as natural supplements. Future studies are required to examine the efficacy of lower doses, including a dose equivalent to functional foods in other animal models of IBD as well as in IBD patients. On the basis of our preliminary findings, we postulate that green tea and its polyphenol fraction may prove to be a useful dietary supplement in the treatment of chronic inflammatory diseases such as IBD.
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FOOTNOTES |
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3 Abbreviations used: CAM, complementary and alternative medicine; EC, (-)-epicatechin; ECG, (-)-epicatechin gallate; EGC, (-)-epigallocatechin); EGCG, (-)-epigallocatechin gallate; GrTP, green tea polyphenols; IBD, inflammatory bowel disease; IFN-, interferon-; IL-2-/- interleukin-2 deficient;
LPL, lamina propria lymphocytes; LPS, lipopolysaccharide; NF-B, nuclear factor-B; SAA, serum amyloid A; TNF-, tumor necrosis factor-;
Manuscript received December 19, 2000. Initial review completed April 12, 2001. Revision accepted April 18, 2001.
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 H. Takano, N. Osakabe, C. Sanbongi, R. Yanagisawa, K.-I. Inoue, A. Yasuda, M. Natsume, S. Baba, E.-I. Ichiishi, and T. Yoshikawa Extract of Perilla frutescens Enriched for Rosmarinic Acid, a Polyphenolic Phytochemical, Inhibits Seasonal Allergic Rhinoconjunctivitis in Humans Experimental Biology and Medicine, March 1, 2004; 229(3): 247 - 254. [Abstract] [Full Text] [PDF]
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 E. Tedeschi, M. Menegazzi, Y. Yao, H. Suzuki, U. Forstermann, and H. Kleinert Green Tea Inhibits Human Inducible Nitric-Oxide Synthase Expression by Down-Regulating Signal Transducer and Activator of Transcription-1{alpha} Activation Mol. Pharmacol., January 1, 2004; 65(1): 111 - 120. [Abstract] [Full Text] [PDF]
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 L. M. Gaetke, H. S. Oz, R. C. Frederich, and C. J. McClain Anti-TNF-{alpha} Antibody Normalizes Serum Leptin in IL-2 Deficient Mice J. Am. Coll. Nutr., October 1, 2003; 22(5): 415 - 420. [Abstract] [Full Text] [PDF]
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