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-Irradiation in the Colorectum of Rats Treated with an Immunosuppressant1
Laboratory of Nutritional Biochemistry, Division of Applied Bioscience, Graduate School of Agriculture, Hokkaido University, Sapporo 060-8589, Japan
2To whom correspondence should be addressed.
 |
ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-irradiation can induce aberrant
crypt foci (ACF) in the rat colorectum. The aim of this study was to
evaluate the effect of dietary sugar beet fiber (SBF) on the
distribution of the CD8+ intraepithelial lymphocyte (IEL)
in the colorectum and on the number of -irradiation–induced ACF of
rats administered anti-asialo GM1 (
AGM1) as an
immunosuppressant. Wistar/ST rats fed a fiber-free diet or the diet
supplemented with SBF (100 g/kg diet) were administrated AGM1 or
normal rabbit serum as a control during the initiation period with
-irradiation. At 5 and 9 wk after the first irradiation, ACF and
total aberrant crypts (AC) per area in the colorectum were counted. The
numbers of ACF (P = 0.0010) and AC
(P = 0.0635) per unit area were lower in the
SBF-fed group than in the rats fed the fiber-free diet. AGM1
administration significantly raised the number of ACF (P
= 0.0001) and AC (P = 0.0006) per area in the
colorectum. Moreover, AGM1 administration during the initiation
period reduced the number of CD8+ IEL per 100 cells in the
epithelial layer (P = 0.0001) of the colon. These
results demonstrate that reduction of the number of CD8+
IEL per 100 cells in the epithelial layer as a result of AGM1
administration promotes the formation of irradiation-induced ACF in
the colorectum. The number of CD8+ IEL per 100 cells in
epithelial layer was lower in the group fed the fiber-free diet
than in the SBF-fed group (P = 0.0522). These
results indicated that the ingestion of dietary SBF suppressed
-irradiation–induced ACF formation through the immune surveillance
in the colorectal mucosa.
KEY WORDS: • aberrant crypt foci • anti-asialo GM1 • CD8+ intraepithelial lymphocyte • rats • sugar beet fiber
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). ACF also appear in the
colonic mucosa of carcinoma-bearing humans as well as in
carcinogen-treated animals (Pretlow et al. 1994
).
They also are observed in tumor-bearing rodents after treatment
with a colorectal carcinogen (Shivapurkar et al. 1992
and 1995
). Therefore, ACF are commonly used as a biomarker for
colorectal cancer. A higher number of aberrant crypts (AC) per focus
may increase the subsequent risk of colorectal cancer (Bird 1995
).
We used -rays as an ACF-inducer in this study, although
1,2-dimethylhydrazine (DMH) or azoxymethane (AOM) is usually used as
the carcinogen. We have developed a method in which ACF are induced by
abdominal -irradiation (Ishizuka et al. 1999
).
-Ray–induced ACF were observed in all of the rat colorectums at 9
wk after the first irradiation (Ishizuka et al. 1999
).
Many carcinogens such as DMH or AOM must be converted to their active
forms by the liver and/or intestinal bacteria (Reddy et al. 1977
, Visek and Clinton 1991
). In contrast,
-rays initiate the cells directly without conversion. It is not
likely, therefore, that the initiation of -rays would be influenced
by luminal contents such as dietary factors or bacterial enzymes, at
least during the initiation periods. It is interesting that -rays
can induce ACF as well as carcinogens. It is unknown whether the
initiation with -rays has the same exact effect on colorectal mucosa
as that of carcinogens such as DMH.
The mucosal epithelium of the intestine has a characteristic
immune system. Intraepithelial lymphocytes (IEL), which are located
between the epithelial cells, play a major role in the initial immune
action against exogenous antigens (Camerini et al. 1993
,
Nauss et al. 1984
). IEL are T cells that have mainly CD8
antigen, and the T-cell receptors consist of 
chains
(Guy-Grand et al. 1991
). IEL have cytotoxic activity and
chemotaxis. The immune response to a tumor is thought to be an early
event leading to the destruction of the majority of tumors before they
become clinically apparent (Beverley 1993
). IEL may play
a role as an immune surveyor at the ACF-growing stage in the
colorectal mucosa. We reported previously that the administration of
anti-asialo GM1 serum (AGM1), which reduces the natural killer
(NK) activity of the peripheral blood lymphocytes (Shimizu et al. 1987
), increased DMH-induced ACF in the rat colorectum
(Ishizuka et al. 1996
). If NK cells attack and kill
abnormal epithelial cells as the target cells in an early
carcinogenesis before forming ACF, then subsequent numbers of ACF
should be lower in the colorectum. The massive formation of ACF after
the administration of AGM1 may be due to a decrease of the NK
activity of IEL and/or to a reduction in the number of IEL themselves.
The enhancement of defecation and the excretion of carcinogens
reduce the risk for colorectal carcinogenesis from the ingestion of
dietary fibers, especially in the case of insoluble fibers. It is
interesting to examine the effect of dietary fiber on early markers for
colorectal carcinogenesis induced by the different initiators (-rays
and DMH). In this study, we used sugar beet fiber (SBF) as a
dietary fiber source. Ingestion of the SBF significantly reduced
the frequency of DMH-induced tumor compared with the fiber-free (FF) diet (Aritsuka et al. 1989
). We
reported previously that SBF also had a suppressing effect against
DMH-induced ACF (Ishizuka and Kasai 1997
), but not
against -ray–induced ACF (Ishizuka et al. 1999
). In
our earlier study, the ingestion of SBF suppressed DMH-induced ACF
in the rat colorectum regardless of the administration of AGM1
(Ishizuka and Kasai 1997
). Because SBF is a relatively
highly fermentable dietary fiber (Hara et al. 1996
), it is an effective material with which to investigate
the relation between ingestion of fermentable dietary fibers in the
large intestine and suppression of colorectal cancer.
In this study, we investigated the suppressive effect of dietary
SBF in -ray–induced ACF. We also examined whether the number of IEL
in the colorectum are influenced by the administration of AGM1 and
whether the ingestion of SBF changed the number of IEL in rats
administered AGM1.
|
MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Male Wistar/ST rats (5 wk old, Japan SLC, Hamamatsu, Japan) were housed
in individual cages in a temperature-controlled (23 ± 2°C)
room under a 12-h photoperiod (light: 0800–2000h). The fiber-free
(FF) diet contained sucrose, casein, corn oil, a mineral mixture and a
modified AIN-76 vitamin mixture, described previously (Hara et al. 1996
). Rats were allowed free access to food and water
throughout the experiment period. All rats were given the FF diet for
7 d during the acclimation period. The study was approved by the
Hokkaido University Animal Use Committee, and the animals were
maintained under the guidelines for the care and use of laboratory
animals, Hokkaido University.
The distribution of CD8+ IEL in the proximal and
distal colon with or without AGM1 administration.
In the experiment for the effect of AGM1 on the distribution of
CD8+ IEL, eight rats were divided into two groups after the
acclimation period. They were injected intraperitoneally with 100
µL of AGM1 (Wako Pure Chemical, Osaka, Japan), or
normal rabbit serum (NRS; Wako Pure Chemical) as described previously
(Ishizuka and Kasai 1997
). The sera were injected on d 0
and 3. On d 5, these rats were killed by decapitation, and their
proximal and distal colons were removed. After being washed, colons
were embedded in OCT compound, rapidly frozen with liquid
nitrogen and stored at -80°C until analysis. Frozen sections of
colonic segments were fixed with acetone for 20 min. After being washed
with PBS, these sections were incubated for 30 min with 10% NRS in PBS
for blocking nonspecific bindings. They were then incubated with
anti-CD8 (MAB1404, Chemicon, Temecula, CA) monoclonal antibody. The
sections were stained with fluorescein isothiocyanate (FITC)-labeled
anti-mouse rabbit immunoglobulin G for 30 min and put into
propidium iodide (PI) solution to stain the nucleus of the cell.
Fluorescent cells were counted by using a confocal laser microscope
(LSM410 Invert Laser Scan Microscope, Oberkochen, Germany). The
frequency of CD8+ IEL was expressed as the number of
CD8+ IEL per 100 mucosal epithelial cells in the same
section.
The effect of SBF on the distribution of CD8+ IEL in
the colon of rats with or without AGM1 administration.
In the experiment testing the effect of AGM1 and dietary SBF on the
distribution of CD8+ IEL in the colon, 16 rats were divided
into two dietary groups and given FF or a diet supplemented with SBF
(100 g/kg FF diet) after the acclimation period. The SBF was donated by
Nippon Beet Sugar MFG (Obihiro, Japan). Each diet group was injected
intraperitoneally with AGM1 or NRS on d 4 and 7. Samplings of the
proximal and distal colons were taken on d 9 as described above and
stored at -80°C until analysis. The methods of analysis were the
same as those in the previous experiment.
The effect of SBF ingestion on -ray–induced ACF in rats with
or without AGM1 administration.
After the acclimation period, 48 rats were divided into two dietary
groups and given the FF or SBF diet. Each diet group was then injected
intraperitoneally with either AGM1 or NRS on d 6, 9, 12, 15 and 18.
The abdomens of these rats were -irradiated on d 11, 15 and 18 using
a 60Co-–irradiator (Cobalt-60 Teletherapy
Apparatus RCR-120-C3; Toshiba, Kanagawa, Japan) under anesthesia with
sodium pentobarbital (Abbott Laboratories, North Chicago, IL), as
reported previously (Ishizuka et al. 1999
). -Rays
from a 60Co source were given at dose rates of
0.64 Gy/min. Five or 9 wk after the first irradiation, rats were killed
by decapitation and their colorectums and ceca removed for ACF and
cecal organic acid determination, respectively. The cecal contents of
rats killed at 9 wk from the first irradiation were frozen and stored
at -40°C until analysis for organic acids. The colorectum samples
were flushed with cold saline and fixed with 10% formalin in PBS for
1 h on flat plates. They were stained with 0.2% methylene blue.
The ACF and AC were counted with a light microscope; then the mucosal
area of the colorectum was measured using a Macintosh computer with a
scanner (Scantouch 210, Nikon, Tokyo, Japan). The ACF and AC in the
colorectums were expressed as the number against the mucosal area. The
number of AC/focus (multiplicity) was also calculated.
Measurement of organic acids in cecal contents.
The concentrations of organic acids (succinate, lactate, acetate,
propionate, butyrate, isovalerate and valerate) in the rat cecal
contents were measured by using HPLC (Shimadzu, Kyoto, Japan) according
to Hoshi et al. (1994)
. Briefly, the cecal contents were
added to sodium hydroxide aqueous solution containing crotonic acid
(Wako Pure Chemical) as an internal standard. After centrifugation, the
fat-soluble substance in the supernatant was removed by extraction
with chloroform. The aqueous phase was filtered through a membrane
filter and applied to HPLC.
Statistical analysis.
The data were analyzed by two-way ANOVA for the distribution of
CD8+ IEL in the proximal and distal colon with or without
AGM1 administration (site and treatment) or by three-way ANOVA
for the effect of SBF on the distribution of CD8+ IEL in
the colon with or without AGM1 administration (site, treatment and
diet) and for the effect of SBF ingestion on -ray–induced ACF with
or without AGM1 administration (diet, treatment and time). Multiple
comparisons for the effect of SBF on -ray–induced ACF were
performed to determine differences among the groups using the
Tukey-Kramer test. The level of significance was P
< 0.05. All statistical calculations were carried out with JMP
computer software (SAS Institute, Cary, NC).
|
RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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AGM1 administration.
No significant difference was observed in total food intake and body
weight gain of the rats. The number of CD8+ IEL
per 100 cells in the epithelial layer was lowered significantly by the
injection of AGM1 in the proximal and distal colon (P
< 0.0001) (Fig. 1
). The number of CD8+ IEL in the proximal colon
was significantly greater than that in the distal colon (P
= 0.0001). The effect of AGM1 on the proportion of
CD8+ IEL was significantly different between the
proximal and distal colon (site x treatment, P = 0.0133).
|
AGM1 administration.
No significant difference was observed in total food intake or body
weight gain of the rats. The proportion of CD8+
IEL was lowered significantly by AGM1 in the colon (P
= 0.0103) (Fig. 2
). The addition of SBF to the FF diet lessened the decrease in the
proportion due to AGM1 treatment (P = 0.0522). No
interaction was observed for site x treatment (P
= 0.7026), treatment x diet (P = 0.8498),
diet x site (P = 0.5015), or diet x treatment x diet (P = 0.2331).
|
-ray–induced ACF in rats with or
without AGM1 administration.
Final body weight and total food intake were significantly influenced
by diet (P = 0.0382 and 0.0003, respectively) and time
(P < 0.0001). A significant interaction between time
and diet was observed for total food intake (P = 0.0279) (Table 1
).
|
). Administration of AGM1 significantly increased the number of ACF
(P = 0.0001). On the other hand, SBF ingestion
suppressed the formation (P = 0.0010) of ACF. The same
tendency was observed for AC (P = 0.0006 for treatment,
P = 0.0635 for diet). The number of AC per focus was
influenced significantly by time (P = 0.0220).
|
). On the contrary, the concentration of isovalerate in the cecum was
greater in the fiber-free group than in the SBF-fed (diet,
P = 0.0004) and in NRS-treated groups than in
AGM1-treated groups (treatment, P = 0.0601). No
significant effects on other organic acids in the cecal contents were
observed due to the administration of AGM1.
|
|
DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). We examined whether the
administration of AGM1 or the ingestion of dietary fiber influences
the proportion of CD8+ IEL cells in the
epithelial layer in rat colon. An interesting result of this study is
that the administration of AGM1 significantly lowered the proportion
of CD8+ IEL cells in the epithelial layer in the
proximal and distal colons (Fig. 1)
. This is the first report that the
administration of AGM1 influences the colonic
CD8+ IEL number in vivo. We have already
confirmed that the administration of AGM1 during the initiation
periods promoted subsequent ACF formation induced by DMH
(Ishizuka et al. 1996
). Moreover, administering AGM1
significantly increased -irradiation–induced ACF in this study
(Fig. 3)
. These results suggest that the administration of AGM1
influences ACF formation during the early phase of carcinogenesis,
likely via CD8+ IEL reduction, regardless of the
initiation method. The expression of other T-cell subsets on IEL or
cytokines involved in the epithelial cell turnover may have been
altered in the colonic epithelium by this treatment.
The proportion of the number of CD8+ IEL
cells in the epithelial layer was greater in the proximal colon than in
the distal colon (Fig. 1)
. In general, carcinogen-induced ACF and
carcinoma in the colon were observed frequently in the distal
colon (McLellan and Bird 1988
). These results suggest
that IEL may participate in the elimination of abnormal epithelial
cells after initiation. If the number of the IEL is related to the
risk of carcinogenesis, IEL may play an important role in immune
surveillance. The relationship between the colonic IEL function and the
effect of dietary fibers should be investigated to clarify the
mechanisms of the inhibitory effect of fibers on colorectal
carcinogenesis and homeostasis. In this report, we studied the effect
of dietary SBF on the proportion of CD8+ IEL in
the colonic epithelial layer. In the proximal colon, dietary SBF
inhibited the decrease in the ratio of CD8+ IEL
in rats treated with AGM1 (Fig. 2)
. A similar trend was observed in
the distal colon. The ingestion of dietary fibers may influence the
expression of CD8 molecules on the surface of IEL, the recruitment of
CD8+ IEL from peripheral blood or the
proliferation of CD8+ IEL in the colonic mucosa.
Another interesting finding of this study is that dietary SBF
suppressed an increase in the number of ACF induced by -rays in the
colon of rats treated with AGM1 (Fig. 3)
. However, SBF had no effect
in the absence of AGM1 treatment. The same result was obtained in
our previous study using DMH as the initiator (Ishizuka and Kasai 1997
). In the previous study, ingestion of SBF strikingly
suppressed DMH-induced ACF, but did not influence -ray-induced
ACF. However, SBF had an inhibitory effect on -ray–induced ACF in
rats treated with normal serum in this study. In the intestinal luminal
environment, factors such as bacterial enzymes influence and convert
DMH before it begins to act as a genuine carcinogen (Reddy et al. 1977
, Visek and Clinton 1991
). The ingestion
of dietary fiber significantly influences these environmental factors
and increases the volume of luminal contents (Folino et al. 1995
). In general, dietary fiber decreases the level of
initiation damage in the colonic epithelial cells through increased
defecation and excretion of these carcinogens (Folino et al. 1995
). Fermentation is an important event that is
related to carcinogenesis. It has been suggested that an acidic pH,
high luminal butyrate concentration, high fecal bulk and a low rate of
epithelial turnover are protective against carcinogenesis
(Kashtan et al. 1992
). It has been reported that highly
fermentable fibers (wheat bran and rice bran) slow proliferation and
raise the concentration of butyrate (Folino et al. 1995
). On the contrary, -rays initiate the intestinal
epithelial cells directly without being influenced chemically by the
luminal factors. Furthermore, the initiation periods lasted only a few
minutes in every irradiation.
The results of this study suggest a novel mechanism for the
inhibitory effect of dietary fiber on colorectal carcinogenesis. The
ingestion of SBF protects against early carcinogenesis in ACF under an
immunosuppressive condition by AGM1 treatment (Fig. 3)
. The
ingestion of SBF may assist immune surveillance of
CD8+ IEL in the colonic mucosa under immune
suppressive conditions. Perrin et al. (1994)
demonstrated that treatment with butyrate at a physiologic
concentration increased the surface expression of the major
histocompatibility complex class I molecule on low immunogenicity cells
derived from colonic carcinoma induced by a carcinogen. Butyrate is one
colonic fermentation product originating from dietary fibers such as
SBF (Hague et al. 1993
, Hara et al. 1996
). It is usually used as an energy source by the colonic
epithelial cells (Fleming et al. 1991
, Roediger 1982
). On the other hand, it induces apoptosis of some colonic
carcinoma cell lines at physiologic concentration after ingestion of
dietary fibers (Hague et al. 1993
). Butyrate is one
candidate for the biological response modifiers in the early phase of
colonic carcinogenesis. Dietary SBF significantly increased the
concentration of many organic acids, especially lactate, acetate and
propionate, as well as butyrate (Table 2)
. In contrast, ingestion of
SBF had an inverse effect on the concentration of isovalerate in the
cecal contents. Branched-chain fatty acids such as isovalerate are
derived from certain amino acids (Thomsen et al. 1982
).
These amino acid metabolites in the luminal contents may affect
homeostasis of the colonic epithelium. In this report, we did not
investigate the effect of organic acids. It would be interesting to
investigate how these organic acids, especially branched-chain
fatty acids, affect cancer.
In this study, the number of -irradiation–induced ACF per
unit area was similar at 5 and 9 wk after the first irradiation. We
expressed ACF frequency as the number per unit area in this study
because the colonic mucosal area was significantly different between
these two dietary groups. Butyric acid originating from SBF is used by
the colonic epithelium and probably results in an increase in the
colonic area. The number of ACF per rat tended to increase with time
(data not shown). The AC/focus (multiplicity) was not affected
significantly by AGM1 treatment or by ingestion of SBF (Fig. 3)
. The
-ray–induced ACF had relatively larger multiplicity than the
DMH-induced ACF (Ishizuka and Kasai 1997
). ACF
induced by -rays are thought to develop rapidly.
In conclusion, the administration of AGM1 decreased the number
of CD8+ IEL per 100 cells in the epithelial layer
in the rat proximal and distal colons. Dietary SBF suppressed an
increase in the number of ACF induced by -rays in colon of the rats
treated with AGM1. These results suggest that a reduction of
CD8+ IEL in colonic epithelium at the initiation
and/or postinitiation phase of carcinogenesis increases subsequent ACF
formation. These results support the notion that the immune system
plays a protective role in the early phase of carcinogenesis. The
ingestion of dietary fibers may affect the immune surveillance to
reduce the risk for colorectal carcinogenesis.
|
ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: AGM1, anti-asialo GM1; AC, aberrant crypts; ACF, aberrant crypt foci; AOM, azoxymethane; DMH, 1,2-dimethylhydrazine; FF, fiber-free; FITC, fluorescein isothiocyanate; IEL, intraepithelial lymphocyte; NK, natural killer; NRS, normal rabbit serum; PI, propidium iodide; SBF, sugar beet fiber.
Manuscript received September 1, 1999. Initial review completed October 11, 1999. Revision accepted March 21, 2000.
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