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Departments of
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Pediatrics,
Microbiology and Immunology,
Human Biological Chemistry and Genetics,
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Pathology,
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Preventive Medicine and Community Health, and
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Sealy Center for Molecular Sciences, University of Texas Medical Branch, Galveston, TX 77555; and
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Department of Surgery, University of Wisconsin, Madison, WI 53706
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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and IFN-
, increased
the expression of KC mRNA and protein in murine epithelial cells.
However, IL-10 was incapable of decreasing the induction of KC, even
though the cells expressed the IL-10 receptor. These results suggest
that the neutrophil chemokine KC is produced by gastrointestinal
epithelial cells in response to inflammatory mediators that are
expressed following exposure to normal flora in animals lacking
IL-10. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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by
macrophages stimulated with LPS and IFN- 2 . Accordingly, mice
become more sensitive to LPS-induced shock by treatment with
anti-IL-10 Abs while lethal endotoxemia and elevated serum TNF-
levels are suppressed upon the administration of IL-10 3, 4 . Through
its effects on APCs, IL-10 also suppresses the development of Th1 cells
5 . Mice deficient in IL-10 initially have normal lymphocyte
development and Ab responses. However, with age, the animals develop
anemia, growth retardation, and a chronic inflammatory bowel disease
6 . The development of colitis in these mice is attenuated when they
are housed in specific pathogen-free conditions that limit their
exposure to flora 6 . This suggests that failure to regulate
immunological responses to the normal flora may play a critical role in
the development of intestinal inflammation.
The host response to the massive antigenic load in the intestinal lumen
is regulated by cytokines that select for protective immunity while
inhibiting excessive amounts of inflammation. The appearance of chronic
intestinal inflammation in IL-10 knock-out
(KO)3 mice suggests that this
cytokine inhibits adverse responses to luminal Ag 6 . In fact, the
colitis in these animals is associated with an increase in T cells
producing TNF- and IFN- 7, 8 . Moreover, the administration of
exogenous IL-10 7 or helper T cell subsets that produce high levels
of IL-10 can prevent or attenuate inflammation in various models of
colitis in mice 9, 10 .
In addition to an increase in lymphocytes, mice with colitis, including
IL-10-deficient mice 7 , often have increased levels of neutrophils in
their intestinal mucosa. In humans with inflammatory bowel disease, one
of the characteristic lesions is the presence of crypt abscesses,
accumulations of neutrophils within the luminal space of the intestinal
epithelial crypt. The chemokines produced by intestinal epithelial
cells are believed to be critical participants in the development of
these inflammatory infiltrates 11, 12, 13 . Chemokines are synthesized in
response to bacterial products and cytokines secreted by a wide variety
of immune, inflammatory cells, as well as epithelial and endothelial
cells 11, 12, 14, 15, 16 . The chemokines, such as IL-8, are potent
chemoattractants for polymorphonuclear neutrophils, whereas ß
chemokines, such as monocyte chemoattractant protein-1, are
chemoattractant for mononuclear cells. The mouse KC gene is a member of
the chemokine family originally isolated from platelet-derived
growth factor-stimulated BALB/c 3T3 fibroblasts 17 . KC is a homologue
of the human GRO/melanoma growth-stimulatory activity family 17, 18 .
Although no structural homologue of IL-8 has been identified in mice,
KC shares 65% sequence identify with human gro- and shares many
functional properties with IL-8 17 . For example, KC transgenic mice
show a marked infiltration of neutrophils at the sites of transgene
expression 19 . KC also binds the IL-8R, and mice deficient in IL-8R
lack neutrophil migration to sites of inflammation 20, 21 . The KC
gene is also induced by LPS, thrombin, double-stranded RNA (poly IC),
IFN-, TNF-, and IL-1 in a number of cell types, including
macrophage, fibroblasts, and endothelial cells 22 .
The studies described above suggest that the disruption in the
regulation of the host response to microbial products can contribute to
the induction of chemokines and inflammatory infiltrates in colitis.
The present study examined the effect of normal flora on the
development of colitis and KC expression in the IL-10-deficient mouse
model by comparing these parameters in animals housed under germfree or
conventional conditions. Our results suggest that expression of the
neutrophil chemokine KC in the intestinal mucosa of mice with
enterocolitis was regulated by the balance between proinflammatory
cytokines (such as TNF- and IFN-) and anti-inflammatory
cytokine IL-10.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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IL-10-deficient mice were generated by Kuhn et al. 6 by the
insertion of neomycin resistance gene (neo) into the IL-10
gene as previously described. Heterozygous animals were provided by
DNAX (Palo Alto, CA) and bred in conventional housing facilities at
University of Texas Medical Branch (UTMB, Galveston, TX). Offspring
were screened for the defect in the IL-10 gene by PCR of DNA isolated
from blood. Briefly, 10 µl of blood was washed in 200 µl of TED
buffer, and proteins were digested by heating the pellet in 40 µl of
0.1% Triton X-100 and 10 µl of 0.4 N NaOH at 95°C for 5
min. After neutralization with 1 M Tris (pH 7.5), the material is
stored until use. DNA solution (10 µl) are added to a PCR mixture
containing 1 sense primer (position 1523, CGG TTC AGT ATA AAA GGG GGA
CC) and 2 antisense primers, the first to native IL-10 (position 1723,
GTG GGT GCA GTT ATT GTC TTC CCG) and the second, to the neo
insert (position 338 of neo, inserted 111 bases 3' to the
IL-10 sense primer, CCT GCG TGC AAT CCA TCT TG). The wild-type (wt,
+/+) gene yields a product of 200 bases, while the neo
primer yields a product of 
449 bases in the disrupted gene. The
effect of the genetic mutation was confirmed by the absence of
detectable levels of IL-10 protein by ELISA of supernatants of
stimulated splenocytes (our unpublished observation). The IL-10
homozygous (-/-), heterozygous (+/-), and wt (+/+) mice were housed
at UTMB in conventional conditions free of specific pathogens. In
addition, some of the same founder heterozygous mice provided by DNAX
were rederived in germfree conditions at the University of Wisconsin
(Madison, WI). These animals were bred and housed in germfree isolators
until being shipped to UTMB in isolator cages to test for evidence of
colitis. Their germfree status was confirmed by microbiological
screening. All procedures were approved by the Animal Care and
Utilization Committees at the respective institutions.
Evaluation of Disease
Clinical Evaluation.
Animals (160) from the breeding colony were examined on a daily
basis over a period of 18 mo. Illness was described as mild, moderate,
and severe according to the following criteria: mild, no obvious change
in behavior or temperament, occasional diarrhea or blood on stool or
around anus; moderate, animal obviously sick, blood in stool and around
anus, may have a rectal prolapse; severe, animals appeared depressed
and cachectic, evidence of bloody diarrhea, and a rectal prolapse was
present. If animals did not die suddenly, they were euthanized when
their body weight was 20% less than the controls.
Evaluation at necropsy. The gross pathology was scored as mild, moderate or severe at the time of euthanasia: mild, a single area of grossly obvious involvement in the large intestine, no obvious cachexia, formed stool; moderate, >1 cm of involvement in one or more areas of the large intestine, some formed stool; severe, blood in the stool, evidence of cachexia. Histopathological analyses were performed on approximately half of the affected mice and controls. Control or IL-10-deficient mice were sacrificed at weaning and when moderately ill. Tissues were fixed in 10% buffered formalin and embedded in paraffin blocks. Subsequently, 4–6-µm thick sections were cut and stained with hematoxylin and eosin before being examined by light microscopy. Each mouse was scored using a modification of a technique that was previously described 23 . Briefly, one point was given for each of the following criteria: number of areas of involvement (lower colon, upper colon, cecum), epithelial disruption, branching of crypts, epithelial dysplasia, and crypt abscesses.
Epithelial cell lines
The murine intestinal epithelial cell line Mode-K 24 was
maintained as adherent cells, at 37°C in a humidified atmosphere of
5% CO2 in air in DMEM media containing 1% nonessential
amino acids, 0.055% (w/v) sodium pyruvate, 10% FCS, 4 mM
L-glutamine (complete DMEM medium). The cells were detached
three times a week, using a solution of 0.25% trypsin in 0.5 mM EDTA
(Sigma, St. Louis, MO). For analysis of the regulation of KC mRNA and
protein, the Mode-K were treated with varying doses of recombinant
murine TNF- (PharMingen, San Diego, CA), IFN- (Boehringer
Mannheim, Mannheim, Germany), or IL-10 (kindly provided by
Schering-Plough Research Institute, Kenilworth, NJ). For data presented
in this report, a single, optimal concentration of these cytokines was
used as noted in Results. The supernatants or the cells were
collected after the culture for 4 h in vitro and assayed for KC
mRNA or protein as described below.
RNA preparation and analysis
RNA was extracted from the epithelial cell line (Mode-K) or the intestinal tissue from control or IL-10 KO mice using RNAzol (Biotecx Laboratories, Houston, TX), following specifications from the manufacturer. Total RNA (20 µg) per sample was separated by electrophoresis on 1.4% agarose-formaldehyde gel and transferred to a Hybond N membrane (Amersham, Buckinghamshire, England) and hybridized with random primed 32P-labeled cDNA probes (106 cpm/ml hybridization solution) for KC and G3PDH (Clontech Laboratories, Palo Alto, CA) for 16 h at 65°C. The filter was then submitted to high stringency washes (at room temperature by 2x SSC, 0.1% SDS at three times and at 55°C by 0.1x SSC, 0.1% SDS at three times), dried, and exposed to Kodak XAR-5 x-ray films at -70°C.
KC protein preparation and analysis
For KC protein determination, colonic tissue from IL-10 -/-, +/-, and +/+ mice in the germfree or conventional conditions were homogenized in 2.0 ml of PBS (pH 7.4) (for 1 min in ultral turrax homogenizer) and supernatants, obtained by centrifugation (1800 rpm for 10 min), and frozen at -80°C in polypropylene tubes until assayed. KC protein was detected by a commercially available ELISA kit (R&D Systems, Minneapolis, MN) and used according to manufacturer’s instructions. The reaction was terminated by adding 100 µl of stop solution to each well with 30 min, and absorbance was measured at a wave length of 450 nm. Tissue KC levels were expressed relative to total protein, which was measured using a commercial protein quantification kit (Pierce, Rockford, IL).
Statistical analysis
Levels of cytokine expression are presented as the mean ± SEM. These data were analyzed by the Student’s t test and considered significant if p values were <0.05. Comparison of mortality rates was evaluated using Kaplan-Meier techniques followed by log-rank tests. All calculations were performed using a microcomputer implementation of the statistical software system SAS (SAS Institute, Cary, NC).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Age-matched homozygous, IL-10-deficient (-/-) mice were combined
into groups, housed under conventional or germfree conditions, and
their mortality was compared with littermates with a normal phenotype
(+/+ or +/-) under identical housing. As shown in Fig. 1
, 100% of the male IL-10-deficient mice
housed in conventional conditions died by 4 mo. During this time, the
female mice displayed mild to moderate disease (data not shown), but
50% of them were still alive after 4 mo. All of the male or
female control mice (+/+ or +/-) housed in conventional conditions
were alive and healthy for up to a year while both IL-10 KO male and
female mice were also clinically normal when they were housed in
germfree conditions (up to 8 mo).
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, marked inflammation
was observed in the IL-10-deficient animals that were housed in
conventional conditions. Abnormal changes included: 1) thickening of
the mucosa, 2) disorganization and hyperplasia of crypts, 3) epithelial
erosion/ulceration, 4) accumulation of bacteria, 5) marked infiltration
of leukocytes, and 6) crypt abscess formation. None of these
inflammatory changes were detected in the IL-10-deficient animals
housed in the germfree conditions or in the wt control mice housed in
conventional conditions.
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Other studies suggest that crypt abscesses form during chronic
intestinal inflammation due to the production of epithelial chemokines
that are stimulated by bacteria and/or cytokines 11, 12, 13 . In view of
the presence of these abscesses in virtually all of the IL-10-deficient
mice with colitis, samples of colonic tissue were screened for the
presence of KC, a murine neutrophil chemoattractant. The levels of KC
mRNA and protein in the colonic tissue of IL-10 KO mice differed based
on the presence of colitis, which was affected by age, gender, and
housing conditions. For example, by 12 wk, the male IL-10 KO mice
housed in conventional conditions demonstrated high levels of KC
expression compared with the similarly aged female mice or weaning mice
(Fig. 3). The frequency of mice
expressing KC and the magnitude of expression were affected by age. KC
mRNA expression was also compared in samples of colonic tissue from
animals housed in conventional or germfree conditions. As shown in Fig. 4, KC mRNA was virtually undetectable in
IL-10 KO mice housed in germfree conditions. The presence or absence of
KC generally correlated with the presence or absence of colitis and the
neutrophil infiltrate detected in the colonic tissues.
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To confirm that KC mRNA expression correlated with the presence of
KC protein, samples of colonic tissue were homogenized and assayed by
ELISA. As shown in Fig. 5, KC protein was
not detected in healthy control mice. In contrast, a significant
induction of KC was detected in colonic tissue from the IL-10 KO mice
housed in conventional conditions. Moreover, the level of KC was lower
in the cohorts (i.e., the females) that showed a more mild form of the
colitis as scored based on clinical appearance and degree of
inflammation detected by histology (mean score and SEM: 4.2 ± 0.5
for males, 2.1 ± 0.3 for females at 4 mo of age;
p < 0.05).
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Several studies have suggested that crypt abscesses in human
disease likely reflect the expression of chemokines in epithelial cells
11, 12, 13 . Thus, using the murine intestinal epithelial cell line
Mode-K, we examined the expression of KC mRNA and protein. As shown in
Fig. 6, Mode-K cells constitutively
expressed low levels of KC mRNA and protein. As intestinal T cells from
IL-10-deficient mice produce IFN- and TNF- during inflammation
7, 8 , KC expression was measured in Mode-K cells after exposure to
these cytokines. TNF- mediated a dose-dependent induction of KC mRNA
and protein (data not shown). Subsequently a suboptimal dose of TNF-
(50 ng/ml) was combined with other cytokines to evaluate cytokine
interactions. Although IFN- (100 U/ml) had little ability to
increase KC mRNA and protein, it markedly enhanced KC expression when
combined with TNF- (Fig. 6).
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). The lack of an inhibitory effect by the
IL-10 was not due to a lack of bioactivity as this preparation did
induce proliferation of an IL-10 dependent cell line (data not shown).
These findings suggest that the effect of IL-10 in vivo may be targeted
toward cells other than the epithelium. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The presence of crypt abscesses is a very reliable marker of some forms of inflammatory bowel disease in humans. These accumulations of neutrophils have been implicated in the perpetuation of chronic inflammation as they can disrupt the epithelial barrier function. For example, migration of neutrophils across the epithelium has been shown to increase permeability 25 . Moreover, luminal neutrophils may also migrate back into the lamina propria 26, 27 . Thus, antigenic material may come in contact more easily with immune/inflammatory cells if the epithelial barrier is compromised, or if the material is engulfed by neutrophils that then return to the lamina propria. The ubiquitous presence of crypt abscesses in this model will permit experimental manipulations directed toward disrupting neutrophil migration to evaluate the role of the neutrophil in the pathogenesis of this disease.
One of the explanations for the accumulation of neutrophils in human inflammatory bowel disease is the presence of IL-8 28, 29 that contributes to the recruitment and activation of neutrophils. KC is a chemokine in mice that is similarly capable of recruiting and activating murine neutrophils 19 . Whereas KC mRNA and protein were absent from normal mouse intestine, the expression of KC was induced significantly as colitis developed. Furthermore, KC was expressed at higher levels in the groups with the worst disease, namely the older, male mice.
In view of the presence of neutrophils adjacent to the crypt
epithelium, the expression of KC by an epithelial cell line was tested.
The data show that both KC mRNA and protein are produced by epithelial
cells. In addition, cytokines that have previously been reported to be
increased in IL-10-deficient mice, including TNF- and IFN-, could
boost the expression of both KC mRNA and protein by the epithelial cell
line. TNF- was able to increase KC expression directly, whereas
IFN- increased KC only when given in combination with TNF-.
Interestingly, KC expression by the epithelial cells was not regulated
by IL-10, even though these cells express IL-10R (Campbell et al.,
manuscript in preparation). Thus, it is possible that the production of
KC by epithelial cells in mice is regulated indirectly by IL-10,
perhaps through its effects on the production of TNF- and IFN- by
adjacent immune or inflammatory cells.
Although the precise mechanisms for the pathogenesis of spontaneous
colitis have yet to be elucidated, several factors may play a role. The
complexity of the immunological interactions is supported by the fact
that modification of various immunological molecules through genetic
engineering can predispose an animal to develop colitis. In addition to
IL-10, mice deficient in IL-2, TGF-ß, class II MHC molecules, and the
/ß TCRs, all develop colitis 30 . Other reports have suggested
that genetic diversity also greatly affects the development of disease
31 . While specific species of bacteria may be sufficient to cause
colitis in susceptible mice, what has otherwise been considered as
"normal flora" is sufficient to trigger colitis in some of these
animal models 23, 30 . The data in this report show that the intensity
of the inflammation, as evidenced by the level of KC and the clinical
presentation, are also affected by the age and gender of the mice.
Several other factors may account for the effect of age on the
manifestation of colitis. For example, inflammation may be delayed
initially since nursing animals receive substantial levels of IL-10
from the colostrum 32 . In these experiments, mice were reared by dams
that were heterozygous for the IL-10 gene mutation. In addition, the
intestinal flora changes dramatically in young mice, and it may take
some time to colonize the animals with the appropriate species to
trigger colitis. In addition, older mice may have more severe forms of
colitis since they have been exposed to the bacterial Ags for longer
periods of time. The differences in the development of colitis among
reports may be accounted for by the fact that their respective animal
facilities vary in their flora and housing practices. Thus, several
factors affecting colonization may contribute to the intensity of the
disease or the rate at which it develops.
The observation that male mice succumbed more quickly to the complications associated with the colitis was unexpected. The male and female animals in these studies were all age-matched and housed in adjacent cages in the same room, suggesting that real gender effects might exist. Given that males were housed next to females, it is possible that sexual behavior triggered aggression and stress in the males that exacerbated the disease. Alternatively, hormones themselves may also modify the expression of spontaneous colitis in these animals. Additional studies will be required to discriminate between these possibilities.
In summary, these studies document that the development of colitis in IL-10-deficient mice is dependent on the presence of microbial flora. In addition to flora, inflammation is regulated by both age and gender. The detection of KC production may provide a reliable marker to objectively evaluate the development of inflammation in these models of colitis and the role of the neutrophil in the pathogenesis of colitis.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Peter B. Ernst, Children’s Hospital Room 2.300, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-0366. E-mail address:
3 Abbreviations used in this paper: KO, knockout; wt, wild type.
Received for publication July 1, 1998. Accepted for publication November 9, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-granule proteins. J. Biol. Chem. 264:4133.
selectively inhibits lipopolysaccharide-inducible JE/monocyte
chemoattractant protein-1 and KC/GRO/melanoma growth-stimulating
activity gene expression in mouse peritoneal macrophages. J.
Immunol. 153:2204.
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