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Infection and Immunity, November 1998, p. 5224-5231, Vol. 66, No. 11
Department of Companion Animal and Special
Species1 and
Department of Microbiology,
Pathology and Parasitology, Center for Gastrointestinal Biology and
Disease,2 College of Veterinary Medicine, North
Carolina State University, Raleigh, North Carolina 27606;
Division of Digestive Diseases and Nutrition, Department of
Medicine and Center for Gastrointestinal Biology and Disease,
School of Medicine, University of North Carolina- Chapel Hill,
Chapel Hill, North Carolina 27599-70803; and
Departments of Surgery and Microbiology, University of
Wisconsin, Madison, Wisconsin,4 and
Department of Immunology, DNAX Corporation, Palo Alto,
California5
Received 25 March 1998/Returned for modification 15 July
1998/Accepted 20 August 1998
Mice with targeted deletion of the gene for interleukin-10 (IL-10)
spontaneously develop enterocolitis when maintained in conventional
conditions but develop only colitis when kept in specific-pathogen-free
(SPF) environments. This study tested the hypothesis that enteric
bacteria are necessary for the development of spontaneous colitis and
immune system activation in IL-10-deficient mice. IL-10-deficient mice
were maintained in either SPF conditions or germfree conditions or were
populated with bacteria known to cause colitis in other rodent models.
IL-10-deficient mice kept in SPF conditions developed colitis in all
segments of the colon (cecum and proximal and distal colon). These mice
exhibited immune system activation as evidenced by increased expression
of CD44 on CD4+ T cells; increased mesenteric lymph node
cell numbers; and increased production of immunoglobulin A (IgA), IgG1,
and IL-12 p40 from colon fragment cultures. Mice populated with
bacterial strains, including Bacteroides vulgatus, known to
induce colitis in other rodent models had minimal colitis. Germfree
IL-10-deficient mice had no evidence of colitis or immune system
activation. We conclude therefore that resident enteric bacteria are
necessary for the development of spontaneous colitis and immune system
activation in IL-10-deficient mice.
Ulcerative colitis and Crohn's
disease, collectively known as inflammatory bowel diseases (IBD) in
people, are chronic immune-mediated diseases of the intestinal tract
with unknown etiologies. Various pathogenic mechanisms have been
proposed, including an appropriate inflammatory response to a luminal
pathogen or abnormal luminal constituent, autoimmunity, or an abnormal
immune response to a normal luminal constituent such as ubiquitous
intestinal bacterial or dietary antigens (43). The
hypothesis that aberrant immune responses to nonpathogenic luminal
bacteria can cause colitis is supported by clinical observations that
decreasing intestinal bacterial concentrations by various techniques
can lead to clinical improvement and decreased intestinal inflammation
(42). The role of normal resident bacterial flora in the
development of chronic intestinal inflammation has been further
demonstrated in several rodent models of experimental colitis, both
induced and spontaneous. For example, HLA-B27 transgenic rats raised
under specific-pathogen-free (SPF) conditions spontaneously develop colitis, gastritis, and arthritis, whereas transgenic rats do not
develop these lesions when maintained under germfree conditions (39, 50). Similarly, T-cell receptor- IL-10 plays a critical role in the shaping of immune responses.
Produced by a variety of cell types, but principally by activated macrophages and Th2 T cells, IL-10 generally promotes the development of humoral, Th2 cytokine-driven immune responses (reviewed in reference
34). Importantly, IL-10 inhibits the development of Th1 immune responses (19, 20), primarily by reducing the
capacity of macrophages to produce IL-12, a potent inducer of Th1
immune responses (6, 7, 14, 47, 48). IL-10 has been proposed to exert a regulatory effect in intestinal mucosa (36, 44). The importance of IL-10 in shaping mucosal immune responses has been
elegantly demonstrated by the spontaneous onset of inflammation in the
IL-10-deficient mouse (27). IL-10-deficient mice
spontaneously develop enterocolitis when housed in conventional
environments, but when housed in SPF conditions IL-10-deficient mice
develop inflammation limited to the colon, suggesting that resident
enteric flora play a role in the development of spontaneous colitis in these mice. We addressed the hypothesis that spontaneous colitis in
IL-10-deficient mice requires the presence of normal enteric bacterial
flora and that various genetically engineered colitis models have a
similar profile of dominant bacterial strains which preferentially
induce inflammation.
Mice.
Mice from a C57BL/6 × 129 Ola background,
including wild-type and heterozygous mice and mice with a targeted
deletion of the IL-10 gene, were generously provided from the breeding
colony at DNAX, Palo Alto, Calif. (3, 27). The genotype of
the mice was confirmed both before and after sacrifice by analysis of
tail tip digests by PCR (27).
Intestinal bacterial population of mice.
Germfree (sterile)
mice (heterozygous and IL-10 deficient) were Caesarian derived by one
of the investigators (E.B.) and were maintained according to standard
techniques (30) in Trexler flexible film isolators at the
Gnotobiotic Animal Facility of the Center for Gastrointestinal Biology
and Disease located at the Laboratory Animal Resources facility of the
North Carolina State University College of Veterinary Medicine,
Raleigh. SPF mice were maintained in a dedicated room at the North
Carolina State University College of Veterinary Medicine or the
University of North Carolina Laboratory Animal Resources facility. The
germfree status was monitored every 2 weeks by aerobic and anaerobic
culture and gram stain of stool samples and/or bedding material.
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Resident Enteric Bacteria Are Necessary for
Development of Spontaneous Colitis and Immune System Activation in
Interleukin-10-Deficient Mice
ABSTRACT
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
INTRODUCTION
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
knockout mice fail to develop colitis in the absence of normal bacteria (16).
Colitis spontaneously develops in interleukin-2 (IL-2)-deficient mice under conventional housing conditions but is greatly attenuated in
germfree conditions (12, 41, 45). Severe combined
immunodeficient mice repopulated with CD4+CD45
RBhi T cells spontaneously develop a wasting syndrome and
colitis, but when these T-cell-repopulated mice are treated with
antibiotics, the wasting syndrome improves or resolves, presumably in
conjunction with improvement in intestinal inflammation
(35). Finally, Lewis rats treated with indomethacin and
antibiotics develop less severe inflammation than rats treated with
indomethacin alone (5, 55). All of these observations are
consistent with intestinal bacteria having a role in either the
initiation or perpetuation of chronic intestinal inflammation.
Reconstitution studies of HLA-B27 transgenic rats and carrageenan-fed
guinea pigs demonstrated that Bacteroides vulgatus was
particularly important to the induction of colitis in these models
(38, 39). Defined bacterial products may also have an
important role in chronic enterocolitis, as evidenced by the chronic
granulomatous inflammation that develops in response to subserosal
injection of sterile peptidoglycan-polysaccharide complexes in
susceptible Lewis rats (32).
MATERIALS AND METHODS
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
Helicobacter PCR. Fecal DNA was purified with the QIAamp Tissue Kit (Qiagen Inc., Chatsworth, Calif.) according to the manufacturer's instructions and as previously described (2). Five microliters of the fecal DNA preparation was added to a PCR with Helicobacter-specific primers graciously provided by Richard Murray (DNAX). Purified Helicobacter DNA from pure cultures served as positive controls. PCR products were resolved and visualized on a 1.8% agarose gel stained with ethidium bromide. Fecal samples from SPF, germfree, and colitis-related-bacteria-colonized mice were tested in identical fashion.
Histopathology. Sections of the stomach, duodenum, jejunum, ileum, and several regions of the large intestine (representing the cecum and proximal and distal colon) were fixed in 10% neutral buffered formalin and stained with hematoxylin and eosin for histologic scoring. Scoring was conducted in blinded fashion on a scale of 0 to 4 with 0 representing no inflammation and 4 representing severe inflammation characterized by widespread infiltration with inflammatory cells, distortion of architecture, and the presence of crypt abscesses and ulcers, as previously described and validated (39). The mean histologic colonic inflammatory score for each mouse was determined by adding the scores for each section of the large intestine examined (minimum of three sections per mouse) and dividing the total by the number of sections examined.
Lymphoid cell preparations and culture. Mesenteric lymph nodes (MLN), which enlarge with colonic inflammation (8), were removed and single cell suspensions were prepared by gentle teasing. Cells were washed and resuspended in complete medium (RPMI 1640; Tissue Culture Facility, University of North Carolina Lineberger Cancer Center, Chapel Hill) supplemented with 5% heat-inactivated fetal calf serum (Irvine Scientific, Santa Ana, Calif.), 2 mM L-glutamine, 1 mM sodium pyruvate, 0.05 mM 2-mercaptoethanol, 50 mg of gentamicin (Sigma, St. Louis, Mo.)/ml, and penicillin (100 U/ml)-streptomycin (100 mg/ml)-amphotericin B (0.25 mg/ml) (Gibco, Life Technologies, Grand Island, N.Y.).
Lymphoid cells were stimulated in vitro with immobilized anti-CD3. Cells were cultured at 106 cells/ml, 0.2 ml per culture, in 96-well flat-bottom plates (Corning Costar, Cambridge, Mass.) that were precoated with 10 µg of anti-CD3/ml (purified by protein A from supernatant of the hamster hybridoma 145-2C11) (28). In previous studies, no increased cellular proliferation or cytokine secretion was observed in cultures of cells stimulated with immobilized normal hamster immunoglobulin, thus ruling out nonspecific stimulation via Fc receptors rather than via CD3 ligation (52). Concanavalin A (Con A) (2 µg/ml; Sigma) and lipopolysaccharide (LPS) (25 µg/ml) (E. coli 055: B5) (Difco Laboratories, Detroit, Mich.) were used as polyclonal stimulators. Lymphoid cell proliferation was measured by incorporation of [3H]thymidine for the final 18 h of a 90-h culture. Cells were cultured in triplicate with medium alone, immobilized anti-CD3, Con A, or LPS. For cytokine detection, duplicate supernatants of anti-CD3-stimulated cells were collected on day 3 and day 6 after culture initiation and stored at
20°C until being assayed.
Colon fragment cultures.
Cultures of colon fragments from
segments of proximal, middle, and distal colon except the cecum were
prepared following published methods (10). Briefly, colon
segments were flushed with phosphate-buffered saline (PBS) to remove
fecal contents, opened lengthwise, cut into 0.5- to 1-cm pieces, and
shaken vigorously for 30 min in PBS. Tissue was then apportioned to
wells (50 to 100 mg of tissue per well) of a 24-well tissue culture
plate (Costar) in duplicate or triplicate, as the amount of tissue
permitted, and cultured in 1 ml of complete medium containing
antibiotics and the antimycotic agent as outlined above. The cultures
were incubated at 37° for 18 h. Culture supernatants were
collected and stored at 20°C until being assayed.
Lymphokine assays. IL-12 p40 was measured by enzyme-linked immunosorbent assay (ELISA) with the commercially available antibodies C15.6 and biotinylated C17.8 (Pharmingen, San Diego, Calif.) for capture and detection, respectively, of the IL-12 p40 subunit. Bound antibodies were detected by using horseradish peroxidase (HRP)-labeled streptavidin (Kirkegaard and Perry Laboratories [KPL], Gaithersburg, Md.). Concentrations of IL-12 p40 were established by comparison of values against a standard curve generated for each assay with recombinant IL-12 p70 (Pharmingen). IL-12 p40 was measured in duplicate culture supernatants in each separate experiment.
Immunoglobulin isotype measurements. Immunoglobulins (immunoglobulin A [IgA], IgG1, and IgG2a) elaborated into colon culture supernatants were measured by ELISA as previously described (51). Secreted immunoglobulins represented both newly synthesized and preformed proteins. Reagents for capture and detection of IgA, IgG1, and IgG2a were affinity purified unlabeled anti-IgA, anti-IgG1, and anti-IgG2a, and HRP-labeled polyclonal goat anti-IgA, anti-IgG1, and anti-IgG2a, respectively (Southern Biotechnology, Birmingham, Al.). Concentrations of immunoglobulins were determined by comparison with standard curves for purified mouse IgA, IgG1, and IgG2a (Pharmingen), respectively.
Flow cytometry. Preparations of lymphocytes were incubated overnight at 4°C in culture medium alone or with either rat monoclonal anti-mouse CD44 (IM7.8.1) (53) or anti-mouse CD45RB (23G2) (4). Supernatants containing these antibodies were prepared in S. Tonkonogy's laboratory from hybridoma cultures. For labeling of CD4 cells, cells were washed twice and incubated with 25 µg of fluorescein isothiocyanate (FITC)-labeled goat anti-rat IgG/ml, absorbed with mouse serum (KPL) for 30 min at 4°C, and then washed twice and incubated with Tricolor-labeled anti-CD4 (clone CT-CD4; Caltag, South San Francisco, Calif.). B cells were detected by first incubating the cells for 30 min at 4°C with 12.5 µg of FITC-labeled goat anti-mouse IgA-IgM-IgG (KPL)ml and then washing the cells twice before detection. Analyses were conducted using a FACScan (Becton Dickinson, San Jose, Calif.) flow cytometer.
Statistics. Statistical comparison of group means was accomplished by performing one-way analysis of variance with a commercial software package (SigmaStat; Jandel Scientific, San Rafael, Calif.). Significance was set at a P value of <0.05, and differences among groups were identified by the Student-Newman-Keuls method. For nonnormally distributed data, comparison of median values was achieved with a Kruskal-Wallis one-way analysis of variance on ranks and group differences identified by Dunn's multiple comparison procedure.
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RESULTS |
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Normal resident luminal bacteria induce colitis in IL-10-deficient mice. To determine the role of enteric bacterial flora in the pathogenesis of colitis in IL-10-deficient mice, mice were maintained in either an SPF or germfree environment. Consistent with previously reported results (3, 27), outbred IL-10-deficient mice reared in SPF conditions developed clinical signs of intestinal inflammation, as evidenced by weight loss and diarrhea beginning at 7 weeks of age. Some mice also developed rectal prolapse. Histologically, colitis was characterized primarily by mucosal hyperplasia, mononuclear infiltrates in the lamina propria, and loss of goblet cells and occasionally by crypt abscesses, crypt ulcers, and transmural inflammation (Fig. 1a). All regions of the colon were affected, confirming the observations of one earlier report (3) but not those of another in which inflammation was limited to the proximal colon (27). It should be noted that the distribution of colon lesions in a given mouse could be quite focal, with severely inflamed areas of mucosa adjacent to comparatively more mildly inflamed mucosa. As has been previously reported (3, 27), SPF IL-10-deficient mice had no evidence of small intestinal inflammation. Wild-type mice raised under SPF conditions had no clinical or histological evidence of gastroenteritis or colitis.
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Colonization of previously germfree adult mice changes the pattern of large intestinal inflammation. We noted that some of our IL-10-deficient mice born in an SPF environment were colonized by Helicobacter hepaticus, detected by PCR analysis of stool. Helicobacter sp. has been implicated as a cause of colitis in some immunodeficient mouse models of colitis (54). To assess whether intestinal inflammation would develop in the absence of Helicobacter infection and whether the age of the host affects the mucosal inflammatory response of a previously germfree animal when transferred to a microbial environment, adult germfree IL-10-deficient and heterozygous mice were transferred to an SPF environment free of Helicobacter. When 20- to 24-week-old IL-10-deficient adult mice were moved from germfree conditions to SPF conditions free of Helicobacter sp., the pattern of inflammation changed compared to that for mice moved into an SPF environment at weaning (3 weeks). The former group of mice exhibited more severe cecal inflammation following at least 5 weeks of bacterial colonization (Fig. 3; Table 1). With bacterial colonization of IL-10-deficient mice at adulthood, cecal ulceration and submucosal inflammation were common, whereas such inflammation was significantly less in IL-10-deficient mice that were weaned into an SPF environment, even one in which Helicobacter was present (Table 1). Adult IL-10-deficient mice moved from germfree to SPF conditions had inflammation in other regions of the colon, though colonic inflammation was not as severe as cecal inflammation (data not shown). These results suggest that the age of IL-10-deficient mice at the time of bacterial colonization profoundly affects cecal inflammation. In addition, these results demonstrate that Helicobacter organisms were not essential for the pathogenesis of colitis in these mice. Some germfree IL-10-deficient mice were housed with bedding contaminated with Helicobacter-infected stools but failed to become positive for Helicobacter as determined by PCR detection of DNA in the stool in the 4 weeks before sacrifice (data not shown).
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Colonization with selected bacteria that cause colitis in other
rodent models of colitis induces mild, delayed inflammation in
IL-10-deficient mice.
To further explore the role of defined
bacterial species in the development of spontaneous colitis in the
IL-10-deficient mouse, adult (>20 weeks old) germfree mice were
populated with six colitis-related bacterial species including B. vulgatus or were colonized with B. vulgatus alone.
Colonization with these groups of bacteria has been previously shown to
promote the development of spontaneous colitis in HLA-B27/
2
microglobulin transgenic rats (39). Colonization of the mice
with these organisms was confirmed by examination of gram stains of
fecal samples. In contrast to the severe inflammation observed in the
IL-10-deficient mice after transfer of germfree adults to SPF
conditions without Helicobacter, the germfree mice colonized
with the colitis-related group of bacteria or B. vulgatus
exhibited only mild inflammation (Table 2). Inflammation was not observed in the
colitis-related flora group until the animals had been in this
environment for 20 weeks. Even so, the inflammation observed in these
mice was less severe than that observed in the germfree IL-10-deficient
mice moved to SPF (without Helicobacter) at 5 weeks
post-colonization. As observed in the mature mice moved from germfree
to SPF conditions, mice moved from germfree to colitis-related flora
conditions had more inflammation apparent in the cecum than other
regions of the colon. Interestingly, two of these mice had overt
gastric antral and duodenal inflammation not observed in the SPF
colonized mice even at longer periods of colonization (data not shown). Adult mice populated with B. vulgatus for 32 weeks likewise
developed only mild colonic inflammation (Table 2). These results show that hosts with different genetic abnormalities (IL-10 deficiency versus overexpression of HLA-B27 transgene) respond differently to the
same defined bacterial stimuli.
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Germfree IL-10-deficient mice have no evidence of immunologic stimulation or activation. To assess the degree of immunological stimulation and activation of mice with different bacterial stimuli, several parameters were evaluated. Total numbers of lymphocytes obtained from the MLN of germfree IL-10-deficient mice were comparable to those obtained from the MLN of germfree heterozygous mice (Table 3). In contrast, SPF IL-10-deficient mice had significantly greater numbers of MLN cells than did SPF wild-type mice, consistent with the presence of an inflammatory response in the colon. Of note, SPF wild-type mice had over twice the number of MLN cells compared with those of germfree heterozygotes, indicating stimulation of the mucosal immune system by resident bacteria. Phenotypic analysis of MLN cells by flow cytometry demonstrated that germfree IL-10-deficient mice had proportions of CD4 and CD8 T cells that were comparable to those of SPF wild-type mice (Table 3). In contrast, SPF knockout mice had lower proportions of CD4 cells than either germfree IL-10 knockouts or wild-type SPF and had greater proportions of CD8 cells than SPF wild-type mice (Table 3). Additionally, the levels of CD44, a lymphocyte homing receptor whose expression is higher on activated and memory T cells than on resting and naive T cells (1, 29), is higher on CD4+ MLN from SPF IL-10-deficient mice than on CD4+ MLN of SPF wild-type mice (Table 3).
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DISCUSSION |
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
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IL-10 plays a crucial role in the modulation of immune responses and recently has been implicated as one of the cytokines mediating mucosal T-cell tolerance (17, 24) to bacterial antigens. Our results show that normal enteric bacteria are essential for the development of spontaneous colitis in IL-10-deficient mice since germfree IL-10-deficient mice had no histologically detectable colitis. In contrast, IL-10 knockout mice maintained in SPF environments had moderate colitis, comparable in character and severity to that of SPF IL-10-deficient mice from previous reports (3, 15, 27, 40). Unlike some previous descriptions in which inflammation was limited to the proximal colon of IL-10-deficient mice (27), inflammation in this study was found in all regions of the colon. Interestingly, severely inflamed areas could lie adjacent to nearly normal areas of mucosa, similar to the focal nature of the "skip lesions" of Crohn's disease. Also, we present novel data regarding the absence of mucosal immune responses, including IL-12 p40 secretion, in the absence of normal luminal bacteria. These data also illustrate the importance of age at the time of bacterial colonization, the ability of Helicobacter-free bacteria to stimulate colitis in this model, and the different capacities of defined bacterial species to induce colitis in different genetically engineered rodents.
Germfree IL-10-deficient mice displayed none of the immune system
activation observed in the SPF IL-10-deficient mice, indicating that
subclinical colitis was not present in the germfree state. In the
absence of viable bacteria, markers of T-cell activation and in vitro
immunoglobulin secretion were not different from those of germfree
heterozygote or SPF wild-type mice. Although IL-10-deficient SPF mice
had increased concentrations of immunoglobulins in their colonic
culture supernatants, B lymphocytes are not essential to the
pathogenesis of colitis in IL-10-deficient mice (15). Therefore, elevated levels of circulating antibody and enhanced mucosal
immunoglobulin production should be considered markers of immune system
activation rather than effector molecules causing tissue damage. Recent
observations that IL-10-deficient mice have anticolonic epithelial cell
antibodies (15) thus may mean that these autoantibodies are
a secondary result of epithelial damage in the setting of a
dysregulated immune response. Moreover, the pattern of in vitro
immunoglobulin secretion with abundant IgG2a in SPF IL-10-deficient
mice is consistent with a Th1-gamma interferon (IFN-
)-driven immune
response (40, 49).
In keeping with a Th1 profile of cytokines, we found that IL-10-deficient mice with colitis had readily detectable amounts of IL-12 p40 in culture supernatants of inflamed colon fragments, presumably reflecting increases in biologically active IL-12 p70 heterodimer. It should be emphasized that these cultures had no in vitro stimuli to promote IL-12 production, suggesting that cells residing in the colon were activated in vivo to produce and secrete IL-12 p40. The production of IL-12 p40 mRNA and biologically active p70 IL-12 from macrophages or dendritic cells is upregulated in vitro in response to many stimuli. Live bacteria and bacterial products such as LPS and lipotechoic acid, as well as prokaryotic DNA, have all been demonstrated to increase production of IL-12 in vitro (9, 11, 22, 25, 26, 33, 48). Our results suggest that in vivo exposure to resident luminal bacterial components may likewise stimulate IL-12 production. IL-12 has recently been incriminated as a mediator of autoimmune disease induced by bacterial products (46) and loss of tolerance to resident luminal bacteria in experimental colitis (17). Furthermore, treatment with neutralizing antibodies to IL-12 prevents the development of colitis in IL-10-deficient mice if treatment is initiated at an early age before development of severe colitis (40), prevents the development of hapten-induced colitis in IL-2-deficient mice (18), and reverses established inflammation in trinitrobenzene sulfonic acid-treated mice (37). Because IL-10 promotes the development of Th2 responses by inhibiting macrophage production of IL-12 (14), it is not surprising that in the absence of IL-10, unregulated colonic production of IL-12 could occur in response to microbial stimulation.
An unexpected finding in this study was the increased severity of cecal inflammation observed in gnotobiotic IL-10-deficient mice that had been colonized with SPF bacteria as adults compared with those colonized at weaning with the same organisms. The difference in the intensity of inflammation may have been related to the age of the animals and the maturity of their mucosal immune system at the time of colonization. Not only is cecal inflammation more aggressive with submucosal inflammation and mucosal ulceration more common following colonization of older IL-10-deficient mice, but the onset of inflammation is more rapid (5 weeks) than in germfree IL-10-deficient mice colonized at weaning (8 to 12 weeks). The submucosal pattern of colitis is more aggressive than that seen in 3-month-old HLA-B27 transgenic rats colonized with SPF bacteria, which developed cecal inflammation confined to the mucosa which was not significantly worse than colitis in B27 transgenic rats born in an SPF environment (39).
H. hepaticus has been recently shown to be associated with cecal inflammation in several immunodeficient mouse strains and has been advanced as a putative cause of experimental colitis in genetically engineered mice (54). However, the development of aggressive typhlitis, and to a lesser degree colitis, in a Helicobacter-free environment does not support an essential role of Helicobacter in the development of colitis in IL-10-deficient mice. However, a potential contribution of Helicobacter infection in the pathogenesis of colitis in IL-10-deficient mice is not excluded. Our observations that resident bacteria in the absence of Helicobacter can cause colitis are particularly important given the widespread colonization of IL-10-deficient mice with this opportunistic pathogen (39a).
The combination of the six colitis-related bacteria used in the present study readily provoked colitis in HLA-B27 transgenic rats which approximated that seen with SPF bacteria (39). The observation that adult germfree IL-10-deficient mice colonized with these same colitis-related flora had delayed onset of very mild colitis compared to that of the germfree mice moved to SPF conditions suggests that all bacterial strains do not have equal capacity to induce intestinal inflammation. Importantly, the mild nature of colitis induced in these mice colonized with the six identical organisms which induce aggressive colitis in the HLA-B27 transgenic rat further supports the notion that other factors, in particular the host genetic background, play a critical role in the development of experimental colitis in response to any given bacterial stimulus. Indeed, inbred C57BL/6 mice with the IL-10 deletion develop mild, delayed-onset colitis in striking contrast to the early and aggressive colitis of IL-10-deficient mice of the 129 Sv background (3). Similarly, we did not observe colonic adenocarcinomas in either the SPF or germfree IL-10-deficient outbred (C57BL/6 × 129) mice followed for up to 38 weeks of age, as were observed in 6-month-old 129 Sv mice (3). Alternatively to differences in genetic background, quantitative differences in the numbers of each bacterium (not measured in this study) may have influenced the development of inflammation, particularly if pro-inflammatory bacteria were limited in their proliferation by noninflammatory bacteria. Further studies will be necessary to determine the dominant enteric bacterial strains that induce or perpetuate colitis in IL-10-deficient mice.
These results point out the inflammatory consequences of unbalanced
immune responses to resident nonpathogenic bacteria but do not
completely explain the mechanisms by which inflammation is mediated.
Possible unregulated mucosal production of IL-12 as suggested by our
results could result in excess production of IFN-, a proinflammatory
Th1 cytokine known to alter epithelial barrier integrity in vitro.
Preliminary observations with IL-10-deficient mice suggest that even in
the germfree state these mice have lower colonic mucosal electrical
resistance than do wild-type mice (46a). Recombinant IL-10
has been shown to prevent IFN--mediated damage to epithelial barrier
integrity in cultured T84 cells (31). It thus is possible
that IL-10-deficient mice have inherent defects in mucosal barrier
function that allow endogenous luminal bacteria and/or bacterial
products to induce colonic inflammation. Alternatively, IL-10-deficient
mucosal macrophages exposed to bacterial antigens could have overly
aggressive cytokine production and antigen-presenting activities in the
absence of immunosuppressive IL-10, perhaps resulting in activation of
T lymphocytes to endogenous bacterial antigens. Exacerbations of
pathologic immune responses have been described in IL-10-deficient mice
infected with Trypanosoma cruzi (23) or
Toxoplasma gondii (21). These results have been
attributed to an intrinsic lack of down regulation of Th1 immune
responses, since administration of exogenous recombinant IL-10 or
neutralizing anti-IL-12 antibodies abrogates pathologic responses in
these models and disease in the infected mice is not attributable to uncontrolled proliferation of the infecting organism. Lastly, an
unbalanced cytokine environment could alter antigen-presenting cell
function (13) to lead to immune responses to normally
nonimmunogenic antigens. Applying these observations to resident
luminal bacteria, we speculate that in the genetically susceptible
host, a dysregulated immune response could establish the cytokine
milieu which promotes pathologic responses to normally nonpathogenic
luminal bacterial antigens.
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FOOTNOTES |
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* Corresponding author. Mailing address: Division of Digestive Diseases and Nutrition, CB # 7080, University of North Carolina, Chapel Hill, NC 27599-7080. Phone: (919) 966-0149. Fax: (919) 966-7468. E-mail: rbs{at}med.unc.edu.
Editor: J. R. McGhee
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REFERENCES |
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
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