| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Regular Articles |
From the Institute of Pathology*
and
Immunology
and Department of
Surgery,§
and the Department of Radiological
Diagnostics and Therapy,
German Cancer
Research Center, Heidelberg, Germany
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Several studies have shown that the local
production of pro-inflammatory cytokines, such as interleukin (IL)-1,
IL-6, and tumor necrosis factor (TNF)-
is considerably increased in
IBD.7-12
This could be due to a dysregulated secretion of
contra-inflammatory cytokines, such as IL-10. IL-10 is thought to be
produced mainly by activated monocytes/macrophages,13
but
production by activated T and B cells has also been
reported.14-16
IL-10 effectively inhibits the
antigen-presenting function of monocytes/macrophages and their
production of pro-inflammatory cytokines (eg, IL-1, IL-6, and TNF-).
Conversely, IL-10 enhances the production of the anti-inflammatory IL-1
receptor antagonist.17-19
Co-stimulatory functions of
macrophages for mitogen-induced T cell proliferation are also inhibited
by IL-10.20
In T cells, IL-10 particularly down-regulates
the production of the T helper 1 cytokines interferon (IFN)-
and
IL-2, whereas T helper 2 cytokines, such as IL-4 and IL-5, seem to be
less affected.21,22
Moreover, IL-10 can induce an
antigen-specific anergic state in human CD4-positive T
cells.23
In B cells, IL-10 stimulates immunoglobulin
production, in particular, IgA synthesis by CD40-activated
cells.24
In view of these functional properties, IL-10
might play a significant role in maintaining a noninflammatory immune
status in the normal intestine. Using reverse transcription polymerase
chain reaction (RT-PCR), basal production of IL-10 mRNA has been
reported to exist in normal bowel tissues.25
However, the
cellular sources are unclear at present.
In IBD, initial reports of increased production of IL-10 mRNA exclusively in UC, but not CD tissues,26 have not been confirmed by subsequent studies, which demonstrated increased mRNA levels in both active UC and CD25 or even decreased production in UC.27 Serum levels of IL-10 protein are also increased in active UC and CD.28 However, concerning local IL-10 bioactivity, it was demonstrated that an elevated production of pro-inflammatory cytokines by IBD mononuclear phagocytes could be down-regulated by external IL-10 in vitro and, even more important, also in vivo by topical treatment with IL-10 enema preparations.29 This indicates that the intrinsic intestinal bioactivity of IL-10 might be insufficient to control local inflammation, despite elevated mRNA levels.
To further investigate the potential role of IL-10 in noninflamed intestine and in IBD, we have studied the tissue-specific expression of IL-10 at the mRNA and protein levels by in situ hybridization (ISH) and immunohistochemistry (IHC), respectively. In addition, IL-10 mRNA was compared with the local expression of IL-1ß mRNA.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Thirty intestinal tissue samples from 24 different IBD patients (12 with CD, 12 with UC) undergoing surgical resection of diseased gut were investigated. Diagnosis was established by conventional clinical and histopathological criteria. Disease duration in patients ranged from 4 weeks to 20 years in CD (median, 8 years; 10 female, 2 male) and from 2 to 27 years (median, 12 years; 4 female, 8 male) in UC. The mean age at surgery was 38 years (range, 21 to 67 years). Seven CD patients and eleven UC patients received immunosuppressive therapy before the operation (corticosteroids; azathioprin in one case). Immediately after resection, small samples of tissue were dissected out, oriented on cork-plates, snap-frozen in liquid nitrogen, and stored at -70°C. Transmural sections 4 µm thick were cut at -20°C and used for IHC and ISH. All UC samples investigated (n = 14) originated from diseased colon. In CD, 12 samples derived from ileum and 4 from colon (n = 16). This included samples from inactive or virtually noninflamed areas in both CD (n = 5) and UC (n = 5). All other samples histologically had inflammatory disease, mostly including erosions, fissures, or larger ulcerations (n = 20). As normal controls, nonaffected ileum (n = 2) and colon (n = 8) from 10 patients undergoing bowel resection for colon cancer or functional disorder (1 case) were obtained. As inflammatory controls, samples from patients with recurrent sigma diverticulitis (n = 2), nonspecific ileitis (n = 1), ischemic enteritis (n = 1, ileum), recurrent appendicitis (n = 1), and thrombangiitis obliterans with chronic ulcerative enteritis (n = 1, ileum) were obtained.
Immunohistochemistry
The following monoclonal primary antibodies (MAbs) were used in the study: mouse anti-human IL-10, 1:50 (MAB 217, clone 23738.11, R&D Systems, Biermann, Bad Nauheim, Germany); mouse anti-human CD68 (macrophage marker), 1:100 (clone KP-1, Dako, Hamburg, Germany); mouse anti-human CD20 (B cell marker), 1:50 (clone L-26, Dako); mouse anti-human CD3 (T cell marker), 10 µg/ml (OKT-3, Ortho, Neckargemünd, Germany); mouse anti-human CD14 (clone MEM 14, kindly provided by Dr. V. Horejsi, Prague, Czech Republic); mouse immunoglobulin G1 (IgG1), IgG2a, IgG2b, and IgM negative control MAb (Dako, Dianova, Hamburg, Germany).
Immunostaining of IL-10 was performed using the
paraformaldehyde-saponin procedure (PSP).30
After cutting,
native cryostat sections were fixed in 2% paraformaldehyde (PFA;
Merck, Darmstadt, Germany) in phosphate-buffered saline (PBS) for 20
minutes at room temperature, followed by a wash in Earle's balanced
salt solution (EBSS; Gibco, Life Technologies, Eggenstein, Germany)
supplemented with 0.01 mol/L HEPES buffer (Gibco). Permeabilization was
performed by incubation of the slides in 0.1% saponin (Riedel de Haen
AG, Seelze, Germany)/EBSS/0.01% HEPES. This buffer was used for all
washings and dilutions of MAbs and secondary reagents. The primary MAbs
were incubated overnight at room temperature with the addition of 2.5
mg/ml normal human immunoglobulins (-venin, Behring, Marburg,
Germany). After washing, the sections were incubated for 20 minutes
with 10% inactivated normal sheep serum diluted in permeabilization
buffer. After flicking off the blocking serum, biotinylated sheep
anti-mouse Ig (1:200; Amersham, Braunschweig, Germany) was added for 30
minutes, followed by streptavidin complexed with biotinylated alkaline
phosphatase for 30 minutes (complex prepared after the manufacturer's
instructions (Dako)). Blocking of endogenous biotin was performed in
some experiments but later was omitted as it did not influence the
results. After subsequent washes with permeabilization buffer,
EBSS/0.01 HEPES without saponin, and finally water, the color reaction
was developed using naphthol AS-bisphosphate (Sigma, Deisenhofen,
Germany) and new fuchsin (Merck, Darmstadt, Germany) as
chromogen.31
After counterstaining with hematoxylin, the
sections were mounted in glycerol-gelatin.
Double staining for IL-10 protein and CD3 or CD68 was also performed using the PSP method. After simultaneous incubation of the slides with anti-IL-10 (IgG2b isotype) plus anti-CD3 (IgG2a isotype) or anti-CD68 (IgG1 isotype), a combination of biotinylated goat anti-mouse IgG2b (Dunn, Asbach, Germany) and peroxidase-labeled goat anti-mouse IgG2a or IgG1 (Dunn) was used, followed by streptavidin-alkaline phosphatase. The alkaline phosphatase reaction (blue color) was developed first using the Fast Blue detection kit (Vector/Camon, Wiesbaden, Germany). 3,3'-Diaminobenzidine (Dako) was used as the substrate for peroxidase (brown color). The slides were mounted directly without further counterstaining.
Single staining of mononuclear cells (MNCs) for CD3, CD16, CD20, and CD68 was performed on native cryostat sections fixed in cold (-20°C) acetone for 10 minutes after a protocol similar to the PSP method, except that Tris-buffered saline (TBS; no saponin) with the addition of 0.2% bovine serum albumin (BSA; Sigma) was used as the diluent and washing medium.
In Situ Hybridization
A 477-bp fragment of human IL-1ß cDNA (bases 11 to 487 of the
sequence published by Nishida et al).32
was subcloned into
the BamHI/Hind III restriction site of
pBluescript II SK(+) (Stratagene, Heidelberg, Germany). A
BamHI/SspI fragment of human IL-10/pcDSR cDNA
(number 68192, American Type Culture Collection, Rockville, MD)
containing a fragment (base pairs 1 to 691) of IL-10 cDNA33
was subcloned into the BamHI/EcoRV restriction
site of pBluescript II KS(-) (Stratagene). The identity of these
contructs was confirmed by sequencing.
Full-length antisense and sense (negative controls) cRNA probes of high specific activity (>108/µg RNA) were transcribed in vitro from linearized templates in the presence of 33P-labeled uridine triphosphate (UTP; >1000 Ci/mmol) (Amersham or DuPont NEN, Bad Homburg, Germany) with T7 and T3 RNA polymerases using an RNA transcription kit (Stratagene). Limited alkaline hydrolysis of the resulting cRNA probes was performed to obtain fragments ranging in length from approximately 50 to 300 bp.34
In situ hybridization was performed as described recently,7 with slight modifications. Under standard precautions to avoid RNAse contamination, cryostat sections were placed onto 3-aminopropyltriethoxysilane-treated slides (Histo-bond slides, Marienfeld, Heidelberg, Germany) and fixed in 4% PFA buffered with 2X SSPE, pH 7.4 (1X SSPE contains 0.15 mol/L NaCl, 0.01 mol/L NaH2PO4 · H2O, 1 mmol/L EDTA) plus 5 mmol/L MgCl2 for 15 minutes. Sections were dehydrated (70%/100% ethanol), air dried, and stored at -70°C until use or directly processed for ISH. Rehydrated slides were digested with proteinase K (Boehringer, Mannheim, Germany), 0.5 mg/ml, for 15 minutes at 37°C and rinsed with 0.1 mol/L glycine (Merck) in 2X SSC (1X SSC contains 0.15 mol/L NaCl, 0.015 mol/L trisodium citrate). After post-fixation (5 minutes at room temperature) with 4% PFA and treatment with iodoacetamide (0.1 mol/L in 0.01 mol/L triethanolamine, pH 8.2; Sigma) for 30 minutes, the slides were acetylated in 0.1 mol/L triethanolamine with 0.25% acetic anhydride (Merck) for 10 minutes and equilibrated with 50% deionized formamide (FA; Fluka, Neu-Ulm, Germany) in 2X SSPE for at least 15 minutes. After shaking off excess solution, semi-dry sections were prehybridized with hybridization mix containing 50% FA/2X SSPE, 10 mmol/L Tris/HCl, pH 7.4, 0.1% sodium dodecyl sulfate (SDS; Serva), 10% dextran sulfate (molecular weight, 500,000; Pharmacia, Uppsala, Sweden), 1X Denhardt's solution (Merck), 500 µg/ml tRNA from brewer's yeast (Boehringer), 500 µg/ml poly A (Boehringer), irrelevant RNA probe labeled with cold UTP, and 100 µg/ml denatured, sonicated herring sperm DNA (Promega, Madison, WI) at 50°C in a sealed chamber filled at the bottom with 50% FA/2X SSPE. After 3 hours, 2 x 106 cpm of [33P]UTP-labeled RNA probe was added and hybridized overnight at 50°C. Post-washings were performed in a shaking waterbath with 50% FA/2X SSPE for 30 minutes at 50°C; 2X SSC/0.1% SDS for 10 minutes at 37°C; 2X SSC/0.1% SDS plus 50 µg/ml RNAse A and 10 U/ml RNAse T1 (Boehringer) for 30 minutes at 37°C; 50% FA/0.5X SSC/0.1% SDS for 30 minutes at 37°C; and 0.1X SSC for 30 minutes at 37°C. Slides were then dehydrated in 50/70/95/100% ethanol containing 0.3 mol/L ammonium acetate (Merck), air dried, dipped in Kodak NTB-2 emulsion (Technomara, Fernwald, Germany) for autoradiography, and exposed at 4°C in the dark for 6 weeks, followed by development in Kodak D-19, fixing in Kodak AL-4 (both from Technomara), and finally staining with hematoxylin and eosin (H&E). Autoradiographs were viewed with a Zeiss photomicroscope (Zeiss, Oberkochen, Germany). Cells with grain numbers of more than three times the background (~20 grains/cell) were considered positive. Incubations with sense cRNA probes served as negative controls.
Slide Evaluations and Statistical Analysis
mRNA
The number of positive cells expressing mRNA for IL-10 and IL-1ß was independently assessed by two of the authors, one of which (B. Helmke) was unaware of the diagnosis. The slides were analyzed using a Zeiss photomicroscope equipped with a video camera (XC-003P, Sony Corp., Köln, Germany) and a color monitor (SyncMaster 17 GLi, Samsung Electronics, Steinbach, Germany). In each case, fractions of 500 nucleated cells were counted in two different representative areas in the lamina propria as well as in the submucosa over adjacent high-power fields (objective x25) using a calibrated grid (total grid area, 0.01 mm2), and the relative percentage of mRNA-expressing cells to the total number was determined. The lamina propria was assessed from the area immediately below the surface epithelium down to the deeper lamina propria. The submucosa was analyzed in a similar fashion from below the lamina muscularis mucosa down to the muscularis propria border. As all nucleated cells were counted, the enumeration included both leukocytes and endothelial cells, fibrocytes, and other cell types that sometimes cannot be distinguished with certainty from leukocytes under the given staining conditions. Typical inflammatory dense lymphoid aggregates, which occurred in the submucosa in highly inflamed cases, were analyzed separate from the remaining submucosa, which contained focally accentuated infiltrates of heterogeneous inflammatory cells (probably pre-existing germinal lymphofollicular complexes at characteristic locations in the mucosa or at the mucosal/submucosal border were not counted). Thus, a total number of up to 3000 cells per case was evaluated. For technical reasons, exact cell counting was considered unreliable at ulcerative sites, and they were excluded from the quantitative analysis. Epithelia were also excluded from this evaluation.
Median values of the respective results were obtained for statistical evaluation, which was performed using the SAS program (Statistical Analysis System for Windows, version 6.11, SAS Institute, Cary, NC). The inter-observer variability was analyzed using the paired t-test (no significant differences were noted). The Wilcoxon's two-tailed test for unpaired samples was used for comparative statistical analysis of the mRNA expression in different disease groups. Differences in expression between lamina propria and submucosa in these groups were analysed using the Wilcoxon matched pairs signed rank test. P values of <0.05 were considered to be significant.
IL-10 Protein
Although reliable protein staining for IL-10 could be achieved in all cases using the PSP method, cell-to-cell enumeration of positive MNCs proved to be difficult because significant immunohistochemical staining was also observed in spaces between MNCs, especially in densely inflamed areas, most probably due to the existence of secreted cytokine in the interstitium. Thus, a score was used for a rough estimation of positive cells. Fractions of 200 nucleated cells were assessed at three different representative sites in the lamina propria and the submucosa and scored as follows: negative, 0; single positive or less than 10% positive cells, 1; >10% to 50% positive cells, 2; >50% positive cells, 3. Differences between median values of the respective results in the different disease groups were statistically analyzed using the Fisher's exact test (two-tailed). P values of <0.05 were considered as significant.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Noninflamed Gut
In noninflamed normal gut, intestinal epithelial cells were found
to express IL-10 mRNA in a diffuse fashion. Some intestinal MNCs in the
noninflamed lamina propria also gave positive hybridization signals,
but epithelial expression predominated (Figure 1, A and B)
. Local production of IL-10 in
noninflamed gut was also detected at the protein level by IHC, where
again epithelia diffusely stained in all cases. In contrast to
epithelia, IL-10 protein was expressed at rather low levels by lamina
propria MNCs (Figure 2, A and B)
. An
exception occurred at sites of organized mucosal lymphoid follicles,
where most MNCs regularly stained for IL-10 protein.
|
|
Epithelia were found to diffusely express both IL-10 mRNA and
protein in inflamed gut in all investigated samples, showing no major
differences in expression patterns between the different disease
groups. However, in addition to this epithelial expression,
significantly increased numbers of MNCs expressing IL-10 were observed
in inflamed tissues, both in CD and UC as well as in cases of other
types of gut inflammation (inflammatory controls). Quantitative
assessment of IL-10 mRNA compared with IL-1ß mRNA and the median
score values for IL-10 protein are summarized in Figure 3, A and B
, and Table 1
.
|
|
, eg,
shows ISH for IL-10 mRNA in a case of UC). Expression of IL-10 mRNA was
especially prominent on heterogeneous accumulations of perivascular
MNCs as well as scattered inflammatory cells. Parallel immunostaining
of tissue sections for CD68 and CD14 indicated that such infiltrates
were rich in macrophages, suggesting that IL-10 mRNA is mainly
expressed by mononuclear phagocytes (Figure 4D)
. In addition,
CD3-positive T cells (Figure 4E)
, but virtually no CD20-positive B
cells (Figure 4F)
, were present within such infiltrates. Thus, the
former likely contribute to local IL-10 production as well.
|
and were co-localized
with CD14- and CD68-positive MNCs, suggesting that macrophages are the
main source of IL-10 mRNA at these peripheral sites (Figure 5C)
.
However, despite the lack of IL-10 mRNA expression, most MNCs inside of
dense lymphoid aggregates stained for IL-10 protein by IHC (Figure 5D)
.
Parallel immunostaining for CD20 revealed that dense lymphoid
aggregates often contained large numbers of B cells in addition to T
cells (Figure 5E)
.
|
Compared with the submucosa, the number of MNCs expressing IL-10 mRNA
was considerably lower in the inflamed lamina propria, even in cases
with high inflammatory activity (medians of 2.85% and 3.45% positive
cells in the lamina propria in active UC and CD compared with 6.55%
and 11.75% in the submucosa; P < 0.01 and <0.001,
respectively; Figures 3 and 4A
). In all disease groups investigated,
only marginally elevated numbers of positive MNCs were observed in the
lamina propria, which did not differ significantly from normal controls
(except for a slight elevation in active CD; P <
0.03).
Staining for IL-10 protein in inflamed gut correlated with the pattern
of mRNA expression but was generally observed on a larger number of
MNCs (Figure 6A
shows an example in a
case of CD). Again, the highest IL-10 expression was observed in the
inflamed submucosa where the majority of infiltrating MNCs stained for
IL-10, both in IBD and in inflammatory control cases (median score of
3.0 in inflamed CD, UC, and inflammatory controls; Table 1
). In highly
inflamed areas, the staining reaction included infiltrating MNCs and
intercellular spaces, most probably due to the presence of cytokines in
the interstitium. Positive staining included dense lymphoid aggregates
as well as macrophage-enriched, mixed inflammatory infiltrates. In such
infiltrates, immunohistochemical double staining revealed IL-10
immunoreactivity on both CD68-positive macrophages and CD3-positive T
cells (Figure 6, B and C)
. The numbers of MNCs that stained for IL-10
protein were considerably lower in the inflamed lamina propria compared
with the submucosa (median score of 3.0 in the submucosa
versus 1.0, 2.0, and 1.5 in the lamina propria in active CD,
UC, and inflammatory controls, respectively; Table 1
). However, at the
protein level the number of IL-10-positive cells was higher
statistically in all disease groups compared with normal controls,
especially in UC and inflammatory controls (P <
0.05). Concerning the lamina propria, IL-10 protein staining of
inflammatory MNCs was higher in UC than in CD whereas no statistical
difference was observed in the submucosa.
|
In noninflamed normal gut, IL-1ß mRNA was expressed by rather
few lamina propria MNCs in subepithelial regions (median of 0.2%
positive cells; Figure 3B
) whereas significantly higher numbers of
IL-1ß mRNA-expressing cells were detected in inflamed gut. There,
elevated numbers of cells expressing IL-1ß mRNA were observed mainly
in the lamina propria compartment, whereas the expression in the
submucosa was significantly lower (Figure 3B
; P < 0.01
and <0.001 in active UC and CD, respectively). In the inflamed lamina
propria, IL-1ß was expressed by focal clusters of intensively labeled
MNCs, presumably macrophages. The highest expression was observed in
active IBD, without significant differences between UC and CD (medians
of 2.45% and 3.45% positive lamina propria cells in active UC and CD
compared with 0.2% in noninflamed controls). The number of
IL-1ß-positive mucosal cells in IBD was significantly higher than in
inflammatory controls not related to IBD (median of 0.7% in the lamina
propria). As recently demonstrated,7
strong expression of
IL-1ß mRNA was also found along the surface of mucosal ulcerations,
where positive cells included both endoluminal granulocytes and
macrophages. Submucosal dense lymphoid aggregates contained only a few
IL-1ß-positive cells (similar to IL-10 mRNA).
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
We detected an elevated intestinal expression of IL-10 by MNCs in IBD. Significantly increased numbers of IL-10-producing inflammatory cells exist in the gut wall in actively inflamed cases, both in UC and CD. Our results are in line with data demonstrating increased IL-10 serum levels in UC as well as CD, correlating with active disease,28 and argue against a general deficiency in the ability to produce IL-10 by these patients. Local MNCs secrete IL-10 presumably with the aim to control the inflammatory process. In this regard, IL-10 is able to efficiently down-regulate enhanced secretion of IL-1ß by intestinal MNCs in IBD (while inducing IL receptor antagonist).29 We have found that elevated expression of IL-10 by inflammatory MNCs in IBD is mainly restricted to the submucosal compartment of the gut wall, both at the mRNA and protein levels, whereas production by lamina propria MNCs remains comparably low. In the same tissue samples, production of IL-1ß mRNA was significantly up-regulated in the inflamed lamina propria, whereas expression of this pro-inflammatory cytokine was comparably low in the submucosa. Thus, our data suggest an inverse relationship in the local expression of IL-10 versus IL-1ß mRNA in these two compartments in IBD.
Concerning the lamina propria, our data indicate that in IBD the extent of IL-10 production by mucosal MNCs may not be sufficient to control the production of pro-inflammatory cytokines such as IL-1ß at this site. The beneficial effect of topical treatment of IBD patients with IL-10 enema preparations29 could thus at least in part be explained by compensating this insufficiency. Reasons for the lack of sufficient IL-10 production by lamina propria MNCs are unclear at present. A constant exposure of mucosal cells to epithelial-derived IL-10 might play a role, as this probably down-regulates IL-10-synthesis by MNCs via autoregulative feedback mechanisms.13 Low production of IL-10 by MNCs in the mucosa, but moderately elevated expression in the submucosa, was also found in inflammatory control cases and thus does not appear to be a specific phenomenon of idiopathic IBD. However, the mucosal expression of IL-1ß was not up-regulated as strongly as in IBD, which in such cases might contribute to a more limited disease course.
Our data do not confirm a predominant activation of IL-10 in UC versus CD. Although IL-10 protein staining on MNCs was higher in UC, this difference applied only for the mucosa but not for the submucosa, and no difference was observed in the mucosa at the mRNA level (submucosal mRNA was even somewhat higher in active CD). Concerning the types of intestinal MNCs, our results indicate that IL-10 mRNA and protein are expressed most prominently by macrophages as well as by T cells. Protein staining basically correlated with the patterns of mRNA expression. A different situation exists at sites of dense lymphoid aggregates, where virtually all cells stain for IL-10 protein but do not express the mRNA. Such sites contain many CD20-positive B cells, and the immunohistochemical reaction most likely detects cell-bound soluble IL-10, which is produced by macrophages in the periphery of such aggregates. In view of the strong epithelial IL-10 expression, one might wonder why lamina propria MNCs do not display a secondary protein staining of this type. One explanation could be higher turnover rates of the cytokine due to the presence of proteolytic enzymes in the mucosa. Alternatively, cells within dense lymphoid aggregates might express higher amounts of IL-10 receptor compared with lamina propria cells.
|
Acknowledgements |
|---|
|
Footnotes |
|---|
Supported by the Deutsche Forschungsgemeinschaft (SFB 405, projects B9 and B6).
Accepted for publication April 24, 1998.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  T. Cacev, S. Radosevic, S. Krizanac, and S. Kapitanovic Influence of interleukin-8 and interleukin-10 on sporadic colon cancer development and progression Carcinogenesis, August 1, 2008; 29(8): 1572 - 1580. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. F. Tomczak, S. E. Erdman, A. Davidson, Y. Y. Wang, P. R. Nambiar, A. B. Rogers, B. Rickman, D. Luchetti, J. G. Fox, and B. H. Horwitz Inhibition of Helicobacter hepaticus-Induced Colitis by IL-10 Requires the p50/p105 Subunit of NF-{kappa}B J. Immunol., November 15, 2006; 177(10): 7332 - 7339. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. E. Qualls, A. M. Kaplan, N. van Rooijen, and D. A. Cohen Suppression of experimental colitis by intestinal mononuclear phagocytes J. Leukoc. Biol., October 1, 2006; 80(4): 802 - 815. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Andrassy, J. Igwe, F. Autschbach, C. Volz, A. Remppis, M. F. Neurath, E. Schleicher, P. M. Humpert, T. Wendt, B. Liliensiek, et al. Posttranslationally Modified Proteins as Mediators of Sustained Intestinal Inflammation Am. J. Pathol., October 1, 2006; 169(4): 1223 - 1237. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. W. Shirkey, R. H. Siggers, B. G. Goldade, J. K. Marshall, M. D. Drew, B. Laarveld, and A. G. Van Kessel Effects of Commensal Bacteria on Intestinal Morphology and Expression of Proinflammatory Cytokines in the Gnotobiotic Pig Exp Biol Med, September 1, 2006; 231(8): 1333 - 1345. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V M Salvati, G Mazzarella, C Gianfrani, M K Levings, R Stefanile, B De Giulio, G Iaquinto, N Giardullo, S Auricchio, M G Roncarolo, et al. Recombinant human interleukin 10 suppresses gliadin dependent T cell activation in ex vivo cultured coeliac intestinal mucosa Gut, January 1, 2005; 54(1): 46 - 53. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Roers, L. Siewe, E. Strittmatter, M. Deckert, D. Schluter, W. Stenzel, A. D. Gruber, T. Krieg, K. Rajewsky, and W. Muller T Cell-specific Inactivation of the Interleukin 10 Gene in Mice Results in Enhanced T Cell Responses but Normal Innate Responses to Lipopolysaccharide or Skin Irritation J. Exp. Med., November 15, 2004; 200(10): 1289 - 1297. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Gasche, P. Grundtner, P. Zwirn, W. Reinisch, S. H. Shaw, A. Zdanov, U. Sarma, L. M. Williams, B. M. Foxwell, and A. Gangl Novel Variants of the IL-10 Receptor 1 Affect Inhibition of Monocyte TNF-{alpha} Production J. Immunol., June 1, 2003; 170(11): 5578 - 5582. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Nakase, K. Okazaki, Y. Tabata, M. Ozeki, N. Watanabe, M. Ohana, S. Uose, K. Uchida, T. Nishi, M. Mastuura, et al. New Cytokine Delivery System Using Gelatin Microspheres Containing Interleukin-10 for Experimental Inflammatory Bowel Disease J. Pharmacol. Exp. Ther., April 1, 2002; 301(1): 59 - 65. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Balabanian, A. Foussat, L. Bouchet-Delbos, J. Couderc, R. Krzysiek, A. Amara, F. Baleux, A. Portier, P. Galanaud, and D. Emilie Interleukin-10 modulates the sensitivity of peritoneal B lymphocytes to chemokines with opposite effects on stromal cell-derived factor-1 and B-lymphocyte chemoattractant Blood, January 15, 2002; 99(2): 427 - 436. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. J. Slavin, R. Maron, and H. L. Weiner Mucosal administration of IL-10 enhances oral tolerance in autoimmune encephalomyelitis and diabetes Int. Immunol., June 1, 2001; 13(6): 825 - 833. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K Bodger, K Bromelow, J I Wyatt, and R V Heatley Interleukin 10 in Helicobacter pylori associated gastritis: immunohistochemical localisation and in vitro effects on cytokine secretion J. Clin. Pathol., April 1, 2001; 54(4): 285 - 292. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Sido, J. Braunstein, R. Breitkreutz, C. Herfarth, and S. C. Meuer Thiol-Mediated Redox Regulation of Intestinal Lamina Propria T Lymphocytes J. Exp. Med., September 18, 2000; 192(6): 907 - 912. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Okada, T. Fujita, K. Minamoto, H. Liao, Y. Naka, and D. J. Pinsky Potentiation of Endogenous Fibrinolysis and Rescue from Lung Ischemia/Reperfusion Injury in Interleukin (IL)-10-reconstituted IL-10 Null Mice J. Biol. Chem., July 7, 2000; 275(28): 21468 - 21476. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
