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*
Department of Pathology, St-Luc University Hospital, the
Experimental Medicine Unit, University of Louvain, and
The Ludwig Institute for Cancer Research, Brussels, Belgium; and
§
School of Biological Sciences, University of Manchester, Manchester, United Kingdom
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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While all tissue mast cells are derived from a common hemopoietic progenitor cell, it is now apparent that they exist in vivo and in vitro as a heterogeneous family of effector cells. Based on their secretory granule proteoglycans and proteases, the differentiated mast cells in rodents are classified into at least two phenotypically distinct populations: connective tissue-type mast cells (CTMC)3 and mucosal mast cells (MMC) (6). Safranin-positive granules of CTMC contain large amounts of heparin proteoglycans and mouse mast cell protease-4 (mMCP-4), -5, and -6, but no mMCP-1 or -2 (7, 8, 9, 10). In contrast, the safranin-negative MMC found in the intestines of helminth-infected mice express mMCP-1 and -2, but not mMCP-5 or -6 (7, 9, 10, 11). In vitro, bone marrow-derived mast cells (BMMC) can be obtained in the presence of IL-3 and have been considered to be the tissue culture equivalent of the MMC subclass, although poorly granulated and still immature (6, 12, 13, 14). Thus, such mast cell lines express neither mMCP-2 nor mMCP-4 (15, 16). However, stem cell factor (SCF) was shown to induce mMCP-4 expression, suggesting that this factor might be involved in the differentiation of CTMC (15). In addition, mMCP-1 and -2 expression was induced in BMMC by IL-9 and IL-10 (11, 16).
Recently, IL-9 transgenic mice, overexpressing the IL-9 gene, have been generated to analyze the in vivo activities of this cytokine (17). With the exception of an increased susceptibility to the development of thymic lymphomas after irradiation or mutagenesis, these mice showed no major abnormality in the immune system. Here, we report that mast cell infiltration is found in the intestinal tract and upper airways of IL-9 transgenic mice. These mast cells are characterized by an intraepithelial localization and a mixed phenotype sharing MMC and CTMC properties, similar to the phenotype of mast cells cultured in vitro in the presence of SCF and IL-9.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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IL-9 transgenic mice were generated using a fusion gene consisting of an IL-9 genomic fragment linked to the promoter of the murine pim-1 gene, including the TATA box and the cap site, followed by two copies of the Eµ enhancer and one copy of the Moloney murine leukemia virus long terminal repeat (17). Two independent strains of homozygous transgenic mice, designated Tg5 and Tg54, were used in this study. Both strains have circulating IL-9 levels >1 µg/ml, while IL-9 is undetectable in the serum of control FVB mice.
Tissue preparation and sections for conventional histology and electron microscopy
Organs were fixed by immersion for 24 h in Bouin’s fixative before embedding in paraffin. Five-micron sections were prepared and stained with hematoxylin-eosin (18), alkaline-Giemsa (18), Blue alcian (19), safranin (19), and chloroesterase-specific stain (20). For electron microscopy, after dissecting and mincing, tissues were fixed in 2.5% glutaraldehyde for 24 h. They were then rinsed in cacodylate buffer, dehydrated in graded ethanol followed by propylene oxide, and embedded in Epon E12. Mast cell numbers per square millimeter were determined from chloroesterase-stained sections of the glandular stomach and trachea and from hematoxylin-eosin sections of the small intestine.
SCF function was blocked in vivo as previously described (21), using the rat anti-murine c-Kit mAb ACK-2 (provided by Dr. S. I. Nishikawa, Institute for Medical Immunology, Kumamoto, Japan). Rat IgG was used as a control Ab of irrelevant specificity. The Abs were administered daily for 4 days to adult male Tg54 mice (n = 5). Animals received 0.5 mg on days 1 and 3, and 1 mg on days 2 and 4. On day 5, the animals were killed, and sections of the small intestine and stomach were removed from each animal, fixed in Carnoy’s fixative, processed, and stained in 0.5% toluidine blue (pH 0.3) before determination of the numbers of mast cells in 20 villus-crypt units for the small intestine or in one high power field of view for stomach mucosae.
Bone marrow derived in vitro cultures
Murine rIL-3 produced in CHO cells was provided by Dr. T. Burgess (The Ludwig Institute, Melbourne, Australia). Murine rIL-9 was produced in the baculovirus system and purified as previously described (22). The cDNA encoding the murine SCF was amplified by PCR based on the published sequence (23) with a 3' primer introducing a stop codon just upstream of the region encoding the transmembrane domain. This cDNA was expressed in COS cells, and the activities of supernatants were assessed by their ability to induce MO7e cell proliferation. These supernatants contained 60 U/ml of SCF, corresponding to approximately 600 ng/ml based on the comparison with recombinant human SCF (PeproTech, Rocky Hill, NJ).
Mouse BMMC were obtained by culturing bone marrow from 4-wk-old BALB/c mice for 15 days in enriched medium (RPMI 1640 containing 0.55 mM L-arginine, 0.24 mM L-asparagine, 1.25 mM L-glutamine, 100 U/ml penicillin, 100 µg/ml streptomycin, 50 µM 2-ME, and 20% FCS) supplemented with various combinations of murine rIL-3 (1 ng/ml), IL-9 (200 U/ml), and SCF-transfected COS cell supernatant (5%). Supernatants from mock-transfected COS cells were used as a control and proved completely inactive. Every 4 days, the nonadherent cells in the cultures were transferred into new flasks and suspended into fresh culture medium supplemented with the appropriate combination of cytokines.
RT-PCR analysis of mMCP transcripts
Total cellular RNA was isolated by the
guanidine-thiocyanate/CsCl ultracentrifugation method, and reverse
transcription was performed on 10 µg of total RNA with an oligo(dT)
primer. cDNA corresponding to 100 ng of total RNA was amplified for 14
cycles by PCR with specific primers as indicated in Table I
. For mMCP-1, -2, and 4, a single PCR
amplification was performed using primers designed from regions that
were perfectly conserved between these genes. An aliquot of the PCR
reaction was run in a 1% agarose gel, blotted onto a nylon membrane,
and hybridized with specific oligonucleotide probes as indicated in
Table I. To check the specificity of the mMCP-1, -2, and -4
oligonucleotide probes, this PCR product was cloned into a pTZ19R
plasmid, and clones whose sequence corresponded to each of these
proteases were included in the blot. Quantification of the
hybridization signal was performed using a PhosphorImager (Molecular
Dynamics, Sunnyvale, CA).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Since during helminth infections, mast cells frequently accumulate
in the digestive tract concomitantly with IL-9 production, we
investigated the possible causative role of IL-9 in this process by
examining the gut of IL-9 transgenic mice. While the epidermoid
esophagus was very similar in transgenic and normal mice, the glandular
stomach in IL-9 transgenic mice showed greater numbers of mast cells,
located mainly between epithelial cells from the upper part of the
mucosa (Fig. 1). Not only were the total
numbers of mast cells increased by a factor of 5 to 10 in transgenic
animals, but those observed in normal mice were mostly located in the
connective tissue. In IL-9 transgenic mice, mast cells appeared
metachromatic with Giemsa staining and positively stained with
chloroesterase-specific staining. Unexpectedly, they were also stained
with safranin (Fig. 1A), a feature considered a
marker of serosal mast cells found in the skin and the peritoneal
cavity. They also had the capacity to bind biotinylated IgE (data not
shown). By electron microscopy, these cells bore nonuniform
electron-dense granules whose membranes were ill defined, and some
cells showed partially degraded granules (data not shown).
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, E and F,
pointing to a possible role for lymphocytes in this process. However,
we did not observe any significant increase in mast cells in other
lymphoid organs, including the thymus, spleen, and lymph nodes of IL-9
transgenic mice, compared with the control strain (data not shown).
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A).
Although these cells are morphologically related to mast cells and were
stained by toluidine blue, we failed to characterize them as mature
mast cells by other current staining methods. They were not
metachromatic with Giemsa staining (Fig. 2C), did not
stain for chloroesterase (Fig. 2D), and showed no
detectable IgE binding (data not shown). These cells were not detected
in normal control mice, whereas they were abundant (
400
cells/mm2) in the lower part of the villi and the upper
part of the crypts in IL-9 transgenic mice. By electron microscopy,
these cells showed granules of a size compatible with mast cell
granules. Many of them were characterized by the presence of
heterogeneous material and crystal-like inclusions, but could easily be
distinguished from eosinophil granules (Fig. 3). Taken together, these histologic and
morphologic features suggest that these cells represent mast cells that
have not (yet) completed the conventional differentiation pathway,
pointing to a relationship with recently identified mast cell
progenitors (24).
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Analysis of sections from the respiratory tract from control and
IL-9 transgenic animals also revealed an increase in mast cell numbers
in IL-9 transgenic mice. These cells were characterized by positive
staining for chloroesterase and contained metachromatic granules. By
contrast, in control mice, mast cells were observed only very rarely in
the respiratory tract. Noticeably, in IL-9 transgenic mice, mast cells
were much more numerous in the upper tract (trachea; Fig. 4, A and B),
whereas they were only occasionally found in bronchioles and alveoli
(data not shown). A striking feature of these cells is their location
within the epithelial cell layer (Fig. 4A). In
adipose tissue surrounding the trachea, only a small increase in mast
cell numbers was observed in IL-9 transgenic vs control mice (data not
shown).
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In addition to the respiratory tract, kidneys of IL-9 transgenic mice
contained increased numbers of mast cells. Interestingly, these cells
were located in the epithelial cell layer of both proximal and distal
tubes (Fig. 4C). In kidneys from control animals,
mast cells were exclusively found in the organ capsule, where only a
slight increase was found in IL-9 transgenic mice (data not shown). No
significant difference was noticed for ureter or bladder.
Intestinal IL-9 transgenic mast cells display characteristics of both mucosal and connective tissue-type mast cells
As previously shown in Figure 1, mast cells found in the glandular
stomach were stained by safranin, a characteristic feature of CTMC, and
thereby contrast with mast cells found in the intestine of
parasite-infected mice, referred to as MMC, which are not stained by
safranin (6). To further determine the phenotype of the IL-9 transgenic
mast cells, we analyzed the expression of mast cell proteases of the
mMCP family, which are differentially expressed in MMC and CTMC (14).
RNA was prepared from the stomachs of IL-9 transgenic and control
mice, and a semiquantitative PCR analysis was performed for Fc
RI,
granzyme B, and mMCP-1, -2, -4, -5, and -7. As shown in Figure 5, IL-9 transgenic mice showed a
strongly increased expression of the 
- and ß-chains of FcRI,
reflecting the mast cell infiltration described above. In addition,
granzyme B, which was previously shown to be induced by IL-9 in mast
cells in vitro (25), together with every mMCP tested were overexpressed
in IL-9 transgenic mice, including mMCP-4 and -5, characteristic of
CTMC, as well as mMCP-1 and -2, representative of MMC proteases. By
PhosphorImager quantification, a 10- to 30-fold increase was observed
in mMCP-1, -2, -4, and -5, whereas mMCP-7 expression, a marker of
immature mast cells (26), was only 3- to 6-fold increased.
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To further analyze the role of IL-9 in the growth and
differentiation of mast cells, we derived in vitro cell lines from bone
marrow progenitors in the presence of SCF, IL-3, and IL-9. As shown in
Figure 6, when these cytokines were used
separately, only IL-3 led to the proliferation of mast cells (based on
the IgE binding). However, the combination of IL-9 and SCF allowed for
the development of mast cell lines in vitro, to a similar extent as
IL-3. These mast cell populations were further characterized by RT-PCR
analysis of their protease expression. In line with previous reports,
BMMC cultured with IL-3 alone expressed only mMCP-5 and -7 along with
granzyme B (Fig. 7). When SCF was added
to IL-3, mMCP-1, -2, and 4 were induced, confirming the activity of SCF
as a mast cell differentiation factor. Most importantly, a similar
extended protease expression pattern was found in the presence of IL-9
and SCF, with even higher levels of mMCP-1, -2, and -4.
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The observations that 1) neither IL-9 nor SCF by itself was
sufficient to induce mast cell growth and differentiation in vitro; and
2) their combination lead to a protease phenotype similar to that
observed in vivo in IL-9 transgenic mice raise the possibility that
these factors are indeed involved in this mast cell hyperplasia. In
line with this possibility, the SCF mRNA was constitutively expressed
in both FVB and IL-9 transgenic mice (Fig. 8).
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, anti-c-Kit Abs inhibited 80 to
90% of intestinal and gastric mastocytosis, demonstrating that
endogenous SCF was required for this in vivo activity of IL-9.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Although it is well established that SCF is required for MMC and CTMC development in vivo (28), its role in mast cell differentiation remains less understood. When IL-3-driven BMMC were restimulated with SCF and IL-9, SCF was found to preferentially up-regulate mMCP-4 (15), which is considered a marker of CTMC, while IL-9 increased the expression of mMCP-1 and -2 (16), which are considered MMC markers. In the present study, simultaneous expression of these proteases was observed in vivo and in vitro in the presence of IL-9 and SCF. This observation raises the possibility that a combination of these cytokines induces the development of a heterogeneous population of mast cells, including IL-9-driven mucosal and SCF-driven serosal mast cells, even though neither SCF nor IL-9 by itself induces any in vitro mast cell development from bone marrow progenitors. Our data do not support this hypothesis, as all IL-9 transgenic mast cells were homogeneously stained by safranin, one of the hallmarks of CTMC, thereby suggesting that these mast cells represent a homogeneous population at a distinct stage of differentiation, with the expression of both serosal and mucosal characteristics. Taken together, our data therefore support an alternative hypothesis, namely that mast cell heterogeneity extends far beyond the CTMC/MMC dichotomy and further suggests that proteases of these two patterns may be simultaneously expressed. This observation also reinforces the recent finding that mast cells can reversibly alter their phenotype protease, and that a static nomenclature is inadequate to describe mast cell populations (29).
An important observation for the mast cell infiltrate in IL-9 transgenic mice is that of its selectivity for the intestinal and respiratory mucosa and particularly its intraepithelial niche. This feature is unlikely to result from tissue-specific transgene expression, since IL-9 was produced ubiquitously in the IL-9 transgenic mice used in this study (17). One possible explanation could lie in the requirement for a cofactor present only in these tissues. Although SCF expression is not restricted to these tissues, it is possible that a third factor may be involved in mast cell development or chemotaxis. In this regard, the observation that mast cells were preferentially found in the vicinity of mucosal lymph nodes might reflect the role of lymphocyte-derived factors. In line with this hypothesis, a potential factor involved in tissue specificity is the involvement of some antigenic stimulation through the respiratory or digestive tract. This might also explain the observation that in the respiratory airways, mast cells accumulate mainly in the trachea and that in the intestinal tract, they vary both in numbers and in histologic characteristics among the esophagus (that did not show any mast cell increase), the glandular stomach (with an increase in mature mast cells), and the small intestine (with an increase in both mature and immature mast cells). Another potential explanation might be related to a yet undefined activity of IL-9 on adhesion molecules expressed by mast cells, endothelial cells, or epithelial cells.
In this respect, site-restricted mast cell infiltration was reported for IL-4 transgenic mice that showed increased numbers of mast cells in the eyelids (30). Interestingly, in these mice, mast cell infiltration resulted in a marked inflammatory reaction involving "piecemeal" degranulation of the mast cells. By contrast, IL-9 transgenic mice do not seem to be affected by their intestinal and respiratory mastocytosis. However, preliminary observations suggest that these mice are more resistant to intestinal dwelling parasitic helminths (31). Further studies will be needed to assess whether they might also be more sensitive to the development of food allergy. Combined with the fact that most IL-9 transgenic mice have a relatively normal survival and exhibit no spontaneous mast cell-associated pathology, our observations indicate that these mice represent a valuable tool to analyze the role of mast cells in various biologic situations.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. J.-C. Renauld, The Ludwig Institute for Cancer Research, Avenue Hippocrate 74, B-1200 Brussels, Belgium. E-mail address:
3 Abbreviations used in this paper: CTMC, cutaneous-type mast cell; MMC, mucosal mast cell; mMCP, mouse mast cell protease; BMMC, bone marrow-derived mast cell; SCF, stem cell factor.
Received for publication April 24, 1997. Accepted for publication December 10, 1997.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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