Scandinavian Journal of Gastroenterology

ISSN: 0036-5521 (Print) 1502-7708 (Online) Journal homepage: http://www.tandfonline.com/loi/igas20

Release of Mast Cell Tryptase from Human

Colorectal Mucosa in Inflammatory Bowel Disease

M. Raithel, S. Winterkamp, A. Pacurar, P. Ulrich, J. Hochberger, E. G. Hahn

To cite this article: M. Raithel, S. Winterkamp, A. Pacurar, P. Ulrich, J. Hochberger, E. G. Hahn

(2001) Release of Mast Cell Tryptase from Human Colorectal Mucosa in Inflammatory Bowel
Disease, Scandinavian Journal of Gastroenterology, 36:2, 174-179, DOI: 10.1080/00365520119214

To link to this article: https://doi.org/10.1080/00365520119214

Published online: 08 Jul 2009.

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 ORIGINAL ARTICLE

Release of Mast Cell Tryptase from Human Colorectal Mucosa in

In ammatory Bowel Disease
M. Raithel, S. Winterkamp, A. Pacurar, P. Ulrich, J. Hochberger & E. G. Hahn
Dept. of Medicine I, Functional Tissue Diagnostics, University Erlangen–Nuremberg, Germany

Raithel M, Winterkamp S, Pacurar A, Ulrich P, Hochberger J, Hahn EG. Release of mast cell tryptase
from human colorectal mucosa in inflammatory bowel disease. Scand J Gastroenterol 2001;36:174– 179.
Background: Histologic detection of mast cells cannot adequately re ect their function and state of
activation, since degranulated mast cells may escape from histologic assessment. To better deŽ ne the role
of mast cells in in ammatory bowel disease, the spontaneous secretion of mast cell tryptase, a highly mast
cell speciŽ c protease, was measured from colorectal samples. Methods: After detection of the initial basal
Downloaded by [Hals-Nasen-Ohren-Klinik] at 03:55 04 December 2017

tryptase release, gut mucosal samples were incubated in a modiŽ ed Hanks/RPMI medium using a mucosa
oxygenation system. Spontaneous tryptase secretion from 153 viable samples of 22 controls, 30 patients
with Crohn disease (CD) and 19 with ulcerative colitis (UC) was followed over 4 h. Tryptase was
measured by radioimmunoassay. Results: The rates of the initial basal tryptase release revealed that mast
cell activation occurs during active in ammation in CD and UC. While the time course of tryptase release
was similar in all three groups, spontaneous tryptase secretion (over 4 h) was found to be signiŽ cantly
enhanced and prolonged only in UC (P < 0.01 compared to controls), but not in CD. Conclusions: This
study provides clear evidence from viable endoscopic colorectal samples that mast cell mediators were
secreted during active in ammation in CD and UC. However, the extent of mast cell involvement and
activation differs considerably between CD and UC. SigniŽ cantly increased rates of tryptase secretion
were found both in non-in amed and in amed tissue of UC, indicating that mast cell involvement is a
typical feature of UC.
Key words: Mast cell; tryptase; ulcerative colitis
Martin Raithel, M.D., Dept. of Medicine I, Functional Tissue Diagnostics, University of Erlangen–
Nuremberg, Krankenhausstr. 12, D-91054 Erlangen, Germany (fax. ‡49 9131 85 36909, e-mail.
martin.raithel@med1.med.uni-erlagen.de)

A
lthough the aetio-pathogenesis of in ammatory bowel
disease (IBD) remains obscure until now, recent
Ž ndings support immunopathogenic alterations in
the mucosal as well as systemic immune response (1). In
in ammatory lesions of Crohn disease (CD) and ulcerative
colitis (UC) several highly activated immune cell types have
been described, including T helper 1 and T helper 2 cells,
CD14-positive macrophages as well as degranulating neu-
trophils and eosinophils (1, 2). Alterations in the number and
distribution of mast cells have also been reported in IBD
(2, 3), but there are no data about the speciŽ c secretory
activity of human mucosal mast cells in this disorder.
In the gastrointestinal mucosa human intestinal mast cells
are mostly tryptase-positive (81%) with only 19% of the total
mast cells exhibiting a tryptase/chymase-positive phenotype
(3). Mast cell tryptase represents a unique mast cell protease
(neutral serine esterase; molecular weight, 134 kD), which
highly speciŽ c demonstrates the presence of activated mast
cells when found in serum, body  uids or intestinal secretions
(3, 4). On the contrary to histamine, substantial amounts of
tryptase are only found in mast cells, whereas basophils
contain negligible amounts (< 0.04 pg/cell) (4).
Since intestinally released histamine may come from
several sources (mast cells, basophils, bacteria, foodstuffs)
(5), assessment of tryptase release from gastrointestinal tissue
has the potential to precisely reveal the actual degree of mast
cell involvement in IBD. Previous functional mediator release
experiments from human gut mucosa have shown that
properly incubated tissue samples can keep mast cells viable
and responsive to certain stimuli (5–8). Therefore, tiny
endoscopically taken mucosal biopsies were used to explore
local secretion of mast cell tryptase from patients with UC and
CD who had actually at the time of colonoscopy no
medication.
Materials and Methods
Patient groups
The study included 153 biopsies of 22 controls, 30
untreated patients with CD and 19 untreated patients with
UC. Age (mean § s), sex and the number of patients
(biopsies) investigated for each group with non-in amed or
in amed IBD tissue are shown in Table I.
The control group underwent elective colonoscopy for the

Ó 2001 Taylor & Francis


Table I. Patient data of the study population
No. No.
biopsies patients
Age
Patient group (n = number) (yr § s)
Normal colorectal mucosa
Control group 36 22 40 § 16
Non-in amed mucosa
Crohn disease 49 19 37 § 9
Ulcerative colitis 23 11 38 § 11
In amed mucosa
Crohn disease 19 11 33 § 17
Ulcerative colitis 26 8 35 § 8
evaluation of abdominal pain, obstipation, peranal bleeding or
anaemia. All of them showed normal endoscopic as well as
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histologic Ž ndings of the lower gastrointestinal tract with the
exception of incidental haemorrhoids in 8 of 22 persons.
Between 1993 and 1998, 30 patients with CD and 19
patients with UC admitted without any speciŽ c medication to
the Department of Medicine I of the University Erlangen–
Nuremberg were included in the study. The diagnosis of CD
and UC was established by clinical, radiological, endoscopi-
cal and histological criteria. Stool cultures were shown to be
negative in all patients. Patients underwent colonoscopy for
the actual assessment of activity and extension of disease or
for surveillance colonoscopy in 6 of 19 UC patients.
In CD 19 patients showed macroscopically normal gut
mucosa without in ammation, whereas 11 patients had both
in amed and non-in amed bowel segments.
In UC 11 patients were found to have normal endoscopic
Ž ndings of the mucosa, while 8 patients had both actively
in amed mucosal areas and unaffected mucosa.
In patients with normal macroscopic appearance of the
mucosa, histologically no or only quiescent signs of in am-
mation (edematous mucosa, loose in ammatory cell inŽ l-
trates) were found. In amed tissue was characterized by
moderate to severe in ammatory reactions (pronounced
in ammatory cell inŽ ltrate, superŽ cial to deep ulcerations,
apthous mucosal lesions, epithelial necrosis, etc.).
This study was approved by the local ethics committee (No.
331/1993) and all patients gave their informed consent to
participate.
Mucosa oxygenation of colorectal samples and tryptase
release
In addition to biopsy samples for routine histology a total of
153 mucosal biopsies (2–4 samples/patient) were taken
endoscopically throughout the lower gastrointestinal tract
from the terminal ileum to the rectum for measurement of
mast cell tryptase.
To purify samples from mucus, faeces or foodstuffs
biopsies were immediately after endoscopic sample taking
(< 10 sec) separately placed into Hanks solution (4 ml, pH 6)
Mast Cell Tryptase in IBD 175
for 45 min. This tryptase secretion within this early time
period was deŽ ned as initial basal tryptase release. Since
mucosal ischemia causes a disturbed mediator response,
Sex biopsy incubation was performed by mucosa oxygenation
(M/F) (5–8). To avoid ischemic conditions the Hanks solution as
well as the incubation medium were bubbled with a steady
10/9  ow of room air, ensuring a sufŽ cient oxygen pressure inside
the tissue.
8/11 After 45 min biopsies wet weights were measured by the
8/3
use of a microbalance (Sartorius, Göttingen, Germany) and
4/7 then placed into the incubation medium for measuring the
5/3 spontaneous tryptase release during 4 h. The Hanks solution
was stored at ¡20 °C until detection of the initial basal
tryptase release by radioimmunoassay.
The incubation medium contained 4 ml of a modiŽ ed
Hanks solution (supplemented with 25 mM Hepes buffer, 1%
fetal calf serum and 0.3% human serum albumine). Tem-
perature (37 °C), oxygen pressure (pO2 , 85–95 mmHg) and
pH (6.9–7.0) were maintained stable by mucosa oxygenation
throughout the whole incubation period of 4 h (5–8).
The biopsies from one patient were separately used for the
measurement of the spontaneous tryptase secretion. At 0, 15,
30, 60, 120, 150, 180, 210 and 240 min, 400 ml of the super-
natant were removed. The released amounts of tryptase were
calculated later for the actual incubation volume by a GW-
BASIC software program. Since mast cell mediators can have
negative feedback effects on mast cell activation, the incu-
bation medium was corrected to a volume of 4 ml at the time
point of 60 min by addition of adequate amounts of incu-
bation medium. The aliquots of each time point were
immediately collected on ice and centrifuged (7 min, 4 °C,
400 g). Thereafter supernatants were stored at ¡20 °C until
performance of the tryptase radioimmunoassay.
The time course of tryptase secretion during 4 h is
expressed as ng tryptase/ml incubation volume and mg wet
weight (ww) (Fig. 1). The effective increase of tryptase
Fig. 1. Time course of tryptase secretion from human gut mucosa in
Crohn disease and ulcerative colitis.
Scand J Gastroenterol 2001 (2)
 176 M. Raithel et al.

secretion resulted from addition of the tryptase amounts

released during the whole incubation period. It re ects the net
tryptase secretion which is given as ng tryptase/mg ww. Since
more than one biopsy was obtained from each person, one
average value of the net tryptase secretion was calculated
from each person and taken for Ž nal statistics to compare the
three groups.
Tryptase was measured by a solid phase radioimmunoassay
(Pharmacia-Upjohn, Freiburg, Germany) using test tubes
coated with an anti-tryptase antibody (4). In brief, 50 ml of
the culture supernatant (or prediluted tryptase standards) were
each added to the corresponding coated test tubes. After
addition of buffer and 1 2 5 I-labelled anti-tryptase antibody the
reaction mixture was incubated for 18 h. After three washings
Fig. 2. Net spontaneous tryptase secretion from human gut mucosa
with saline the bound radioactivity of the coated tubes was in Crohn disease and ulcerative colitis during 4 h of mucosa
measured by a gamma counter. The sensitivity limit of the oxygenation. SigniŽ cance level: 1 P < 0.01 versus control group.
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assay was 0.5 ng/ml (4). Intra- and interassay variations of
tryptase measurement from culture supernatants were 9.8%
and 4.7%, respectively. Intraindividual variation of sponta-
neous tryptase secretion from different samples taken from
the lower gastrointestinal tract of normal colorectal mucosa
amounted to 19 § 9% and in IBD to 26.2 § 12%.
For descriptive statistics the median and the 25%–75%
percentile were given. For testing the null hypothesis among
the three groups, the Kruskal–Wallis test for multiple groups
was used. SigniŽ cance levels are given in parentheses.
Results
Initial basal tryptase release during the wash-out period
The rates of the initial basal tryptase secretion within
45 min after sample taking are listed in Table II. Normal
colorectal mucosa was found to release only small amounts of
tryptase physiologically.
Non-in amed mucosa from CD showed a similar secretion
rate as controls, but biopsies from actively in amed CD tissue
had an at least two-fold increased tryptase release compared
with that of normal colorectal mucosa. The highest rates of
the initial basal release of tryptase were obtained in UC even
Table II. Initial basal release of tryptase from human colorectal
mucosa in in ammatory bowel disease
Initial basal tryptase release
Group (ng tryptase/mg ww)
Normal colorectal mucosa
Control group 1.6 (0.6–4.2)
Non-in amed mucosa
Crohn disease 1.8 (0.3–3.6)
Ulcerative colitis 3.6 (2.9–7.2)*
In amed mucosa
Crohn disease 4.2 (2.6–6.2)†
Ulcerative colitis 10.8 (5.8–22.0)*†‡
Initial basal release of tryptase was deŽ ned as the released amount
of tryptase within 45 min after endoscopic sample taking. SigniŽ -
cance levels: *P < 0.05 (versus control group); †P < 0.05 (versus
non-in amed IBD mucosa); ‡P < 0.05 (versus Crohn disease).
The number is the median of the net spontaneous tryptase secretion.
The intervals above and below represent 25% and 75% percentiles
of tryptase secretion rates in each group.
with an at least two-fold increased tryptase secretion in
unaffected mucosa and a six-fold increased release in affected
mucosa.
In amed IBD tissue exhibited each a signiŽ cantly higher
initial basal release than non-in amed tissue (CD, P < 0.05;
UC, P < 0.05). When comparing CD with UC, the initial
basal release of tryptase was signiŽ cantly enhanced in
in amed UC tissue (P < 0.05).
Time course of spontaneous tryptase release from gut
mucosal samples
Although mast cell hyperplasia has been described in CD
and UC (2, 3, 7), the pattern of tryptase secretion revealed no
major differences between spontaneous tryptase secretion of
normal gut mucosa and in amed or non-in amed IBD tissue
(Fig. 1). Tryptase secretion increased gradually with time in
all three groups.
However, the extent of spontaneous tryptase secretion
during 4 h of biopsy cultivation varied among controls, CD
patients and UC. The time course of tryptase release in CD
was entirely equal to that of controls. But in UC tryptase
secretion was found to be clearly elevated compared to
controls and CD.
Net spontaneous tryptase secretion during 4 h of biopsy
cultivation
The rates of the spontaneous tryptase secretion from viable
tiny endoscopic samples during 4 h of mucosa oxygenation
are illustrated in Fig. 2 as medians and 25%–75% percentile.
Net spontaneous tryptase secretion in controls was 1.2 (0.7–
2.7) ng/mg ww.
In contrast to the initial basal release, net spontaneous
tryptase secretion during 4 h of biopsy cultivation revealed no
difference between unaffected and affected IBD tissue. The

Scand J Gastroenterol 2001 (2)


secretion rate in CD was 1.7 (1.0–2.1) and 1.8 (0.6–2.9) ng/
mg ww, respectively, in unaffected and affected mucosa. In
UC tryptase secretion from non-in amed and in amed tissue
was considerably higher 3.7 (1.2–8.0) and 3.6 (1.4–7.6) ng/
mg ww, respectively. Interestingly, net spontaneous tryptase
secretion from UC mucosa was again each signiŽ cantly
higher than in controls (P < 0.01), indicating a prolonged and
sustained mast cell activation in UC. Although CD tissue
showed a clearly lower net tryptase secretion than UC
mucosa, a statistical signiŽ cance between UC tissue and CD
tissue was just not obtained.
Discussion
Although mast cell hyperplasia in the gut is a feature of IBD
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(2, 3, 6), the role of mast cells in this disease is still a matter of
debate. Histologic detection of mast cells can reveal an
increase in mast cell numbers, but it cannot adequately re ect
their functional state of activation, since degranulated mast
cells may escape from histologic assessment (6, 9).
To precisely detect mast cell secretion from gastrointestinal
tissue, mucosa oxygenation was performed using tiny viable
endoscopic samples. This approach enables the quantitative
determination of several immune mediators like histamine,
arachidonic acid metabolites, TNF, eosinophilic cationic
protein and mast cell tryptase (5–8). Mast cell tryptase
represents a highly speciŽ c mast cell protease (neutral serine
esterase) which is constitutively expressed by all mast cell
types including the mucosal mast cell subtype (3). However,
several investigations have shown that tryptase is only
released from mast cells upon stimulation and indicates a
speciŽ c mast cell involved reaction (3, 4, 8). With the
availability of a speciŽ c radioimmunoassay for this unique
mast cell marker endoscopic samples were used to assess mast
cell involvement and activation in IBD.
Spontaneous release of tryptase was found to occur
physiologically in normal colorectal mucosa. This indicates
the presence of low numbers of activated mast cells as normal
constituents of the innate mucosal immunity (3). Since
endoscopically taken samples mainly contain parts of the
mucosa (epithelium, lamina propria) and rarely submucosa,
the observed tryptase secretion is thought to come primarily
from tryptase-positive mucosal mast cells (3).
Like other mast cell subtypes human intestinal mast cells
have the ability to dramatically increase in number or enhance
their activity in several pathologic conditions including IBD.
Investigation of the initial basal tryptase release revealed that
mucosal samples from actively in amed IBD tissue secrete
signiŽ cantly higher amounts of tryptase within 45 min after
sample taking than non-in amed IBD mucosa or normal
colorectal mucosa. Although the extent of the initial basal
release was signiŽ cantly greater in affected UC tissue than in
in amed CD tissue, this Ž nding indicates that in both diseases
mast cell secretory activity becomes up-regulated during the
Mast Cell Tryptase in IBD 177
expression and manifestation of acute mucosal in ammation.
In CD the amount of the initial basal tryptase release increases
by 2.3 and in UC by 3.0 when comparing the rates of the
initial basal tryptase secretion from non-in amed and
in amed tissue. Although traumatization of the tissue by
sample taking contributes to the rate of initial basal release,
the results obtained suggest that extracellularly located
tryptase is rapidly washed out within 45 min from affected
CD tissue and in amed or non-in amed UC tissue. These
results are in accordance with Ž ndings from other investiga-
tors who found either on the basis of electron microscopy,
immuno-histochemistry or histamine secretion evidence for
an ongoing mast cell degranulation in IBD (2, 5, 10–14). Such
an event in vivo may well explain the elevated rate of the
initial basal release of tryptase in active IBD and this appears
to be associated with mucosal disease activity, since in amed
CD or UC tissue secretes more than double the initial basal
release of tryptase than unaffected tissue.
In contrast to the initial basal release of tryptase, the rate of
the spontaneous tryptase release in viable IBD tissue during
the subsequent incubation period of 4 h showed no differences
between affected and unaffected IBD tissue. It could be
argued that during the period of the initial basal release, apart
from mast cell speciŽ c tryptase several other soluble factors,
which induce degranulation of mucosal mast cells such as
neuropeptides (e.g. substance P), chemokines, c-kit ligand,
complement factor C3a and C5a, lymphocyte-derived factors,
intestinal epithelial associated components, oxygen radicals,
etc., are rapidly washed out from IBD tissue (7, 9, 15, 16).
However, the results of 4 h of mucosa oxygenation
demonstrate that there are further important differences
between CD and UC in terms of quantitative mast cell
tryptase secretion. Although the time course of tryptase
secretion during 4 h of biopsy cultivation was similar in all
three groups investigated, the rates of the net spontaneous
tryptase secretion indicate that a higher degree of mast cell
involvement with a prolonged mediator secretion is a typical
feature of UC, but not of CD. In CD the time course of
tryptase secretion, as well as the amount of spontaneous
tryptase secretion, were quite similar as in normal colorectal
mucosa, whereas UC tissue released in both disease stages
signiŽ cantly enhanced amounts of tryptase. This Ž nding, on
the basis of a highly speciŽ c mast cell marker, clearly
indicates that mucosal mast cell involvement plays a greater
role in UC than in CD. In fact similar observations have been
made in former studies by measurement of the tissue
histamine content or histamine secretion (5, 13, 17), by
assessment of the clinical response using a mast cell stabilizer
(disodium cromoglycate) (18, 19) or analysis of IgG4 - and
IgE-containing immune cells (20, 21).
The presence of tryptase in biological  uids has been
reported to be strongly connected with or attributable to
activated mast cells (3, 4, 8, 22). The overall increased
spontaneous tryptase secretion even in unaffected UC tissue
is a striking and unexpected Ž nding. Since mast cell numbers
Scand J Gastroenterol 2001 (2)
 178 M. Raithel et al.

have not been quantiŽ ed in this study, the enhanced tryptase
secretion in UC indicates that either the number of secreting
6.
(activated) mast cells or the extent of activation of mast cells
is generally higher than in normal colorectal mucosa. The
presence of secreting mast cells in non-in amed tissue of UC
7.
is in clear contrast to the activity of other mononuclear cells,
whose activity is strongly correlated to mucosal disease
activity (2). In conclusion, these Ž ndings suggest that UC is a 8.
mast cell mediated or modiŽ ed disease. Tryptase is known to
stimulate interleukin 8 production, generate C3a anaphyla-
toxin from complement factor C3, increase eosinophil and
neutrophil recruitment or epithelial cell proliferation (23–28), 9.
which are typical pathophysiological events of UC (3, 4).
Although the precise mechanisms (stimuli) for tryptase
10.
release in UC are not yet clear, it is concluded that persistent
and prolonged mast cell mediator secretion in UC may induce
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disease, ulcerative colitis and allergic enteropathy. Int Arch
Allergy Immunol 1995;108:127– 33.
Raithel M, Hochberger J, Hahn EG. Effect of colonoscopy-
premedication containing diazepam and pethidine on the release
of mast cell mediators from gut mucosal samples. Endoscopy
1995;27:415– 23.
Raithel M, Schneider Th, Hahn EG. Effect of substance P on
histamine secretion from gut mucosa in in ammatory bowel
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Raithel M, Pacurar A, Winterkamp S, Dalbay S, Ell C, Hahn
EG. Analysis and characteristics of mast cell tryptase and
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enterology 1986;91:746– 86.
Dvorak AM, Monahan RA, Osage BE, Dickerson RG. Crohn’s
disease: transmission electron microscopic studies: 2: immuno-
logic in ammatory response: alterations of mast cells, basophils,

or support the recruitment of other in ammatory cells into gut
mucosa (3, 23, 27, 28).
When summarizing all results of the initial basal tryptase
release and of the following spontaneous tryptase secretion
over 4 h, it becomes evident that the extent of ongoing mast cell
involvement and secretion differs considerably between CD
and UC. This difference in mast cell secretory activity may—
among several other reasons—be well explained by different
immunopathological cytokine pathways (e.g. CD TH1 cyto-
kines, UC TH2 cytokines) (1, 29). UC has been linked with a
TH2-dominated immune response and mast cells are widely
regarded as important effector cells in immune responses
associated with TH2 cells (27, 29). Thus it appears likely that
the observed initial and sustained spontaneous release of
tryptase from gut mucosal mast cells in UC results, at least in
part, from activating or priming effects of TH2 cytokines on
the mucosal mast cell subtype (27).
Acknowledgements
This study was supported by grants from Deutsche For-
schungsgemeinschaft, Bonn, Germany (DFG, El 150/1-1).
The authors are grateful to the staff of the endoscopy unit and
especially to Mrs. Rosemarie Seidenfaden for her excellent
technical assistance.
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 Mast Cell Tryptase in IBD 179

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by Crohn’s disease intestinal lamina propria mononuclear cells.
Gastroenterology 1997;112:1169– 78.

Received 9 June 2000

Accepted 14 August 2000
Downloaded by [Hals-Nasen-Ohren-Klinik] at 03:55 04 December 2017

Scand J Gastroenterol 2001 (2)