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IMMUNOBIOLOGY
From the Department of Internal
Medicine/Gastroenterology and the Department of Anatomy, Medical School
of Hannover, Germany; and the Department of Medicine II, University of
Erlangen, Germany.
Mast cells are inflammatory and immunoregulatory cells resident in
tissues. They develop from bone marrow-derived progenitor cells that
enter the tissue through the blood circulation. The specific
localization and migration of mast cells in tissues is dependent on
their interaction with extracellular matrix (ECM) proteins. Adhesion of
human mast cells isolated from intestinal mucosa and cultured in the
presence of stem cell factor (SCF) to ECM proteins is analyzed. It was
observed that SCF is a unique cytokine enhancing mast cell adhesion to
all tested ECM proteins (fibronectin, laminin, collagen I, III, IV, VI,
XIV) up to 5-fold, particularly to fibronectin (54% ± 12% of mast
cells) and to denatured collagens (40% ± 12% on cyanogen
bromide-cleaved peptides of collagen I). Most noteworthy, preculture of
mast cells with interleukin-4 (IL-4), in addition to SCF, reduced their
potency to adhere to ECM proteins to one third compared to mast cells
cultured with SCF alone. Mast cell adhesion was preferentially mediated
by Mature mast cells are thought to be involved in
physiological processes, such as host defense against bacteria and
tissue remodeling.1,2 Apart from these functions, which
are not understood in detail, mast cells are known to be of particular importance in the pathophysiology of immediate-type allergic reactions and of other chronic inflammatory diseases.3 Humoral
effector functions of human mast cells The specific localization and migration of mast cells in tissues is
dependent on their interaction with extracellular matrix (ECM)
proteins.10 Cell adherence to ECM proteins is mediated by
specific cell adhesion receptors, mainly cell surface receptors of the
integrin family. Integrins are heterodimers of noncovalently linked
No information is available, however, on the adhesion of human mast
cells derived from mucosal tissue to ECM proteins and its regulation by
cytokines. A major reason for that is the difficulty in obtaining
sufficient amounts of purified mast cells isolated from human mucosal
tissue. Using recently developed methods for the isolation and culture
of human mast cells derived from intestinal mucosa, we could show that
SCF and IL-4 regulate mast cell proliferation and mediator
release.5,19 Moreover, we found that mast cells survive in
coculture with human umbilical vein endothelial cells dependent on
membrane-bound SCF and on adhesion molecules such as vascular cell
adhesion molecule-1 on endothelial cells, suggesting that additional
molecules (eg, adhesion receptors) may be important for mast cell
regulation.20 In the current study, we examined the
capacity of human mast cells derived from intestinal tissue and
cultured for 2 to 3 weeks to adhere to different ECM proteins, such as
collagens, laminin and fibronectin, and the regulation of mast cell
adhesion and integrin expression by SCF, IL-4, and other factors.
Isolation and culture of human intestinal mast cells
Mast cell adhesion assay
Stimulation and inhibition of mast cell adhesion During adhesion, mast cells were challenged with SCF (PeproTech) at various concentrations (0.1-1000 ng/mL [0.05-540 nM]), with IL-3 (R&D Systems, Wiesbaden, Germany), IL-4 (Novartis), IL-6, IL-10, IL-13 (PeproTech), NGF (R&D Systems), TNF- (Becton Dickinson, San Jose,
CA) or IFN- (PharMingen, San Diego, CA), each at 100 ng/mL (30-65 nM), with TGF- (PeproTech) at 10 ng/mL (4 nM), with IL-8
(PeproTech), the complement cleavage products C3a and C5a (gifts from
C. A. Dahinden, Bern, Switzerland), each at 10 7 M,
or by cross-linking of the high-affinity IgE receptor (Fc RI) using
the mAb 29C6 at 100 ng/mL (6.5 nM) (provided by Hoffman-La Roche,
Nutley, NJ). In another set of experiments, adhesion blocking mAbs
directed against 1-integrins (CD29, clone P4C10; Biomol, Hamburg,
Germany), 2-integrins (CD18, clone MHM23; DAKO, Glostrup, Denmark),
and v3 (CD51, clone 23C6; Southern Biotechnology, Birmingham, AL)
were assessed. Mast cells were preincubated at 37°C for 10 minutes
with an isotype control, anti-CD18 or anti-CD51, each at a final
concentration of 3 µg/mL, or 1:100 dilution of anti-CD29 according to
the specification sheets. To inhibit specific signaling pathways, cells
were incubated with apigenin, Gö6976, or wortmannin (all from
Calbiochem, La Jolla, CA) for 1 hour before stimulation at the
concentrations indicated.
Immunocytochemistry Immunocytochemistry was performed using antibodies (overnight incubation) against human tryptase (mAb, 230 ng/mL [15 nM]; Chemicon, Temecula, CA) and human chymase (mAb, 100 ng/mL [6.5 nM]; Chemikon) as primary antibodies and the LAB-SA detection system (Histostain-Plus kit; Zymed Laboratories, San Francisco, CA) as described.5,19Scanning electron microscopy Microscopic coverslips were coated with ECM proteins, and adhesion assays were performed as described above. Adherent cells were fixed in freshly prepared Karnovsky fixative (2.5% glutaraldehyde and 4% paraformaldehyde in 0.1 M cacodylate-HCl buffer, pH 7.4) for 2 hours and rinsed in 0.1 M cacodylate buffer overnight. Thereafter, cells were dehydrated in a graded series of ethanol (30%, 50%, 70%, 90%, and 100%) and were air- dried at room temperature. The cells were coated with gold-palladium before examination using a scanning electron microscope (Philips 505, Eindhoven, The Netherlands).Reverse transcription-polymerase chain reaction Total RNA was prepared from human intestinal mast cell preparations, and genomic DNA was removed as described.6 Complementary DNA was synthesized using Superscript reverse transcriptase (Life Technologies, Eggenstein, Germany) and polymerase chain reaction (PCR) was carried out for 35 cycles (60 seconds at 94°C, 80 seconds at 60°C, 70 seconds at 72°C) using Taq DNA polymerase (Life Technologies) and specific primer pairs (sense; antisense) for the integrin subunits1 5'-TGTTCAGTGCAGAGCCTTCA-3';
5'-CCTCATACTTCGGATTGACC-3'), 2 5'-AGGCTCTGATCCACCTGAGC-3';
5'-TCACCAACCTCAAGCCCTCC-3'), 3 5'-GGGGACTGCCTGTGTGACTC-3';
5'-CTTTTCGGTCGTGGATGGTG-3'), 1 5'-CTACAAGATGGAGGATGGG-3'; 5'-GCCTCAGTGAATCAATCAAGGG-3'), 2 5'-CTGCTTCAGTGCAAAGTTCA-3'; 5'-CCCGTTCCAAATT- CTGGTAG-3'), 3 5'-GTGGTCAGGGTCAGAAGACC-3'; 5'-GGAGAAGAAGCCGTGGAAGA-3'), 4 5'-CCACCTTGGTCCTCATGTCAT-3';
5'-CATGCGCAACATTCTGATCCT-3'), 5 5'-AACAGGATGGCTAGGATGAT-3';
5'-ACAAGTTGCTGACTCCATTG-3'), 6 5'-GTGTTGCCAACC- AGAATGGC-3';
5'-CAGTCACTCGAACCTGAGTG-3'), V 5'-GGATCTTGCCCTCAGTGAAG-3';
5'-CATGAGGTTGAAGCTGCTCC-3'). PCR products were separated on a 1%
agarose gel containing ethidium bromide (500 ng/mL [1.3 µM]) and
then were photographed.
Flow cytometry For each labeling, 1 × 105 mast cells (purity, 98% or greater) were washed twice (4 minutes, 400g) and resuspended in PBS supplemented with 0.1% BSA, 0.1% sodium azide, and 250 µg/mL rabbit IgG. Cells were labeled using the primary mAbs directed against CD11a (Coulter-Immunotech), CD11b (Coulter-Immunotech), CD11c (PharMingen), CD18 (Coulter-Immunotech), CD29 (Coulter-Immunotech), activated conformation of CD29 (clone HUTS-21, PharMingen), CD49a (Coulter-Immunotech), CD49b (PharMingen), CD49c (PharMingen), CD49d (Coulter-Immunotech), CD49e (Coulter-Immunotech), CD49f (PharMingen), or CD61 (PharMingen), respectively. Appropriate isotype controls were performed. After incubation at 4°C for 45 minutes, cells were washed and labeled with the secondary antibody goat anti-mouse IgG fluorescein isothiocyanate (FITC) or goat anti-mouse IgG1 FITC (Southern Biotechnology). Flow cytometric analysis was performed using the FACSCalibur system (Becton Dickinson).
Stem cell factor promotes adhesion of human intestinal mast cells to extracellular matrix proteins Human mast cells were isolated from intestinal tissue and cultured in the presence of SCF. Adhesion to laminin-1, fibronectin, collagens, and denatured collagens (1 and 2 chains and CNBr-cleaved peptides
of collagen type I) was tested using a mast cell adhesion assay with
and without the addition of 100 ng/mL (54 nM) SCF. In the absence of
SCF, mast cell adhesion to fibronectin, but not to collagens and almost
never to laminin-1, was observed. Addition of SCF to the adhesion assay
caused a 2- to 5-fold increase in mast cell adhesion to all tested ECM
proteins. In the presence of SCF, mast cell adhesion was again highest
(up to 74%) to fibronectin, but substantial adhesion was also observed
to laminin-1, the 1 and 2 chains of collagen I, and, even more
pronounced, to CNBr peptides of collagen I (Figure
1A). Figure 1B shows that mast cell
adhesion to fibronectin and to CNBr peptides of collagen type I is
enhanced by SCF in a dose-dependent manner, reaching maximum at 10 to
1000 ng/mL (5.4-540 nM) SCF (ED50 = 0.5 ng/mL [0.27 nM]
SCF in each case).
IL-3 enhances mast cell adhesion to fibronectin Apart from SCF, a broad spectrum of other cytokines and growth factors was tested for their capacity to modulate mast cell adhesion to collagen I, the2 chain of collagen I, and fibronectin. Only IL-3
caused a significant increase in mast cell adhesion to fibronectin
(21% compared with 10% without cytokines). However, adhesion rates to
collagen I and the 2 chain of collagen I were not changed by IL-3
(Figure 2A). Moreover, we found that the
stimulation of mast cells by FcRI cross-linking leads to a 2.5-fold
enhancement of mast cell adhesion to collagen I, the 2 chain of
collagen I, and fibronectin. In contrast, the addition of C3a, C5a, NGF and other cytokines for 90 minutes failed to modulate mast cell adhesion to fibronectin (Figure 2B). Treatment of mast cells with IL-4,
in addition to SCF, did not alter SCF-induced mast cell adhesion
(Figure 2B). IL-4 also did not have a significant effect on mast cell
adhesion after prolongation of the adhesion assay up to 6 hours
(Figure 2C).
Preincubation with IL-4 strongly reduces mast cell adhesion Recently, we showed that the addition of IL-4 to the culture medium strongly enhances proliferation and mediator release of human intestinal mast cells.5 Furthermore, IL-4 enhances the production of Th2-type cytokines in mast cells, but it does not affect or even down-regulate proinflammatory cytokines.6 To analyze the effect of IL-4 preincubation on adhesion, mast cells cultured for 2 weeks with SCF were compared with mast cells cultured for the same time with IL-4 in addition to SCF. Mast cell adhesion was again tested in the presence or absence of SCF. When mast cells had been cultured with IL-4, adhesion to all tested ECM proteins was clearly reduced, particularly if SCF was added to the adhesion assay (Figure 3A). The IL-4-dependent reduction of mast cell adhesion occurred in a dose-dependent fashion the ED50 of IL-4 was approximately 500 pg/mL
(Figure 3B).
Adhesion is not restricted to a mast cell subtype Mast cell subtypes that bind to fibronectin were studied by immunocytochemistry using antibodies against human tryptase and chymase. In all experiments, the adherent mast cells were always tryptase-positive. We found 54% ± 6% (mean ± SD, n = 3) chymase-positive cells (also called connective tissue-type mast cells) if cells were cultured with SCF alone. Confirming recent data, we found more chymase-negative cells (mucosal-type mast cells) if cells were cultured with SCF and IL-4 (36% ± 6% chymase-positive cells).5 Analysis of adherent mast cells after 90 minutes revealed that the percentage of chymase-positive cells was not changed after adhesion, suggesting that interaction with ECM proteins is not restricted to a particular mast cell subclass.Adhesion to fibronectin is accompanied by pronounced cell spreading The ultrastructural morphology of adherent mast cells was analyzed by scanning electron microscopy. After mast cell adhesion in the presence of SCF, we observed differences in mast cell morphology depending on the kind of matrix protein. Particularly on fibronectin (Figure 4A-B), a pronounced spreading of mast cells was observed. Cell spreading was accompanied by the formation of pseudopodia. In contrast, mast cells adhering to collagen type I showed no or only thin pseudopodia (Figure 4C-D).
Human intestinal mast cells express a number of integrins Using mast cells directly after their isolation (purity, 95%) or after culture in the presence of SCF for 14 days (purity, 99% or greater), we found messenger RNA (mRNA) expression for the integrin receptor subunits1, 2, 3, 2, 3, 4, 5, and V by
reverse transcription (RT)-PCR (Figure
5A). These findings were confirmed for
cultured mast cells by flow cytometry analysis. Almost all mast cells
(98% to 100% positive cells) expressed the 1 integrins 41
(VLA-4) and 51 (VLA-5). Approximately 84% to 87% of the cells
were positive for 21 (VLA-2) and 31 (VLA-3). The 2
integrins L2 (LFA-1), X2, and M2 (Mac-1) were found on 90%, 55% or 17%, respectively, of the cells. Vitronectin receptor V3 was detected on 80% of the cells. Interestingly, neither challenge of the mast cells with SCF in the adhesion assay nor culture
of mast cells with IL-4 affected the expression of integrins on the
mRNA or on the protein level (not shown).
Mast cell adhesion is mainly mediated by integrin subunits
detected on human intestinal mast cells, we incubated the cells with
blocking mAbs directed against 1, 2, and V3 before
examining adhesion to fibronectin. Results shown in Figure 5B
demonstrate that pretreatment of cells with anti-1 (anti-CD29)
inhibited mast cell adhesion to fibronectin by 83%, compared to 42%
with anti-V3 (anti-CD51). In contrast, pretreatment with
anti-2 (anti-CD18) did not affect mast cell adhesion to fibronectin. The combined addition of the mAbs caused no further inhibition of mast
cell adhesion, indicating that mast cell adhesion to fibronectin is
mainly mediated by 1 integrins.
Stem cell factor and Fc 1 epitope on mast cells. The HUTS-21 1 epitope is
recognized by a specific antibody after a change of the conformation of
the 1 subunit of VLA integrins. Expression of the HUTS-21 1
epitope correlates with the ligand-binding activity of VLA
integrins.24 We found by flow cytometric analysis a
constitutive expression of the HUTS-21 1 epitope on mast cells at
low level. Stimulation of the cells with 100 ng/mL (54 nM) SCF or by
FcRI cross-linking using 100 ng/mL (6.5 nM) mAb 29C6 induced a clear up-regulation of the HUTS-21 1 epitope, suggesting that SCF and FcRI cross-linking increases the affinity of 1 integrins to ECM
proteins (Figure 5C).
Treatment with apigenin or wortmannin inhibits stem cell factor-induced mast cell adhesion To look for signaling pathways involved in mast cell adhesion, cultured mast cells isolated from human intestinal tissue were treated with specific inhibitors before stimulation with SCF. Gö6976, a specific inhibitor of protein kinase C, had no effect on mast cell adhesion.25 In contrast, SCF-induced mast cell adhesion was totally blocked by apigenin, which inhibits mitogen-activated protein kinase (MAPK)-associated signaling pathways, and wortmannin, a specific inhibitor of phosphatidylinositol 3-kinase (PI3K) (Figure 6A).26,27 Inhibitory effects of apigenin and wortmannin on mast cell adhesion were reflected by their effects on HUTS-211 epitope expression. Apigenin and
wortmannin inhibited the up-regulation of HUTS-21 1 in response to
stimulation with SCF, whereas Gö6976 did not (Figure 6B). These
findings suggest an involvement of PI3K and MAPK, but not protein
kinase C, in SCF-induced mast cell adhesion and an involvement of a
change of the conformation of 1.
Tissue factors involved in mast cell regulation have been poorly
defined. Here, we provide evidence that mature human mast cells
isolated from intestinal tissue and cultured in the presence of SCF
interact with and are modulated by selected ECM proteins such as
fibronectin and denatured collagens. These cells bind spontaneously to
fibronectin, as reported earlier for human cutaneous mast cells and for
the immature human mast cell line HMC-1.16,17 The adhesion
rate was similar to that described for cutaneous mast cells
(approximately 14%), whereas HMC-1 cells showed a spontaneous adherence of up to 80%.17 We found that the adhesion of
intestinal mast cells increased up to 5-fold in response to stimulation
with SCF, the ligand of c-kit. These data strongly suggest
that the high spontaneous adhesion rate of HMC-1 is attributed to the
point mutations in the coding sequence of the proto-oncogene
c-kit, causing ligand-independent activation of
c-kit in these cells.28 Murine bone
marrow-derived mast cells also adhere to fibronectin if they are
challenged with SCF.13 We observed a similar increase of
mast cell adhesion to different types of collagen, strongly suggesting
that SCF has a general capacity for promoting mast cell adhesion to ECM
proteins. Mast cell adhesion was also up-regulated after IgE receptor
cross-linking and, to a lesser degree, by IL-3, whereas a number of
other factors (NGF, IFN- An increasing body of evidence indicates that mast cells are also
involved in chronic inflammatory reactions such as Crohn disease and
are thought to be Th1-driven and typically associated with tissue
fibrosis.32,33 In previous studies, we also found evidence
for increased mast cell activation in patients with inflammatory bowel
disease, including Crohn disease, compared to healthy
controls.34-36 Little is known, however, about the
regulation of mast cells in Crohn disease and of the role of mast cells
in the pathogenesis of intestinal fibrosis. Gelbmann et
al33 reported an accumulation of mast cells in the
muscularis propria of strictures in Crohn disease. Interestingly, these
mast cells were colocalized with ECM proteins such as laminin, but not
with fibronectin or vitronectin, whereas collagens were not examined in
this study. We found that SCF, which is known to be produced mainly by
activated fibroblasts, strongly enhances mast cell adhesion not only
toward fibronectin and laminin but also toward denatured or fragmented
ECM proteins, such as Cell adhesion to ECM proteins is predominantly mediated by
integrins.11 Previous studies showed that human mast cells
from uterus, lung, and skin express the The inhibition of SCF-induced mast cell adhesion by wortmannin and
apigenin suggest an involvement of PI3K and MAPK. PI3K is though to be
involved in the adhesion of bone marrow-derived mouse mast cells.
Kinashi et al39,40 reported a role for PI3K in receptor
tyrosine kinase-stimulated adhesion and in affinity modulation of
VLA-5. In contrast, involvement of the MAPK pathway in the induction of
mast cell adhesion is a novel observation. MAPK is found to be involved
in the suppression of integrin activation in Chinese hamster ovary
cells, but the elements of this pathway are not yet
identified.41 Of note, the inhibition of PI3K and MAPK
pathways resulted in the inhibition of the SCF-induced HUTS-21 In conclusion, our data demonstrate that SCF and IL-4 regulate the adhesion of cultured human intestinal mast cells to ECM proteins. These findings may be of particular relevance for the regulation of mast cell migration, proliferation, and effector functions under normal conditions and in the course of inflammatory reactions.
We thank Nicole Abraham (Department of Gastroenterology and Hepatology, Medical School of Hannover); Susanne Fassbender and Kerstin Werner (Department of Anatomy, Medical School of Hannover); and Monika Schmid and Renate Ackermann (Department of Gastroenterology, Free University of Berlin) for excellent technical assistance.
Submitted September 11, 2000; accepted September 21, 2001.
Supported by the Deutsche Forschungsgesellschaft (SFB280-C8 and SFB366-C5).
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Stephan C. Bischoff, Dept of Internal Medicine/Gastroenterology, Medical School of Hannover, D-30623 Hannover, Germany; e-mail: bischoff.stephan{at}mh-hannover.de.
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© 2002 by The American Society of Hematology.
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  A. Chigaev, A. Waller, O. Amit, L. Halip, C. G. Bologa, and L. A. Sklar Real-time Analysis of Conformation-sensitive Antibody Binding Provides New Insights into Integrin Conformational Regulation J. Biol. Chem., May 22, 2009; 284(21): 14337 - 14346. [Abstract] [Full Text] [PDF]
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 L. J. Dawes, J. A. Eldred, I. K. Anderson, M. Sleeman, J. R. Reddan, G. Duncan, and I. M. Wormstone TGF{beta}-Induced Contraction Is Not Promoted by Fibronectin-Fibronectin Receptor Interaction, or {alpha}SMA Expression Invest. Ophthalmol. Vis. Sci., February 1, 2008; 49(2): 650 - 661. [Abstract] [Full Text] [PDF]
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 J. Sawada, S. Shimizu, T. Tamatani, S. Kanegasaki, H. Saito, A. Tanaka, N. Kambe, T. Nakahata, and H. Matsuda Stem Cell Factor Has a Suppressive Activity to IgE-Mediated Chemotaxis of Mast Cells J. Immunol., March 15, 2005; 174(6): 3626 - 3632. [Abstract] [Full Text] [PDF]
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 D. Fairweather, S. Frisancho-Kiss, S. A. Yusung, M. A. Barrett, S. E. Davis, S. J.L. Gatewood, D. B. Njoku, and N. R. Rose Interferon-{gamma} Protects against Chronic Viral Myocarditis by Reducing Mast Cell Degranulation, Fibrosis, and the Profibrotic Cytokines Transforming Growth Factor-{beta}1, Interleukin-1{beta}, and Interleukin-4 in the Heart Am. J. Pathol., December 1, 2004; 165(6): 1883 - 1894. [Abstract] [Full Text] [PDF]
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 B. T. Edelson, Z. Li, L. K. Pappan, and M. M. Zutter Mast cell-mediated inflammatory responses require the {alpha}2{beta}1 integrin Blood, March 15, 2004; 103(6): 2214 - 2220. [Abstract] [Full Text] [PDF]
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 M. Babina, S. Guhl, A. Starke, L. Kirchhof, T. Zuberbier, and B. M. Henz Comparative cytokine profile of human skin mast cells from two compartments--strong resemblance with monocytes at baseline but induction of IL-5 by IL-4 priming J. Leukoc. Biol., February 1, 2004; 75(2): 244 - 252. [Abstract] [Full Text] [PDF]
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G. Sellge, A. Lorentz, T. Gebhardt, F. Levi-Schaffer, H. Bektas, M. P. Manns, D. Schuppan, and S. C. Bischoff Human Intestinal Fibroblasts Prevent Apoptosis in Human Intestinal Mast Cells by a Mechanism Independent of Stem Cell Factor, IL-3, IL-4, and Nerve Growth Factor J. Immunol., January 1, 2004; 172(1): 260 - 267. [Abstract] [Full Text] [PDF]
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V. Lam, J. Kalesnikoff, C. W. K. Lee, V. Hernandez-Hansen, B. S. Wilson, J. M. Oliver, and G. Krystal IgE alone stimulates mast cell adhesion to fibronectin via pathways similar to those used by IgE + antigen but distinct from those used by Steel factor Blood, August 15, 2003; 102(4): 1405 - 1413. [Abstract] [Full Text] [PDF]
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 K. Sasaki, T. Tsuji, T. Jinushi, J. Matsuzaki, T. Sato, K. Chamoto, Y. Togashi, T. Koda, and T. Nishimura Differential regulation of VLA-2 expression on Th1 and Th2 cells: a novel marker for the classification of Th subsets Int. Immunol., June 1, 2003; 15(6): 701 - 710. [Abstract] [Full Text] [PDF]
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P. Forsythe and A. D. Befus Inhibition of Calpain Is a Component of Nitric Oxide-Induced Down-Regulation of Human Mast Cell Adhesion J. Immunol., January 1, 2003; 170(1): 287 - 293. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
RI-mediated signals.
Clin Exp Allergy.
1993;23:270-275