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Blood, Vol. 95 No. 6 (March 15), 2000:
pp. 2052-2058
IMMUNOBIOLOGY
From the Department of Veterinary Clinic, Faculty of Agriculture,
Tokyo University of Agriculture and Technology, Fuchu; and the
Department of Otolaryngology, Nihon University School of Medicine,
Chiyoda-ku, Tokyo, Japan.
Despite being a well-characterized neurotrophic factor, nerve growth
factor (NGF) influences survival, differentiation, and functions of
mast cells. We investigated whether NGF was able to induce directional
migration of rat peritoneal mast cells (PMCs). NGF clearly induced
chemotactic movement of PMCs in a dose-dependent manner with the
drastic morphological change and distribution of F-actin, which was
completely blocked by pretreatment with Clostridium botulinum
C2 toxin, an actin-polymerization inhibitor. Because PMCs constitutively express the NGF high-affinity receptor (TrkA) with a tyrosine kinase domain, we focused on downstream effectors in signaling cascades following the TrkA. NGF rapidly activated both mitogen-activated protein kinase (MAPK) and
phosphatidylinositol 3-kinase (PI3K), and the addition of inhibitors
specific for MAPK kinase and PI3K suppressed cell migration and these
signals. In the coculture system with PMCs and fibroblasts, which
produce biologically active NGF, directional migration of PMCs to
fibroblasts was observed, and the addition of anti-NGF polyclonal
antibodies significantly suppressed the migration of PMCs. These
findings suggested that NGF initiated chemotactic movement of PMCs
through both MAPK and PI3K signaling pathways following TrkA
activation. Thus, locally produced NGF may play an important role in
mast cell accumulation in allergic and nonallergic inflammatory conditions.
(Blood. 2000;95:2052-2058)
Numerous mast cells accumulate at local
tissues for various conditions such as wound healing, tumors, host
defense responses against helminth parasites and ectoparasites, and
acute and chronic allergic disorders.1-4 Proliferation and
differentiation of mast cells are regulated by some growth factors from
at least 2 distinct cell populations: T cells (interleukin 3 [IL-3],
IL-4, IL-9, and IL-10)5-8 and fibroblasts (stem cell factor
[SCF] and nerve growth factor [NGF]).9-11 In several in
vitro studies,12-15 IL-3, SCF, and other factors, such as
transforming growth factor- NGF is a target-derived neurotrophic factor that is necessary for the
survival, development, and functions of peripheral and central
neurons.23-25 Biological actions of NGF are mediated
through 2 types of specific receptors with distinct
affinities26,27: 75-kd glycoprotein (p75LNGFR)
and a 140-kd molecule with a transmembrane tyrosine kinase domain that
is coded by the trk proto-oncogene28 (TrkA).
Autophosphorylation of TrkA leads to some second messenger cascades
including activation of the mitogen-activated protein kinase (MAPK) and
phosphatidylinositol 3-kinase (PI3K), which eventually induce gene
expression in neuronal cells.29,30 Although freshly
isolated PMCs express TrkA but not p75LNGFR on the surface
of the membrane,16 signal cascades in the postreceptor process have not been clearly defined. In the present
study we demonstrate that (1) stimulation of rat PMCs with NGF induced rapid activation of both MAPK and PI3K signals, following tyrosine phosphorylation of the TrkA protein, leading to their
chemotactic migration with polymerization of actin filaments and (2)
biologically active NGF produced by 3T3 fibroblasts actually induced
migration of rat PMCs.
Isolation of PMCs
Cytokines and other reagents
Chemotaxis assay Various concentrations of NGF (500 µL) or the assay medium alone were applied into each well of 24-well culture plates (Nalge Nunc International, Roskilde, Denmark). After 10-mm tissue culture inserts (Nalge Nunc International) were placed into each well, 5 × 104 PMCs (500 µL) were added into each insert. The lower compartment of the well was separated from the cell suspension in the upper compartment with an 8-µm pore-size polycarbonate membrane of the culture inserts. PMCs were incubated for 3 hours at 37°C in a humidified atmosphere flushed with 5% carbon dioxide (CO2) in air. Following aspiration of nonadherent PMCs in the upper compartment, cells adherent to the upper surface of the membrane were removed by scraping with a rubber blade. Migrated cells adherent to the lower surface of the membrane were fixed with methanol for 5 minutes and stained with 0.5% toluidine blue. The membranes were mounted on glass slides by routine histological methods. The total number of mast cells that migrated across the membrane was counted under a light microscope. In some experiments, rabbit anti-NGF (1:500 dilution) or anti-SCF (5 ng/mL) pAb was added to 50 ng/mL NGF or 1 ng/mL rSCF in the lower compartments.Atomic force microscopy We applied 50 ng/mL NGF or the assay medium alone into 24-well culture plates, and then culture inserts were placed into each well. A total volume of 500 µL cell suspension was added in each culture insert. After incubation for 3 hours, the polycarbonate membrane was fixed with 3% paraformaldehyde/PBS for 15 minutes. Surface structure of migrating cells on the membrane was examined with an atomic force microscope (SPM-9500; Shimadzu, Kyoto, Japan).Pretreatment of Clostridium botulinum C2 toxin PMCs (2 × 106 cells/mL) were preincubated for 2 hours with or without 300 ng/mL C botulinum C2 toxin (component I, 100 ng/mL; component II, 200 ng/mL) in -MEM
containing 1% BSA. C botulinum C2
toxin has an adenosine 5'-diphosphate-ribosyl (ADP-ribosyl) transferase activity to nonmuscle actin monomer at arginine 177 (Arg-177), which results in the inhibition of actin filament
assembly.32 The pretreated cells were resuspended in the
assay medium and allowed to demonstrate the chemotactic ability of NGF.
Pretreatment of PMCs with signal transduction inhibitors Before being applied to a chemotaxis assay, PMCs were preincubated for 1 hour with the following inhibitors: 50 ng/mL K-252a (Calbiochem-Boehring, La Jolla, CA), a TrkA inhibitor34,35; 100 µmol/L PD98 059 (New England Biolabs, Beverly, MA), a MAPK/ERK kinase 1 inhibitor36; or 50 µmol/L LY294 002 (Calbiochem-Boehring), a PI3K inhibitor.37 The PMCs were pretreated with inhibitors or a diluent solution (0.5% dimethylsulfoxide assay medium), resuspended in the assay medium, and allowed to demonstrate chemotactic ability of NGF.Western blot analysis of tyrosine phosphorylated protein Freshly isolated PMCs (1-2 × 106 cells) were incubated for 4 hours in-MEM with 1% BSA in 60-mm plastic culture
dishes (Nalge Nunc International). This was followed by pretreatment
with or without the signal transduction inhibitors for 1 hour at
37°C in a humidified atmosphere flushed with 5% CO2 in
air. After treatment with 50 ng/mL NGF for 5 minutes or 30 minutes, the
cells were washed twice with ice-cold PBS. The cells were lysed in
buffer containing 50 mmol/L Tris-HCl (tris[hydroxymethyl]
aminomethane hydrochloride; pH 7.4), 1% Triton X-100, 150 mmol/L NaCl (sodium chloride), 1% nonidet P-40 (NP-40), 1 mmol/L
Na3VO4, 1 mmol/L C8H10FNO2S/HCl, and 1 µg/mL
aprotinin, then frozen and thawed 3 times. Lysates were centrifuged at
15 000 rpm for 20 minutes, and supernatants were incubated with
anti-MAPK/ERK1/2 or anti-PI3K pAb conjugated with protein-A beads
(Sepharose CL-4B, Pharmacia Biotech) at 4°C overnight with gentle
rotation. After washing with lysis buffer twice, the immunocomplex was
resuspended in 50 µL of electrophoresis buffer containing 250 mmol/L
Tris-HCl (pH 6.8), 20% glycerol, 5% SDS (sodium dodecyl sulfate), 5%
2-mercaptoethanol, 12% urea, and 0.1% bromophenol blue and boiled for
5 minutes. Samples were subjected to 12% SDS-polyacrylamide gel
electrophoresis and then electrically transferred to a membrane
(Immobilon-P; Millipore, Bedford, MA). For detection of phosphorylated
MAPK, the membrane was immunoblotted with phosphospecific MAPK pAb
(1:1000 dilution) at 4°C overnight and followed to reincubate with
horseradish peroxidase-conjugated antirabbit IgG pAb. For detection of
phosphorylated PI3K, the membrane was immunoblotted with horseradish
peroxidase-conjugated antiphosphotyrosine mAb at a concentration of 1 µg/mL for 1 hour at room temperature. The phosphorylated protein
products were visualized with an enhanced chemiluminescent detection
reagent (Amersham, Arlington Heights, IL), and the images
were analyzed (Gel Print 200i/VGA and Basic Quantifier; Genomic
Solutions, Ann Arbor, MI) to determine their relative intensity.
3T3 fibroblast-derived chemotactic activity A 3T3-Swiss albino fibroblast line (Japanese Cancer Research Resources Bank, Tokyo, Japan) was maintained in DMEM supplemented with 10% FCS, 50 U/mL penicillin, and 50 µg/mL streptomycin at 37°C in a humidified atmosphere flushed with 5% CO2 in air. A total of 5 × 105 3T3 fibroblasts was seeded in 1 mL of culture medium in 24-well culture plates. The culture medium was removed 2 days later, and a confluent monolayer of 3T3 fibroblasts was washed gently 3 times. After 500 µL of the assay medium supplemented with anti-NGF and/or anti-SCF pAb or control pAb was applied onto the monolayer, culture inserts were placed into each well. PMCs were added into each culture insert, and then a chemotaxis assay was carried out as described previously. In another experimental group, the confluent 3T3 fibroblasts were fixed with 1% paraformaldehyde before a chemotaxis assay.Statistical analysis Student's t test was performed for statistical analysis of the data, and P < .05 was taken as the level of significance.
Migration of PMCs induced by NGF NGF (50 ng/mL) was placed in the lower compartment, and then PMCs were incubated for various hours in the upper compartment. PMCs that migrated toward the lower surface of the polycarbonate membrane through 8-µm pores were markedly increased at 2 hours, and 3 hours later, the maximum number of 254 cells was reached (Figure 1A). PMCs were still migrating 4 hours later, but cells detached from the membrane toward the lower compartment were detected. In contrast, medium alone without NGF had no effect on migration of PMCs in culture for up to 4 hours. Various concentrations of NGF (0.5, 5, and 50 ng/mL) were applied in the lower compartment, and then PMCs were incubated for 3 hours in the upper compartment (Figure 1B). The addition of NGF resulted in a significant increase in the number of migrated PMCs in a dose-dependent manner; the minimum effective dose of NGF was 5 ng/mL.
Checkerboard analysis of NGF-induced migration We conducted experiments to determine whether the mast cell migratory response induced by NGF was due to directional (chemotaxis) or random (chemokinesis) activation. As shown in Table 1, checkerboard analyses with various concentrations of NGF in the upper and lower compartments demonstrated the gradient-dependent migration of PMCs. Moreover, the addition of increasing concentrations of NGF in the upper compartment led to slight dose-dependent migration to the lower compartment without NGF. Thus, we concluded that predominant chemotaxis and slight chemokinesis were induced by NGF.
Specificity of NGF-induced chemotaxis To determine the specificity of NGF on chemotactic response of PMCs, rabbit anti-NGF pAb (1:500 dilution) or anti-SCF pAb (5 µg/mL) was added to the assay medium containing the optimal dose of NGF (50 ng/mL) or the optimal dose of rSCF (1 ng/mL)38 in the lower compartment (Figure 1C). When PMCs were cultured in the upper compartment for 3 hours, both NGF and rSCF led to chemotactic migration of PMCs; the chemotactic ability of NGF was about 2-fold more potent than that of rSCF. The addition of anti-NGF pAb completely abolished the NGF-induced chemotaxis of PMCs, whereas rabbit control pAb or anti-SCF pAb had no effect on it. Neither anti-NGF pAb nor control pAb neutralized the rSCF-induced chemotaxis.Shape of PMCs stimulated with NGF After stimulation with 50 ng/mL NGF for 3 hours, PMCs on the polycarbonate membrane were fixed with 3% paraformaldehyde/PBS. The surface structure of PMCs migrating on the lower surface of the membrane through pores was scanned with an atomic force microscope. Figure 2 clearly shows that PMCs exposed to the optimal dose of NGF resulted in a drastic shape change with a polarized morphology. On the other hand, PMCs exposed to control medium alone remained resting, with little or no shape alteration.
F-actin formation in PMCs treated with NGF As F-actin formation is well known to be associated with cell motility, we next examined migratory PMCs on the distribution of F-actin. F-actin taken from PMCs that were passing through the pore toward 50 ng/mL NGF was stained with Oregon Green 488-phalloidin, and a strong positive reaction was detected at the plasma membrane, particularly at the protrusion site of the polarized cell (Figure 3A). To determine whether the polymerization of actin filaments was caused by stimulation with NGF, PMCs were pretreated with C botulinum C2 toxin, an actin-polymerization inhibitor, for 2 hours before the chemotaxis assay; this pretreatment inhibited the NGF-mediated F-actin formation (Figure 3A). In addition to confocal laser scanning microscopic analysis, flow cytometric analysis clearly demonstrated that enhanced formation of F-actin was induced by treatment with 50 ng/mL NGF, but it was completely inhibited by pretreatment with C botulinum C2 toxin (Figure 3B). Next, we attempted to determine the possible inhibitory effect of C botulinum C2 toxin on NGF-mediated chemotactic movement; the pretreatment with C botulinum C2 toxin resulted in complete neutralization of the chemotactic response of PMCs to NGF (Figure 4).
Signal transduction pathways triggered by NGF The TrkA high-affinity receptor has a tyrosine kinase domain, and binding of NGF to TrkA immediately induces its autophosphorylation and initiates several second messenger signal pathways such as activation of the MAPK and PI3K cascades in neuronal tissues.29,30 We have recently demonstrated that rat PMCs express only TrkA and that NGF tyrosine phosphorylates the TrkA receptor, thereby resulting in the rescue of PMCs from apoptosis.16 Therefore, we attempted to determine whether the NGF-induced chemotactic response of PMCs was influenced by blockage of phosphorylation of TrkA, MAPK/ERK kinase 1, and PI3K by using specific inhibitors K-252a, PD98 059, and LY294 002, respectively. When PMCs were pretreated with 50 ng/mL K-252a inhibitor for 1 hour, the NGF-induced chemotaxis was completely inhibited (Figure 5). Pretreatment with 100 µmol/L PD98 059 and 50 µmol/L LY294 002 reduced the NGF-induced chemotactic response by 38% and 73%, respectively, and pretreatment with both the inhibitors led to an additive blocking effect that was comparable to the inhibitory effect induced by the pretreatment with the K-252a inhibitor. To define rapid activation of MAPK/ERK1/2 and PI3K, PMCs were treated with 50 ng/mL NGF for 30 minutes or 5 minutes, respectively. As shown in Figure 6, phosphorylation of the tyrosine residues was detected for both the signal molecules after the NGF treatment; pretreatment with inhibitor PD98 059 or LY294 002 completely eliminated the NGF-mediated phosphorylation of the individual signal molecules.
Migration of PMCs to NGF produced by 3T3 fibroblasts We next examined whether NGF produced by fibroblasts actually induced migration of PMCs. When a confluent monolayer of 3T3-Swiss albino fibroblasts was seeded on the bottom of the lower compartment and PMCs were applied into the upper compartment, the number of migratory PMCs was markedly increased (Figure 7A). Neither control medium alone nor paraformaldehyde-fixed 3T3 fibroblasts induced chemotactic migration of PMCs. To define chemoattractants of PMCs produced by 3T3 fibroblasts, anti-NGF pAb and/or anti-SCF pAb was added to the lower compartment onto a monolayer of 3T3 fibroblasts (Figure 7B). The addition of anti-NGF or anti-SCF pAb decreased migration response of PMCs by 47% and 20%, respectively, as compared with 3T3 fibroblasts with control pAb; the application of both anti-NGF and anti-SCF pAbs more significantly inhibited cell migration toward 3T3 fibroblasts in the lower compartment.
Directed migration of a variety of inflammatory cells toward a chemical gradient of specific chemoattractants locally produced in inflamed tissues is the first integrated event in the process of allergic and nonallergic inflammatory responses.39,40 Chemoattractant ligands stimulate specific receptors on the cell surface that initiate several second messenger cascades; this action results in a change in F-actin distribution from azimuthal symmetry around the cell rim to concentration at a particular region involved in migratory behavior.41 In this study, we provided novel evidence that NGF enabled rat PMCs, which are classified as connective tissue-type mast cells, to rapidly migrate toward a concentration gradient of NGF in vitro. The PMCs treated with NGF manifested rapid distribution of F-actin and a polarized shape change with cytoplasm spread and lamellipodia protrusion. These manifestations were completely inhibited by the pretreatment with C botulinum C2 toxin. These cytoskeletal events following exposure to NGF appear to be consistent with the results reported in human B lymphocytes.42 Furthermore, the consequence of checkerboard analyses with various concentrations of NGF demonstrated that predominant chemotactic movement and slight random activation (chemokinesis) were induced by NGF.
We wish to thank Drs J. Bienenstock and A. M. Stanisz (McMaster University, Hamilton, Ontario, Canada) for supplying ultrapurified NGF; Dr I. Ohishi (Nippon Veterinary and Animal Science University, Tokyo, Japan) for providing C botulinum C2 toxin; and Amgen (Thousand Oaks, CA) for providing rSCF.
Submitted July 8, 1999; accepted November 18, 1999.
Supported by grant 09460137 from the Ministry of Education, Science, Sports, and Culture, Tokyo, Japan; and grants 3-2-4 and RCP 1999-4120 from the Pioneering Research Project in Biotechnology and Recombinant Cytokine's Project provided by the Ministry of Agriculture, Forestry, and Fisheries, Tokyo, Japan.
Reprints: Hiroshi Matsuda, Department of Veterinary Clinic, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo 183-8509, Japan; e-mail: hiro{at}cc.tuat.ac.jp.
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.
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 Y. Jiang, G. Chen, Y. Zhang, L. Lu, S. Liu, and X. Cao Nerve Growth Factor Promotes TLR4 Signaling-Induced Maturation of Human Dendritic Cells In Vitro through Inducible p75NTR 1 J. Immunol., November 1, 2007; 179(9): 6297 - 6304. [Abstract] [Full Text] [PDF]
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 C. L. Weller, S. J. Collington, A. Hartnell, D. M. Conroy, T. Kaise, J. E. Barker, M. S. Wilson, G. W. Taylor, P. J. Jose, and T. J. Williams Chemotactic action of prostaglandin E2 on mouse mast cells acting via the PGE2 receptor 3 PNAS, July 10, 2007; 104(28): 11712 - 11717. [Abstract] [Full Text] [PDF]
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G. Ugolini, S. Marinelli, S. Covaceuszach, A. Cattaneo, and F. Pavone The function neutralizing anti-TrkA antibody MNAC13 reduces inflammatory and neuropathic pain PNAS, February 20, 2007; 104(8): 2985 - 2990. [Abstract] [Full Text] [PDF]
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 Z. Shi, K. Y. Arai, W. Jin, Q. Weng, G. Watanabe, A. K. Suzuki, and K. Taya Expression of Nerve Growth Factor and Its Receptors NTRK1 and TNFRSF1B Is Regulated by Estrogen and Progesterone in the Uteri of Golden Hamsters Biol Reprod, May 1, 2006; 74(5): 850 - 856. [Abstract] [Full Text] [PDF]
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L. Bracci-Laudiero, L. Aloe, M. C. Caroleo, P. Buanne, N. Costa, G. Starace, and T. Lundeberg Endogenous NGF regulates CGRP expression in human monocytes, and affects HLA-DR and CD86 expression and IL-10 production Blood, November 15, 2005; 106(10): 3507 - 3514. [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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J. Ahamed, R. T. Venkatesha, E. B. Thangam, and H. Ali C3a Enhances Nerve Growth Factor-Induced NFAT Activation and Chemokine Production in a Human Mast Cell Line, HMC-1 J. Immunol., June 1, 2004; 172(11): 6961 - 6968. [Abstract] [Full Text] [PDF]
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 P. R. Borghesani, J. M. Peyrin, R. Klein, J. Rubin, A. R. Carter, P. M. Schwartz, A. Luster, G. Corfas, and R. A. Segal BDNF stimulates migration of cerebellar granule cells Development, March 5, 2003; 129(6): 1435 - 1442. [Abstract] [Full Text] [PDF]
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A. Genovese, G. Borgia, L. Bjorck, A. Petraroli, A. de Paulis, M. Piazza, and G. Marone Immunoglobulin Superantigen Protein L Induces IL-4 and IL-13 Secretion from Human Fc{varepsilon}RI+ Cells Through Interaction with the {kappa} Light Chains of IgE J. Immunol., February 15, 2003; 170(4): 1854 - 1861. [Abstract] [Full Text] [PDF]
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M. Uzumcu, S. D. Westfall, K. A. Dirks, and M. K. Skinner Embryonic Testis Cord Formation and Mesonephric Cell Migration Requires the Phosphotidylinositol 3-Kinase Signaling Pathway Biol Reprod, December 1, 2002; 67(6): 1927 - 1935. [Abstract] [Full Text] [PDF]
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 G. Path, A. Braun, N. Meents, S. Kerzel, D. Quarcoo, U. Raap, G. W. Hoyle, W. A. Nockher, and H. Renz Augmentation of Allergic Early-Phase Reaction by Nerve Growth Factor Am. J. Respir. Crit. Care Med., September 15, 2002; 166(6): 818 - 826. [Abstract] [Full Text]
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 D. Torrents, R. Torres, F. de Mora, and P. Vergara Antinerve Growth Factor Treatment Prevents Intestinal Dysmotility in Trichinella spiralis-Infected Rats J. Pharmacol. Exp. Ther., August 1, 2002; 302(2): 659 - 665. [Abstract] [Full Text] [PDF]
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K. Kawamoto, J. Aoki, A. Tanaka, A. Itakura, H. Hosono, H. Arai, Y. Kiso, and H. Matsuda Nerve Growth Factor Activates Mast Cells Through the Collaborative Interaction with Lysophosphatidylserine Expressed on the Membrane Surface of Activated Platelets J. Immunol., June 15, 2002; 168(12): 6412 - 6419. [Abstract] [Full Text] [PDF]
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 F. Niyonsaba, K. Iwabuchi, H. Matsuda, H. Ogawa, and I. Nagaoka Epithelial cell-derived human {beta}-defensin-2 acts as a chemotaxin for mast cells through a pertussis toxin-sensitive and phospholipase C-dependent pathway Int. Immunol., April 1, 2002; 14(4): 421 - 426. [Abstract] [Full Text] [PDF]
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H. Kobayashi, G. J. Gleich, J. H. Butterfield, and H. Kita Human eosinophils produce neurotrophins and secrete nerve growth factor on immunologic stimuli Blood, March 15, 2002; 99(6): 2214 - 2220. [Abstract] [Full Text] [PDF]
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 J. Teng, Z.-Y. Wang, and D. E. Bjorling Estrogen-induced proliferation of urothelial cells is modulated by nerve growth factor Am J Physiol Renal Physiol, June 1, 2002; 282(6): F1075 - F1083. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
, monocyte chemotactic protein, and
anaphylatoxins C3a and C5a, were found to induce mast cell migration.
However, exact mechanisms of mast cell recruitment to the affected
sites have been poorly understood. In prior studies, we demonstrated
that NGF is able to promote proliferation of murine bone
marrow-derived cultured mast cells, induce a phenotypic change to
connective tissue-type mast cells,
RI-mediated
degranulation.