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CHEMOKINES
From the Department of Pathology, University of
Michigan Medical School, Ann Arbor, and the Department of Immunology,
National Institute on Aging, Baltimore, MD.
Eosinophils are effector cells that play an important role in the
damage induced by the allergic process by releasing inflammatory mediators and proteolytic factors after activation. Stem cell factor
(SCF) is a primary cytokine involved in hematopoiesis and mast cell
differentiation, proliferation, and activation. Studies have also
indicated that SCF is directly involved in pathogenesis of allergic
airway inflammation. In the present study, we examined the ability of
SCF to activate murine eosinophils for increased mediator release and
up-regulation of chemokines. Initial data demonstrated that eosinophils
have significant levels of surface c-kit protein, SCF receptor.
SCF-activated eosinophils degranulate and release eosinophil peroxidase
and leukotriene C4 in a dose-dependent manner. In addition,
SCF was further shown to induce the release of CC chemokines, RANTES,
macrophagederived chemokine (MDC), macrophage inflammatory
protein-1 The pathophysiologic changes that occur during
allergic reactions have been associated with the recruitment,
activation, and degranulation of eosinophils at the site of the
response. Eosinophils are granulated leukocytes predominant in a number
of allergic diseases, such as allergic asthma, allergic rhinitis, and
atopic dermatitis.1-3 They play an important role as
effector cells in parasite infections, with their ability to release
cationic proteins, lipid mediators, cytokines, and chemokines that can directly cause damage to tissue or lead to the exacerbation of the
inflammatory response. Although eosinophils are hypothesized to be a
primary effector cell in diseases such as asthma, the activation of
these cells is still not completely understood. Thus, comprehending
which mediators are involved in eosinophil activation may be important
for determining the therapeutic target for treatment of allergic diseases.
Stem cell factor (SCF), a primary cytokine involved in hematopoiesis,
mast cell differentiation, and mast cell activation,4,5 binds to its surface receptor, c-kit, which is a member of the receptor
tyrosine kinase family. Previous data have identified that structural
cells such as fibroblasts, airway epithelial cells, endothelial cells,
and bronchial smooth muscle cells are able to produce
SCF.6-10 Endogenous SCF occurs in both transmembrane and
soluble forms11 and the relative importance of either form during hematopoiesis or disease is not known. Previously, SCF has been
shown to activate the adhesion of eosinophils to fibronectin and
vascular cell adhesion molecule 1 in vitro,12 suggesting that SCF may activate the eosinophil to become immobilized in the
tissue compartment. Furthermore, SCF appears to play a significant role
in eosinophil-associated inflammation in allergic airway inflammation.13,14 In the present study, we investigated
whether SCF induces activation of eosinophils to release eosinophil
peroxidase (EPO), leukotriene C4 (LTC4), and CC
chemokines. The additional analysis by gene array highlighted the broad
class of genes that were highly up-regulated by SCF in eosinophils.
Many of the gene products have been shown to be important mediators
involved in allergic and chronic/fibrotic inflammation and may
facilitate a number of detrimental responses.
Animals
Eosinophil purification
c-kit expression by flow cytometry The flow cytometry analysis of eosinophils was performed to determine c-kit receptor expression. The procedure was performed on ice in Dulbecco phosphate-buffered saline (D-PBS) with 1% fetal bovine serum (FBS) and 0.09% sodium azide. A total of 1 × 106 cells was used to block mouse Fc receptor with Fc block (1 µg/100 µL; Pharmingen, San Diego, CA) for 20 minutes at 4°C. Pelleted cells were fixed and permeabilized for 20 minutes at 4°C. Diluted polyclonal anti-c-kit or control antibodies were incubated for 30 minutes at 4°C. After incubation, cells were stained with an antimouse c-kit fluorescein isothiocyanate (FITC)-labeled antibody or isotype control (Pharmingen) for 30 minutes at 4°C. Cells were washed and the pelleted cells resuspended in D-PBS containing 1% FBS and 0.09% sodium azide until analyzed by flow cytometry.Stimulation of eosinophils with murine recombinant SCF Eosinophils (3 × 106 cells/well) were incubated in complete Dulbecco modified Eagle medium (DMEM) with 10% fetal calf serum (FCS) in the presence or absence of SCF (R & D Systems, Minneapolis, MN) in different concentrations (1, 10, and 100 ng/mL) at 37°C in 5% CO2 for 6 and 18 hours. After stimulation, cells were centrifuged and the cell-free supernatant recovered to measure CC chemokines.Measurement of EPO or LTC4 To analyze EPO or LTC4 release from the eosinophils suspended in phenol red-free DMEM, cells were allowed to incubate for 4 hours in response to SCF. The supernatant from the activated cells (2 × 106 eosinophils) was harvested and the EPO level in the cell-free supernatant was determined as previously described.16 Briefly, o-phenylenediamine (OPD; 10 mg) was dissolved into 5.5 mL distilled H2O. Then, 1.5 mL OPD solution was added to 8.5 mL of a Tris (tris(hydroxymethyl)aminomethane) buffer (pH 8.0) followed by the addition of 7.5 µL H2O2. Using a 96-well plate, 100 µL substrate solution was added to 50 µL sample. After 30 minutes the reaction was quenched with 50 µL 4 M H2SO4 and the absorbance was read at 490 nm. The relative increase in samples was then compared. As a positive control, eosinophils (2 × 106 cells) were sonicated and measured as total EPO. A negative control was used by sonicating neutrophils (2 × 106).The LTC4 levels were analyzed by specific enzyme-linked immunosorbent assay (ELISA) LTC4 kit (Cayman Chemical, Ann Arbor, MI) according to the manufacturer's instructions. The sensitivity of the LTC4 ELISA was 2 pg/mL. Quantification of CC chemokines Extracellular immunoreactive murine CC chemokines (RANTES, macrophage-derived chemokine [MDC], C10, and macrophage inflammatory protein 1 [MIP-1]) were quantified using a
modified double-ligand procedure of ELISA.17 This ELISA
method consistently detected CC chemokine levels over 20 pg and did not
cross-react with other cytokines. The 96-well flat-bottomed microtiter
plates were coated with 50 µL/well of either rabbit anti-CC chemokine
antibodies (1 µg/mL in 0.6 M NaCl, 0.26 M
H3BO4, and 0.08 N NaOH, pH 9.6) for 16 hours at
4°C, and then washed (PBS, pH 7.5, 0.05% Tween 20). Blocking of
nonspecific binding sites was accomplished by incubating plates with
PBS containing 2% BSA for 90 minutes at 37°C. Plates were rinsed
thoroughly with wash buffer and aqueous samples were added. Following a
1-hour incubation at 37°C, plates were washed and biotinylated rabbit
anti-CC chemokine antibody was added and incubated for 30 minutes at 37°C. Plates were then washed and chromogen substrate
added, and they were subsequently read at 490 nm.
Immunoarray gene selection cDNAs were chosen on a logical basis from IMAGE consortium clones (http://genome.wustl.edu/est/est_general/est_project_intro.html). Clones were obtained from a master set of approximately 15 000 sequence-verified, T1 phage-negative cDNA clones obtained from Research Genetics (Huntsville, AL), a commercial supplier of IMAGE consortium clones. Individual clones were selected if they were considered to play an important role in immune function or regulation, the development in the immune system, intracellular signaling, or programmed cell death. cDNA clones for a small number of genes were produced in our laboratory by polymerase chain reaction (PCR) amplification and the insert sequenced. The list of cDNA elements of the Immunoarray is publicly available at the following Web address: http://www.grc.nia.nih.gov/branches/rrb/dna/array.htm.Insert amplification and cDNA microarray printing Clones were grown in deep 96-well plates in Terrific Broth containing 200 mg/mL ampicillin. After overnight growth, plasmid DNA was prepared using a commercial 96-well kit (Qiagen, Valencia, CA). Clone inserts, generally between approximately 350 and 850 bp, were PCR amplified using a standard pair of forward 5'-CTGCAAGGCGATTAAGTTGGGTAAC-3' and reverse 5'-GTGAGCG GATAACAATTTCACACAGGAAACAGC-3' (Research Genetics, Carlsbad, CA) primers. The quality and quantity of the PCR products were accessed by running each PCR product on a 2% agarose gel. PCR products were denatured with 0.1 M NaOH and spotted onto Nytran + Supercharged nylon membranes (Schleicher and Schuell, Dassel, Germany) using a GMS417 Microarrayer (Affymetrix, Woburn, MA). Two replicates of 1152 cDNA clones were printed on each filter for a final feature number of 2304 spots per array. Each membrane had a 2.5 × 7.5-cm total dimension. The diameter of the spotting pin was 300 mM. Membranes were UV cross-linked using a Stratagene Stratalinker at 60 mJ (Stratagene, La Jolla, CA).Hybridization Immunoarrays were prehybridized in 4 mL Microhyb hybridization buffer (Research Genetics), containing 10 mL of 10 mg/mL human Cot I DNA (denatured at 95°C for 5 minutes prior to use; Life Technologies, Carlsbad, CA) and 10 mL of 8 mg/mL poly(dA) (denatured at 95°C for 5 minutes prior to use; Research Genetics). One to 5 mg total RNA was labeled with [33P]deoxycytidine triphosphate (dCTP) by reverse transcription (RT) for each time point or treatment. After 4 hours of prehybridization at 42°C, approximately 107 cpm/mL of heat-denatured probe was added to each prehybridization mix, followed by 18 hours of further incubation at 42°C in a roller oven. Hybridized arrays were rinsed in 50 mL of 2 times standard sodium citrate (SSC) and 1% sodium dodecyl sulfate (SDS) twice at 55°C followed by 1 to 2 times of washing in 2 times SSC and 0.1% SDS at 55°C for 10 minutes. The microarrays were exposed to phosphorimager screens for 1 to 3 days. The screens were then scanned in a Molecular Dynamics STORM PhosphorImager (Sunnyvale, CA) at 50-µm resolution. Gene expression was determined from microarray experiments by capturing the pixel density (ie, volume) of each spot using ImageQuant 5.1 Software (Molecular Dynamics).Real-time RT-PCR analysis Five micrograms total RNA from specific samples was reversed transcribed into cDNA using a prescribed reverse transcriptase kit from PE Biosystems. Primers and probe sets for RANTES, TARC, CxCR3, CxCR5, and GADPH have been predeveloped by PE Biosystems using a patented technique for optimal and specific amplification. Briefly, during PCR, a fluorogenic probe, consisting of an oligonucleotide with both a reporter and a quencher dye attached, anneals specifically between the forward and reverse primers. When the probe is cleaved by the 5' nuclease activity of the DNA polymerase, the reporter dye is separated from the quencher dye and a sequence-specific signal is generated. With each cycle, additional reporter dye molecules are cleaved from their respective probes, and the fluorescence intensity is monitored during the PCR. This real-time detection generates quantitative data based on the PCR at early cycles when PCR fidelity is the highest. Just as important, the real-time PCR system has a linear dynamic range of at least 5 orders of magnitude, reducing the need for serial dilutions. These computer-linked operations, using the specialized software, make the quantitation of PCR products achievable and because each well has its own internal standard (GAPDH) with a different fluorescent dye marker, the product can be instantly quantitated and compared to other samples.Statistical and cluster analysis Measurement of transcript abundance was compared in 2 ways. Time-course samples were analyzed by directly comparing each sample relative to a time-matched control. The raw data of each gene were log10 transformed, followed by the calculation of fold increase in the intensity of the signal generated over the results from the control-treated cells. These calculations were then compared to the intensity of the bands to ensure that the relative fold increases were biologically significant and not due to aberrant background levels. Data from cellular activation experiments for mediator release were analyzed by ANOVA and significance was determined with P < .05. Eosinophil populations from 4 different preparations were analyzed for gene array expression at the 1 hour time point and 2 different preparations at the 6-hour and 18-hour time points. For the gene to be considered to be significantly up-regulated it was required to be activated more than 2.0-fold in all repeats that were probed. Gene expression raw data and log values were averaged using mean ± SD. For all tests, statistical significance was considered to be at the P < .05 level.
Expression of c-kit on eosinophils Mice infected with S mansoni were used to elicit and isolate eosinophils by intraperitoneal injection of SEAs isolated from parasite eggs. These mice have a high level of circulating eosinophils (> 50% of circulating granulocytes) as previously described.15 The peritoneal cells were harvested after 48 hours and eosinophils were isolated to about 97% purity using magnetic bead separation. To investigate whether the eosinophils can express c-kit receptor, flow cytometry analysis was used. The results in Figure 1 indicate that eosinophils were strongly positive for c-kit surface protein, SCF receptor, as previously reported.12
Detection of EPO, LTC4, and chemokine release in SCF-stimulated eosinophils Eosinophils are important effector cells that need to be activated to release their inflammatory mediators and carry out their functions. To investigate the role of SCF in eosinophil degranulation and activation, EPO and LTC4 release were assessed. EPO is an eosinophil granule protein released after cell activation and is one of several granular enzymes that are released from activated eosinophils that can lead to tissue damage. We observed that SCF induced EPO release in a dose-dependent manner in 4-hour stimulation cultures (Figure 2). These data suggest that SCF has the ability to induce eosinophil degranulation and may have a role in mediating eosinophil activation leading to tissue damage.
A set of mediators that has been closely linked to the pathophysiology
changes in asthma are the cysteinyl leukotrienes. Eosinophils have the
capacity to synthesize lipid-derived mediators, including LTC4 after activation of the lipoxygenase pathway. We
observed that SCF (10 and 100 ng/mL) was able to stimulate eosinophils to release LTC4 by 4 hours after SCF stimulation (Figure
3). Only minimal levels of
LTC4 were found at 1 hour after activation (data not
shown), indicating that LTC4 was generated de novo. Taken together these data suggest that SCF can induce eosinophil
degranulation as well as initiate the activation of the lipoxygenase
pathway leading to the release of LTC4. These events
may have a significant impact on exacerbating airway damage and
inflammation and prolong airway reactivity in lungs of individuals
with asthma.
Eosinophils have previously been shown to release a number of cytokines
and chemokines after specific stimulation. To investigate whether SCF is able to activate eosinophils to produce and release CC
chemokines, various concentrations of SCF were used to activate the
eosinophils. We observed that SCF-stimulated eosinophils differentially released significant levels of RANTES, MDC, MIP-1
Gene array analysis of SCF activation of eosinophils The ability to analyze the activation of a large number of genes has recently been an area of great interest for possibly identifying new targets of research and activation patterns of stimulated cells. We have begun to investigate how SCF can regulate specific families of genes previously associated with disease progression using gene array technology. In our analysis, we investigated distinct families of genes in a temporal fashion after SCF activation. Our data in Table 1 indicate that SCF is a potent regulator of eosinophil gene expression, especially at 1 hour after activation. It is also very informative to examine the temporal expression of many of these genes and get a sense of downstream effects of SCF stimulation of the eosinophils. We have displayed some of the more interesting data in Table 1 that link known or hypothesized functions of eosinophils with disease progression. Interestingly, some of the genes seem to be differentially activated at the different time points, suggesting that there is likely a secondary response to the primary activation. A number of chemokines and their receptors are up-regulated by SCF in eosinophils, relating to the above data on chemokine protein release. Although there was not a significant increase in the expression of any interleukin (IL) gene, there were receptors, such as IL-11RA and IL-2RG that were significantly up-regulated, suggesting that SCF stimulation may allow the eosinophils to be more susceptible to regulation by these factors. The up-regulation of fibroblast growth factor 5 (FGF5), FGF7, and transforming growth factor3 (TGF3) gene expression 1 hour after SCF stimulation demonstrates that SCF may have a role in activation of eosinophils during resolution and fibrosis. Additionally, a number of adhesion and
costimulation molecules were also up-regulated, including specific  and integrins. Altogether, we found more than 100 genes that were
up-regulated by SCF by greater than 3-fold at 1 hour (many of which are
not listed) indicating the potent activating role of SCF on
eosinophils. The future experiments will focus on key aspects of
particular genes and move to our in vivo models of allergic responses
to address the impact of SCF on the expression patterns of particular
genes. The fact that we observed extremely high expression of some
genes compared with controls, such as RANTES, may not necessarily
translate into similar increases in protein. Thus, specific data will
always need to be carefully analyzed. The most highly expressed genes
after 18 hours of SCF activation are expanded in Figure
5 and demonstrate the differences in gene
families compared with those listed in Table 1, which were highly
up-regulated at 1 hour after SCF stimulation. Although we cannot
completely rule out that some of the contaminating cells, such as
macrophages (1%-2%), are participating in the response, our data from
additional studies indicate that peritoneal macrophages are not
directly activated by SCF (data not shown).
To further verify that our gene array was not overestimating the
expression of genes analyzed, we further assessed selected genes by
quantitative real-time PCR procedures. As previously described, freshly
isolated eosinophils (> 97% pure) were stimulated with SCF for 1 and
18 hours and the isolated mRNA was analyzed using specific predeveloped
probe/primer sets for representative chemokines and chemokine
receptors. The data in Figure 6 indicate that both the chemokines (RANTES, MDC, and TARC) and chemokine receptors (CxCR3 and CxCR5) demonstrated similar regulation at 1 and 18 hours after stimulation as observed by the gene array analysis. In
addition, the magnitude of the up-regulation appeared to be greater
than the gene array had indicated. This was especially observed with
RANTES, MDC, and TARC, which had more than 1200-, 8.8-, and 230-fold
increase over unstimulated control eosinophils compared with the
approximate 235-, 2.0-, and 25-fold increase, respectively, as assessed
by gene array. Thus, the overall analysis by gene array may actually
underestimate the level of gene expression, but can be used to indicate
the most highly up-regulated genes.
SCF is a known inducer of mast cell proliferation, mast cell degranulation, and matrix protein adhesion and is required for inhibition of mast cell apoptosis.5,18-24 Our previous studies have identified that SCF production during allergic inflammation can contribute significantly to the induction of the eosinophilic inflammatory responses and the airway hyperreactivity via direct mast cell activation.13,14,25 The results from this study suggest that SCF can play an important role in eosinophil activation, inducing degranulation, leukotriene, and CC chemokine production. The finding that eosinophils express a functional c-kit receptor for SCF reveals that activation of eosinophils via this pathway during allergic responses can be an important mechanism to perpetuate the inflammatory process. A previous seminal study has demonstrated that human peripheral blood eosinophils express a functional c-kit receptor that allows better adhesion and migration.12 The activation of eosinophils by SCF may have implications during multiple diseases, including allergic and fibrotic diseases where eosinophil infiltration is often coincident with severe end-stage disease.10,26-28 Interestingly, in vitro analysis indicates that eosinophil interaction with fibroblast, which can express high levels of surface SCF, can increase eosinophil survival and activation.29-33 Thus, SCF-induced eosinophil activation may play a complimentary role in the progression of multiple inflammatory diseases locally within inflamed tissue. In this study we used antigen-elicited eosinophils from parasite-infected animals that may be representative of an activated environment normally encountered by an infiltrating eosinophil. Although the eosinophils were removed from the infected animals, we cannot discount that the parasite infection itself altered the reactivity of the eosinophils. However, the level and number of genes that were up-regulated by SCF, especially at one hour after stimulation, indicated that SCF is a significant stimulus for eosinophil activation and mediator release. For example, the up-regulation of fibroblast growth factors, such as FGF5 and FGF7 (KGF), may lead to examination of novel interactions between SCF-producing structural cells and eosinophils. The up-regulation of integrins is consistent with an original publication demonstrating up-regulation of eosinophil adherence events after SCF stimulation.12 Over the years, our laboratory has been interested in the role of chemokines and their receptors during disease progression. These initial gene expression studies have indicated novel expression of a number of genes related to inflammatory and activation events, including CxCR3 and CxCR5 that had not previously been described. The expression of these chemokine receptors was verified by quantitative real-time PCR analysis. A previous study has also examined gene expression in eosinophils after IL-5 activation and found that a number of genes related to survival, adhesion, and migration were up-regulated, but concentrated primarily on the survival/apoptosis pathways.34 Thus, these data together will allow further investigations into a number of novel areas related to SCF activation of eosinophils and the association to disease progression. The ability of SCF/c-kit interactions to increase eosinophil adherence12 may serve as one of many initial stimuli for eosinophil migration into inflamed tissue. Once the eosinophil has migrated into the inflamed tissue, it needs to be activated to release inflammatory mediators. In the present studies, SCF was able to induce eosinophil degranulation and activate up-regulation of additional chemokine receptors, and, therefore, may be important for eosinophil migratory and tissue stasis functions. These aspects likely have a direct impact on airways disease progression. The subsequent release of mediators, such as leukotrienes and EPO, has a role in the airway hyperreactivity response and tissue damage. LTC4 has previously been identified as an inducer of airway hyperreactivity.35-38 Recently, we have found that SCF can directly induce airway hyperreactivity when instilled into the airways of normal mice via the activation of mast cells and release of cysteinyl leukotrienes, LTC4, D4, and E4.39 The fact that SCF also appears to be an important eosinophil activator for LTC4 production suggests that SCF may be an excellent target for therapy in patients with allergic asthma. SCF was also shown to induce CC chemokine production and suggests that
activation of these eosinophils may lead to increased inflammatory cell
recruitment. The data in the present study have demonstrated that
SCF-stimulated eosinophils can produce chemokines,39 including RANTES, MIP-1 In conclusion, the present study has demonstrated an important role for SCF mediating eosinophil release of EPO, LTC4, and CC chemokines. Furthermore, SCF up-regulated a significant and diverse array of inflammation-related gene expression suggesting a significant role of SCF in the progression of eosinophil-related disease. Thus, blocking SCF may be an important approach for targeting therapy in allergic disease.
We thank Pam Lincoln and Holly Evanoff for technical assistance. The schistosome-infected mice were graciously supplied by Dr Fred Lewis at the Laboratory of Biomedical Research Institute.
Submitted May 25, 2001; accepted August 21, 2002.
Supported by National Institutes of Health grants, HL59178, AI36302, and HL31963. S.H.P.O. is a postdoctoral fellow of the Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP), Brazil.
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: Nicholas W. Lukacs, University of Michigan Medical School, Department of Pathology, 1301 Catherine St, Ann Arbor, MI 48109; e-mail: nlukacs{at}umich.edu.
1. Boyce JA. The pathobiology of eosinophilic inflammation. Allergy Asthma Proc. 1997;18:293-300[CrossRef][Medline] [Order article via Infotrieve]. 2. Gleich GJ. Mechanisms of eosinophil-associated inflammation. J Allergy Clin Immunol. 2000;105:651-663[CrossRef][Medline] [Order article via Infotrieve]. 3. Walsh GM. Eosinophil granule proteins and their role in disease [in process citation]. Curr Opin Hematol. 2001;8:28-33[CrossRef][Medline] [Order article via Infotrieve]. 4. Columbo M, Horowitz EM, Botana LM, et al. The human recombinant c-kit receptor ligand, rhSCF, induces mediator release from human cutaneous mast cells and enhances IgE-dependent mediator release from both skin mast cells and peripheral blood basophils. J Immunol. 1992;149:599-608[Abstract]. 5. Ashman LK. The biology of stem cell factor and its receptor C-kit. Int J Biochem Cell Biol. 1999;31:1037-1051[CrossRef][Medline] [Order article via Infotrieve]. 6. Kim YK, Nakagawa N, Nakano K, Sulakvelidze I, Dolovich J, Denburg J. Stem cell factor in nasal polyposis and allergic rhinitis: increased expression by structural cells is suppressed by in vivo topical corticosteroids. J Allergy Clin Immunol. 1997;100:389-399[CrossRef][Medline] [Order article via Infotrieve]. 7. Miyamoto T, Sasaguri Y, Sasaguri T, et al. Expression of stem cell factor in human aortic endothelial and smooth muscle cells. Atherosclerosis. 1997;129:207-213[CrossRef][Medline] [Order article via Infotrieve].
8.
Jippo-Kanemoto T, Adachi S, Ebi Y, et al.
BALB/3T3 fibroblast-conditioned medium attracts cultured mast cells derived from W/W but not from mi/mi mutant mice, both of which are deficient in mast cells.
Blood.
1992;80:1933-1939 9. Linenberger ML, Jacobson FW, Bennett LG, Broudy VC, Martin FH, Abkowitz JL. Stem cell factor production by human marrow stromal fibroblasts. Exp Hematol. 1995;23:1104-1114[Medline] [Order article via Infotrieve]. 10. Fireman E, Kivity S, Shahar I, Reshef T, Mekori YA. Secretion of stem cell factor by alveolar fibroblasts in interstitial lung diseases. Immunol Lett. 1999;67:229-236[CrossRef][Medline] [Order article via Infotrieve].
11.
Vogel W, Lammers R, Huang J, Ullrich A.
Activation of a phosphotyrosine phosphatase by tyrosine phosphorylation.
Science.
1993;259:1611-1614
12.
Yuan Q, Austen KF, Friend DS, Heidtman M, Boyce JA.
Human peripheral blood eosinophils express a functional c-kit receptor for stem cell factor that stimulates very late antigen 4 (VLA-4)- mediated cell adhesion to fibronectin and vascular cell adhesion molecule 1 (VCAM-1).
J Exp Med.
1997;186:313-323 13. Lukacs NW, Strieter RM, Lincoln PM, et al. Stem cell factor (c-kit ligand) influences eosinophil recruitment and histamine levels in allergic airway inflammation. J Immunol. 1996;156:3945-3951[Abstract].
14.
Campbell E, Hogaboam C, Lincoln P, Lukacs NW.
Stem cell factor-induced airway hyperreactivity in allergic and normal mice.
Am J Pathol.
1999;154:1259-1265 15. Lukacs NW, Standiford TJ, Chensue SW, Kunkel RG, Strieter RM, Kunkel SL. C-C chemokine-induced eosinophil chemotaxis during allergic airway inflammation. J Leukoc Biol. 1996;60:573-578[Abstract].
16.
Campbell EM, Kunkel SL, Strieter RM, Lukacs NW.
Temporal role of chemokines in a murine model of cockroach allergen-induced airway hyperreactivity and eosinophilia.
J Immunol.
1998;161:7047-7053
17.
Campbell EM, Charo IF, Kunkel SL, et al.
Monocyte chemoattractant protein-1 mediates cockroach allergen-induced bronchial hyperreactivity in normal but not CCR2 18. Lin TJ, Bissonnette EY, Hirsh A, Befus AD. Stem cell factor potentiates histamine secretion by multiple mechanisms, but does not affect tumour necrosis factor-alpha release from rat mast cells. Immunology. 1996;89:301-307[CrossRef][Medline] [Order article via Infotrieve].
19.
Costa JJ, Demetri GD, Harrist TJ, et al.
Recombinant human stem cell factor (kit ligand) promotes human mast cell and melanocyte hyperplasia and functional activation in vivo.
J Exp Med.
1996;183:2681-2686 20. Galli SJ, Tsai M, Wershil BK. The c-kit receptor, stem cell factor, and mast cells: what each is teaching us about the others. Am J Pathol. 1993;142:965-974[Abstract]. 21. Dastych J, Metcalfe DD. Stem cell factor induces mast cell adhesion to fibronectin. J Immunol. 1994;152:213-219[Abstract]. 22. Newlands GF, Coulson PS, Wilson RA. Stem cell factor dependent hyperplasia of mucosal-type mast cells but not eosinophils in Schistosoma mansoni-infected rats. Parasite Immunol. 1995;17:595-598[Medline] [Order article via Infotrieve].
23.
Newlands GF, Miller HR, MacKellar A, Galli SJ.
Stem cell factor contributes to intestinal mucosal mast cell hyperplasia in rats infected with Nippostrongylus brasiliensis or Trichinella spiralis, but anti-stem cell factor treatment decreases parasite egg production during N brasiliensis infection.
Blood.
1995;86:1968-1976
24.
Tsai M, Shih LS, Newlands GF, et al.
The rat c-kit ligand, stem cell factor, induces the development of connective tissue-type and mucosal mast cells in vivo: analysis by anatomical distribution, histochemistry, and protease phenotype.
J Exp Med.
1991;174:125-131 25. Undem BJ, Lichtenstein LM, Hubbard WC, Meeker S, Ellis JL. Recombinant stem cell factor-induced mast cell activation and smooth muscle contraction in human bronchi. Am J Respir Cell Mol Biol. 1994;11:646-650[Abstract]. 26. Hallgren R, Bjermer L, Lundgren R, Venge P. The eosinophil component of the alveolitis in idiopathic pulmonary fibrosis: signs of eosinophil activation in the lung is associated with impaired lung function. Am Rev Respir Dis. 1989;139:373-383[Medline] [Order article via Infotrieve].
27.
Minshall EM, Leung DY, Martin RJ, et al.
Eosinophil-associated TGF-beta1 mRNA expression and airways fibrosis in bronchial asthma.
Am J Respir Cell Mol Biol.
1997;17:326-333 28. Levi-Schaffer F, Weg VB. Mast cells, eosinophils and fibrosis. Clin Exp Allergy. 1997;27(suppl 1):64-71. 29. Birkland TP, Cheavens MD, Pincus SH. Human eosinophils stimulate DNA synthesis and matrix production by dermal fibroblasts. Arch Dermatol Res. 1994;286:312-318[CrossRef][Medline] [Order article via Infotrieve].
30.
Pincus SA, Ramesh SH, Wyler DJ.
Eosinophils stimulate fibroblast DNA synthesis.
Blood.
1987;70:572-574 31. Shock A, Rabe F, Dent G, et al. Eosinophils adhere to and stimulate replication of lung fibroblasts in vitro. Clin Exp Immunol. 1991;86:185-190[Medline] [Order article via Infotrieve].
32.
Spoelstra FM, Hovenga H, Noordhoek JA, Postma DS, Kauffman HF.
Changes in CD11b and L-selectin expression on eosinophils are mediated by human lung fibroblasts in vitro.
Am J Respir Crit Care Med.
1998;158:769-777 33. Hogaboam C, Kunkel SL, Strieter RM, et al. Novel role of transmembrane SCF for mast cell activation and eotaxin production in mast cell-fibroblast interactions. J Immunol. 160:6166-6171.
34.
Temple R, Allen E, Fordham J, et al.
Microarray analysis of eosinophils reveals a number of candidate survival and apoptosis genes.
Am J Respir Cell Mol Biol.
2001;25:425-433 35. Wenzel SE. Arachidonic acid metabolites: mediators of inflammation in asthma. Pharmacotherapy. 1997;17:3S-12S[Medline] [Order article via Infotrieve].
36.
O'Byrne PM.
Leukotrienes in the pathogenesis of asthma.
Chest.
1997;111:27S-34S 37. Busse WW. Leukotrienes and inflammation. Am J Respir Crit Care Med. 1998;157:S210-S213[Medline] [Order article via Infotrieve]. 38. Christie PE, Schmitz-Schumann M, Spur BW, Lee TH. Airway responsiveness to leukotriene C4 (LTC4), leukotriene E4 (LTE4) and histamine in aspirin-sensitive asthmatic subjects. Eur Respir J. 1993;6:1468-1473[Abstract].
39.
Oliveira SH, Hogaboam CM, Berlin A, Lukacs NW.
SCF-induced airway hyperreactivity is dependent on leukotriene production.
Am J Physiol Lung Cell Mol Physiol.
2001;280:L1242-L1249 40. Zlotnik A, Morales J, Hedrick JA. Recent advances in chemokines and chemokine receptors. Crit Rev Immunol. 1999;19:1-47[Medline] [Order article via Infotrieve]. 41. Rossi D, Zlotnik A. The biology of chemokines and their receptors. Annu Rev Immunol. 2000;18:217-242[CrossRef][Medline] [Order article via Infotrieve]. 42. Orlofsky A, Wu Y, Prystowsky MB. Divergent regulation of the murine CC chemokine C10 by Th(1) and Th(2) cytokines. Cytokine. 2000;12:220-228[CrossRef][Medline] [Order article via Infotrieve].
43.
Hogaboam CM, Gallinat CS, Taub DD, Strieter RM, Kunkel SL, Lukacs NW.
Immunomodulatory role of C10 chemokine in a murine model of allergic bronchopulmonary aspergillosis.
J Immunol.
1999;162:6071-6079
44.
Steinhauser ML, Hogaboam CM, Matsukawa A, Lukacs NW, Strieter RM, Kunkel SL.
Chemokine C10 promotes disease resolution and survival in an experimental model of bacterial sepsis.
Infect Immun.
2000;68:6108-6114 45. Wu Y, Prystowsky MB, Orlofsky A. Sustained high-level production of murine chemokine C10 during chronic inflammation. Cytokine. 1999;11:523-530[CrossRef][Medline] [Order article via Infotrieve].
46.
Gonzalo JA, Pan Y, Lloyd CM, et al.
Mouse monocyte-derived chemokine is involved in airway hyperreactivity and lung inflammation.
J Immunol.
1999;163:403-411 47. Bochner BS, Bickel CA, Taylor ML, et al. Macrophage-derived chemokine induces human eosinophil chemotaxis in a CC chemokine receptor 3- and CC chemokine receptor 4-independent manner. J Allergy Clin Immunol. 1999;103:527-532[CrossRef][Medline] [Order article via Infotrieve]. 48. Galli G, Chantry D, Annunziato F, et al. Macrophage-derived chemokine production by activated human T cells in vitro and in vivo: preferential association with the production of type 2 cytokines. Eur J Immunol. 2000;30:204-210[CrossRef][Medline] [Order article via Infotrieve].
49.
Andrew DP, Chang MS, McNinch J, et al.
STCP-1 (MDC) CC chemokine acts specifically on chronically activated Th2 lymphocytes and is produced by monocytes on stimulation with Th2 cytokines IL-4 and IL-13.
J Immunol.
1998;161:5027-5038
50.
Imai T, Chantry D, Raport CJ, et al.
Macrophage-derived chemokine is a functional ligand for the CC chemokine receptor 4.
J Biol Chem.
1998;273:1764-1768
51.
Chvatchko Y, Hoogewerf AJ, Meyer A, et al.
A key role for CC chemokine receptor 4 in lipopolysaccharide-induced endotoxic shock.
J Exp Med.
2000;191:1755-1764
52.
Godiska R, Chantry D, Raport CJ, et al.
Human macrophage-derived chemokine (MDC), a novel chemoattractant for monocytes, monocyte-derived dendritic cells, and natural killer cells.
J Exp Med.
1997;185:1595-1604 53. Sallusto F, Palermo B, Lenig D, et al. Distinct patterns and kinetics of chemokine production regulate dendritic cell function. Eur J Immunol. 1999;29:1617-1625[CrossRef][Medline] [Order article via Infotrieve].
© 2002 by The American Society of Hematology.
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  V. A. Dolgachev, M. R. Ullenbruch, N. W. Lukacs, and S. H. Phan Role of Stem Cell Factor and Bone Marrow-Derived Fibroblasts in Airway Remodeling Am. J. Pathol., February 1, 2009; 174(2): 390 - 400. [Abstract] [Full Text] [PDF]
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 M. J. Sinnamon, K. J. Carter, L. P. Sims, B. LaFleur, B. Fingleton, and L. M. Matrisian A protective role of mast cells in intestinal tumorigenesis Carcinogenesis, April 1, 2008; 29(4): 880 - 886. [Abstract] [Full Text] [PDF]
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V. Dolgachev, A. A. Berlin, and N. W. Lukacs Eosinophil Activation of Fibroblasts from Chronic Allergen-Induced Disease Utilizes Stem Cell Factor for Phenotypic Changes Am. J. Pathol., January 1, 2008; 172(1): 68 - 76. [Abstract] [Full Text] [PDF]
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 K. Nakagome, M. Dohi, K. Okunishi, R. Tanaka, T. Kouro, M. R. Kano, K. Miyazono, J.-i. Miyazaki, K. Takatsu, and K. Yamamoto IL-5-Induced Hypereosinophilia Suppresses the Antigen-Induced Immune Response via a TGF-beta-Dependent Mechanism J. Immunol., July 1, 2007; 179(1): 284 - 294. [Abstract] [Full Text] [PDF]
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S. I. Ochkur, E. A. Jacobsen, C. A. Protheroe, T. L. Biechele, R. S. Pero, M. P. McGarry, H. Wang, K. R. O'Neill, D. C. Colbert, T. V. Colby, et al. Coexpression of IL-5 and Eotaxin-2 in Mice Creates an Eosinophil-Dependent Model of Respiratory Inflammation with Characteristics of Severe Asthma J. Immunol., June 15, 2007; 178(12): 7879 - 7889. [Abstract] [Full Text] [PDF]
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 J. I. Ellyard, L. Simson, A. Bezos, K. Johnston, C. Freeman, and C. R. Parish Eotaxin Selectively Binds Heparin: AN INTERACTION THAT PROTECTS EOTAXIN FROM PROTEOLYSIS AND POTENTIATES CHEMOTACTIC ACTIVITY IN VIVO J. Biol. Chem., May 18, 2007; 282(20): 15238 - 15247. [Abstract] [Full Text] [PDF]
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 V. Dolgachev, M. Thomas, A. Berlin, and N. W. Lukacs Stem cell factor-mediated activation pathways promote murine eosinophil CCL6 production and survival J. Leukoc. Biol., April 1, 2007; 81(4): 1111 - 1119. [Abstract] [Full Text] [PDF]
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 Y.-H. Lin, J. Friederichs, M. A. Black, J. Mages, R. Rosenberg, P. J. Guilford, V. Phillips, M. Thompson-Fawcett, N. Kasabov, T. Toro, et al. Multiple Gene Expression Classifiers from Different Array Platforms Predict Poor Prognosis of Colorectal Cancer Clin. Cancer Res., January 15, 2007; 13(2): 498 - 507. [Abstract] [Full Text] [PDF]
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B. C. Kuenen, G. Giaccone, R. Ruijter, A. Kok, C. Schalkwijk, K. Hoekman, and H. M. Pinedo Dose-Finding Study of the Multitargeted Tyrosine Kinase Inhibitor SU6668 in Patients with Advanced Malignancies Clin. Cancer Res., September 1, 2005; 11(17): 6240 - 6246. [Abstract] [Full Text] [PDF]
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 A. A. Berlin and N. W. Lukacs Treatment of Cockroach Allergen Asthma Model with Imatinib Attenuates Airway Responses Am. J. Respir. Crit. Care Med., January 1, 2005; 171(1): 35 - 39. [Abstract] [Full Text] [PDF]
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 M. V. Khodoun, T. Orekhova, C. Potter, S. Morris, and F. D. Finkelman Basophils Initiate IL-4 Production during a Memory T-dependent Response J. Exp. Med., October 4, 2004; 200(7): 857 - 870. [Abstract] [Full Text] [PDF]
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 J. Cortes, P. Ault, C. Koller, D. Thomas, A. Ferrajoli, W. Wierda, M. B. Rios, L. Letvak, E. S. Kaled, and H. Kantarjian Efficacy of imatinib mesylate in the treatment of idiopathic hypereosinophilic syndrome Blood, June 15, 2003; 101(12): 4714 - 4716. [Abstract] [Full Text] [PDF]
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A. Pardanani, T. Reeder, L. F. Porrata, C.-Y. Li, H. D. Tazelaar, E. J. Baxter, T. E. Witzig, N. C. P. Cross, and A. Tefferi Imatinib therapy for hypereosinophilic syndrome and other eosinophilic disorders Blood, May 1, 2003; 101(9): 3391 - 3397. [Abstract] [Full Text] [PDF]
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Abstract
Introduction
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