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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 91 No. 5 (March 1), 1998:
pp. 1527-1532
Secretoneurin, a Novel Neuropeptide, Is a Potent Chemoattractant
for Human Eosinophils
By
Stefan Dunzendorfer,
Peter Schratzberger,
Norbert Reinisch,
Christian M. Kähler, and
Christian J. Wiedermann
From the Laboratory of Intensive Care Medicine, the Division of
General Internal Medicine, the Department of Medicine, University of
Innsbruck, Innsbruck, Austria.
 |
ABSTRACT |
Secretoneurin (SN), a 33-amino acid neuropeptide, is derived from
secretogranin II that is released from sensory afferent C-fibers by
capsaicin. Described functions of secretoneurin include chemotaxis of
monocytes and endothelial cells, and inhibition of endothelial cell
proliferation. Inhibition of monocyte chemotaxis by staurosporine
indicated involvement of specific signaling pathways. We have tested
effects of SN, substance P (SP), and interleukin-8 (IL-8) on eosinophil
migration in modified Boyden chambers including signaling mechanisms of
neuropeptide and cytokine stimulation of human eosinophils. Experiments
showed SN as eosinophil chemoattractant comparable in its potency to
IL-8. Checkerboard analysis, usage of a specific anti-SN-antibody, and
receptor desensitization experiments confirmed the chemotactic
activity. Preincubation of the cells with effective concentrations of
staurosporine or tyrphostin-23 showed no effect, whereas treatment with
wortmannin (WTN) or 3-isobutyl-1-methylxantin (IBMX) completely blocked
SN-induced migration. Additionally, experiments ruled out
tyrphostin-23- and WTN-sensitive signaling pathways for
SP-induced chemotaxis of eosinophils. We conclude that
SN-stimulated human eosinophil chemotaxis is mediated via a unique and
specific signal transduction pathway that involves activation of
phosphodiesterases and WTN-sensitive enzymes, ie, phospholipase D and
phosphatidylinositol-3-kinase. In contrast, we report that activation
of the latter and tyrosine kinases is required for
SP-induced chemotaxis of eosinophils.
| |
INTRODUCTION |
SENSORY NEUROPEPTIDES are small amino
acid molecules released from the afferent c-fibers of peripheral nerve
endings.1 Several peptides have been identified and in
accordance with the involvement of primary afferent nerve fibers in
neurogenetic inflammation,2 the sensory neuropeptides have
been identified as potent mediators of inflammatory and immunologic
reactions. Moreover, small quantities of some of the peptides, eg,
substance P (SP), have been detected in peritoneal mast cells,
platelets, and eosinophils, indicating that sensory neuropeptides may
also be obtained from nonneuronal sourses during an inflammatory
response.3
Secretoneurin (SN) is a newly discovered 33-amino acid peptide derived
from secretogranin II (chromogranin C).4 It is widely distributed throughout the central and peripheral nervous systems and
can be coreleased with SP and calcitonin gene-related peptide from
sensory afferent c-fibers by capsaicin,5 suggesting that it
might represent another member of the group of inflammatory neuropeptides. SN may in fact be a regulator of neurogenic inflammation since it was shown to increase monocyte but not lymphocyte chemotaxis, to deactivate neutrophil chemotaxis, and to affect fibroblast, endothelial, and smooth muscle cell migration.6-9 Recently,
a receptor for SN has been identified (manuscript
submitted)*, but less is known about
mechanisms involved in signaling and cell activation by SN.
Many substances including chemokines, neuropeptides, complement
fragments, and eicosanoids have been shown to attract
eosinophils10-13 or to promote their transendothelial
migration.14 With regard to the above-mentioned properties
of SN and the knowledge of neuropeptide-induced alteration of
eosinophil functions, we investigated the effects of SN on the
chemotaxis of human eosinophils, known as prominent inflammatory cells
thought to play a major role in the pathogenesis of allergic diseases,
and we compared its effects with SP and the cytokine interleukin-8
(IL-8). For reasons of comparison we performed additional experiments
with RANTES, a well-known potent eosinophil chemotaxin, and
formyl-Met-Leu-Phe (fMLP), and  -endorphin, as another neuropeptide.
Checkerboard analysis, usage of specific antibodies, and receptor
desensitization experiments served to reveal the specific effect of SN
on eosinophil directed migration (chemotaxis). Furthermore, we studied
possible signaling pathways in human eosinophils following receptor
ligation by the substances investigated.
| |
MATERIALS AND METHODS |
Reagents.
RPMI 1640 with phenol-red was from Biological Industries (Kibbutz Beit
Haemek, Israel). Bovine serum albumin (BSA) was from Behring Werke AG
(Marburg, Germany). SP, IL-8, 3-isobutyl-1-methylxantin (IBMX),
wortmannin (WTN), staurosporine, and tyrphostin-23 were from Sigma
Chemical Corp (St Louis, MO). Human SN was purchased from Neosystems
(Strassbourgh, France) and anti-human SN-antibody was a gift from R. Fischer-Colbrie (Institut of Pharmacology, University of Innsbruck).
Monoclonal mouse-anti human IL-8 antibody was from Serotec Ltd (Oxford,
UK). MACS magnetic microbeads were from Miltenyi Biotec (Bergisch
Gladbach, Germany), and nitrocellulose filters (5-µm pore size) were
from Sartorius AG (Goettingen, Germany). All stock solutions, except
staurosporine and tyrphostin-23, were stored at  20°C before use.
All other reagents not further specified were from Sigma.
Isolation of eosinophils.
For preparation of eosinophils we used MACS (magnetic cell sorting)
CD16 microbeads according to the manufacturer's protocol for isolation
of untouched human eosinophils by depletion of CD16+ cells.
In brief, granulocytes were obtained from buffy coats (mixed with Hanks' balanced salt solution [HBSS]
without Ca2+ and Mg2+ in a ratio of 3:1) by
dextran sedimentation and centrifugation through a layer of
Ficoll-Hypaque (Nycomed Pharma AS, Oslo, Norway). To
remove most of the mononuclear cells this step was
performed twice and was followed by hypotonic lysis of contaminating
erythrocytes using sodium chloride solution.15 After
washing, cells were resuspended in 50 µL/5 × 107 cells
ice-cold MACS buffer (phosphate-buffered saline [PBS] with 5 mmol/L
EDTA and 0.5% BSA) and an equal volume of MACS colloidal superparamagnetic microbeads conjugated with monoclonal anti-human CD16
antibodies was added for an incubation time of 30 minutes at 6°C.
Recommended volumes of ice-cold MACS buffer were added to the
cell/microbead mixture and the cell suspension was loaded onto the top
of the prewashed separation column. The eluate containing CD16 eosinophils was collected, washed, and resuspended
in RPMI 1640/0.5% BSA. To increase sensitivity, the separation
procedure was repeated. Purity of sorted eosinophils was greater than
98%, as determined by morphology and FACS analysis. Contaminating
cells were less than 1% lymphocytes, less than 1% neutrophils and
basophils, and monocytes/macrophages at neglectible cell counts.
Eosinophil chemotaxis.
Chemotaxis assays were performed using a modified 48-well Boyden
microchemotaxis chamber (Neuroprobe, Bethesda, MD) in which a 5-µm
pore-sized cellulose nitrate filter separates the upper and lower
chamber.16 Eosinophils were resuspended in RPMI 1640/0.5% BSA to a final concentration of 1 × 106 cells/mL and 50 µL of the cell suspension was placed into the upper chamber.
Eosinophils were allowed to migrate toward various concentration
gradients of the soluble chemoattractants in the lower chamber for 60 minutes. For checkerboard analysis cells were resuspended in RPMI
1640/0.5% BSA containing various concentrations of SN just before
transferring them to the upper chamber. To ensure the specific
chemotactic effect of SN, a specific anti-human
SN-antibody (dilution 1:1,000) or a monoclonal mouse
anti-human IL-8 antibody (10 µg/mL) was added to the chemoattractants
in the lower chamber. With the same intention eosinophils were
pretreated with SN (0.1 µmol/L) for 10 minutes before they migrated
toward chemoattractans. Further to investigate the effects of enzyme
blockade, eosinophils were incubated with staurosporine (10 ng/mL),
tyrphostin-23 (10 ng/mL), WTN (10 nmol/L), and IBMX (1 µmol/L),
respectively, for 30 minutes at 37°C in humidified atmosphere (5%
CO2). After washing twice, the assay was proceeded as
described above. After the migration period the nitrocellulose filters
were dehydrated, fixed, and stained with hematoxylin-eosin. Migration
depth of the cells into the filters was quantified by microscopy,
measuring the distance (µm) from the surface of the filter to the
leading front of cells. Random migration was less the 60 µm in all
experiments. Data are expressed as "Chemotaxis Index," which is
the ratio between the distance of directed and undirected migration of
eosinophils into the nitrocellulose filters.
Statistical analyses.
Data are expressed as mean and standard error of the mean (SEM) of the
"Chemotaxis Index." Means were compared by Kruskal-Wallis analysis of variance and by Mann-Whitney U-test. A difference with
P < .05 was considered to be significant. Statistical
analyses were calculated using the StatView software package (Abacus
Concepts, Berkley, CA).
| |
RESULTS |
Migration toward various concentrations of soluble chemoattractants.
Freshly prepared eosinophils were allowed to migrate toward various
concentrations of SN (0.1 pmol/L to 10 µmol/L), SP (0.01 pmol/L to 1 µmol/L), or IL-8 (1 fmol/L to 0.1 µmol/L) for 60 minutes at 37°C
in humidified atmosphere. The dose-response curve for each
chemoattractant occured as bell-shaped with a maximal response at a
concentration of 0.1 µmol/L of SN, 0.1 nmol/L of SP, and 1 nmol/L of
IL-8. The lowest doses tested were not able to produce a significant
migration. Increasing statistical significance of migration was
observed for increasing concentrations, except the highest, of SN and
IL-8 (Fig 1, left panel). For comparison,
various concentrations of RANTES (1 fmol/L to 0.1 µmol/L), fMLP (0.01 pmol/L to 1 µmol/L) or -endorphin (0.01 pmol/L to 1 µmol/L) were also used as chemoattractants. RANTES-induced chemotaxis reached significance at a concentration of 0.1 pmol/L and peaked at 1 nmol/L.
Eosinophils responded to fMLP, but to a lesser extent as compared to
SN. Maximal migration was seen at 10 nmol/L with a chemotaxis index
roughly equal produced by a concentration two logarithmic decades below
the concentration of maximal response to SN. High-dose -endorphin
slightly stimulated eosinophil migration, but none of the
concentrations tested excerted statistically significant migration
toward -endorphin (Fig 1, right panel).
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| Fig 1.
Migration of eosinophils into nitrocellulose
micropore filters (5-µm pore size) toward various concentrations of
soluble chemoattractants. Various concentrations of SN (0.1 pmol/L to
10 µmol/L), SP (0.01 pmol/L to 1 µmol/L), IL-8 (1 fmol/L to 0.1 µmol/L) (left panel), RANTES (1 fmol/L to 0.1 µmol/L), fMLP (0.01 pmol/L to 1 µmol/L), or -endorphin (0.01 pmol/L to 1 µmol/L)
(right panel) were placed in the lower wells of a modified Boyden
chamber. RPMI 1640/0.5% BSA served as control to determine random
migration. Thereafter 50 µL of human eosinophils at 1 × 106 cells/mL were added to the upper wells and were allowed
to migrate for 60 minutes at 37°C (humidified atmosphere; 5%
CO2). After fixing and staining of the filters migration
depth was quantified microscopically. Data are expressed as mean ± SEM of the "Chemotaxis Index," which is the ratio between the
distance cells migrate toward test substances and that toward control
medium. n = 6. Statistical analyses: Mann-Whitney U-test after
Kruskal Wallis analysis of variance (P < .01); n.s., not
significant; *, P < .05; **, P < .01.
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|
Checkerboard analysis for SN-induced chemotaxis.
To distinguish between SN-induced chemokinesis (increased random
migration) and chemotaxis (directed movement of cells along a
chemotactic gradient) we performed a checkerboard analysis. Eosinophils
were resuspended in medium or medium containing various concentrations
of SN (0.01 nmol/L to 0.1 µmol/L) just before transferring the cells
to the upper chamber. Addition of 0.1 µmol/L of SN exclusively to the
upper compartment resulted in a slightly enhanced migratory response of
eosinophils. A gradually increasing concentration gradient of SN
between the lower and the upper compartment led to increased and highly
significant migration of the cells toward the lower compartment,
uncovering the migratory response of eosinophils to SN as true
chemotaxis (directed migration) (Table 1).
Specifity of SN-induced chemotaxis.
To prove the specificity of the effect of SN on eosinophils, cells were
allowed to migrate toward chemoattractants alone or chemoattractants in
combination with a specific anti-human SN-antibody (dilution 1:1,000)
or a monoclonal mouse anti-human IL-8 antibody in the lower chamber. As
shown in Fig 2 (left panel), the
SN-antibody was able to block the migratory response to SN (0.1 µmol/L). The IL-8 antibody also nearly completely reduced
IL-8-induced chemotaxis, whereas combinations of the antibodies with
non-antibody-specific targets had no effect on SN-, SP-, and
IL-8-induced eosinophil chemotaxis (Fig 2, left panel).
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| Fig 2.
Specifity of SN on eosinophil chemotaxis into
nitrocellulose micropore filters (5-µm pore size). Maximal effective
concentrations of SN (0.1 µmol/L), SP (0.1 nmol/L), or IL-8 (1 nmol/L) with or without SN-antibody (dilution 1:1,000) and anti-human
IL-8 antibody (10 µg/mL), respectively, were placed in the lower
wells of the chamber. RPMI 1640/0.5% BSA alone or with each antibody
served as control. Thereafter 50 µL of human eosinophils at 1 × 106 cells/mL were added to the upper wells and were allowed
to migrate for 60 minutes at 37°C (humidified atmosphere; 5%
CO2) (left panel). In another set of experiments cells
were pretreated with SN (0.1 µmol/L) for 10 minutes, washed twice,
and thereafter allowed to migrate towards chemoattractants or medium
(right panel). After fixing and staining of the filters migration depth
was quantified microscopically. Data are expressed as mean ± SEM of
the "Chemotaxis Index," which is the ratio between the distance
cells migrate toward test substances and that toward control medium. n
= 6. Statistical analyses: Mann-Whitney U-test after Kruskal Wallis analysis of variance (P < .01); n.s., not significant; *,
P < .05; **, P < .01.
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|
For verification of receptor-regulatory pathways for SN mediated
effects, eosinophils were pretreated with 0.1 µmol/L of SN for 10 minutes or remained untreated. After washing twice, cells migrated
toward chemoattractants. A difference in the migratory response between
the treated and the untreated group was observed only for chemotaxis
toward SN (0.1 µmol/L) but not toward SP, IL-8, RANTES, and fMLP (Fig
2, right panel).
Effects of enzyme-blockers on eosinophil chemotaxis.
For this purpose, eosinophils were treated either with staurosporine
(10 ng/mL), tyrphostin-23 (10 ng/mL), WTN (10 nmol/L), or IBMX (1 µmol/L) or remained untreated for control. After an incubation period
of 30 minutes, cells were washed twice. Staurosporine, itself a weak
stimulator of migration, had no effect on the migratory response
induced by all agents tested. Random migration as well as SN (0.1 µmol/L)- and IL-8 (1 nmol/L)-induced chemotaxis remained unaffected
by pretreatment of eosinophils with tyrphostin-23. In contrast, SP (0.1 nmol/L)-induced chemotaxis was reduced to baseline levels by this
tyrosine kinase blocker (Fig 3, left
panel). WTN and IBMX showed no effect on random migration and
IL-8-induced chemotaxis, whereas only WTN completely reduced
SP-induced migration. Both drugs highly significant reduced cells
response to SN, with higher potency of WTN as compared to IBMX (Fig 3,
right panel).
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| Fig 3.
Effects of enzyme blockers on eosinophil chemotaxis into
nitrocellulose micropore filters (5-µm pore size). Eosinophils
remained untreated or were treated for 30 minutes at 37°C (humidified
atmosphere 5% CO2) with staurosporine (10 ng/mL),
tyrphostin-23 (10 ng/mL) (left panel), WTN (10 nmol/L), or IBMX (1 µmol/L) (right panel). After washing twice, 50 µL of human
eosinophils at 1 × 106 cells/mL were added to the upper
wells and were allowed to migrate for 60 minutes at 37°C (humidified
atmosphere; 5% CO2) toward chemoattractants or medium
control. After fixing and staining of the filters migration depth was
quantified microscopically. Data are expressed as mean ± SEM of the
"Chemotaxis Index," which is the ratio between the distance cells
migrate toward test substances and that toward control medium. n = 6. Statistical analyses: Mann-Whitney U-test after Kruskal Wallis analysis
of variance (P < .01); n.s., not significant; *, P < .05; **, P < .01.
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| |
DISCUSSION |
Neutrophils and eosinophils are the major classes of granulocytes that
emigrate from the bloodstream but their accumulation patterns in
inflammed tissue are strikingly different; neutrophils are rapidly
recruited into sites of acute bacterial infection, whereas eosinophils
are predominantly recruited into tissues with allergic inflammation or
parasitic infection.17 Leukocyte chemotaxis is a complex
phenomenon that includes polarization and orientation in the direction
of the highest concentration of the chemoattractant; nevertheless,
signal transduction pathways that mediate this complicated process are
not yet fully understood.18
The goal of our study was to rule out whether and by which mechanisms
SN, a novel neuropeptide, elicits eosinophil chemotaxis. First we
compared a panel of chemoattractants, including SN, for elicitation of
chemotaxis of eosinophils in vitro. Our results are in accordance with
findings published previously for eosinophil Boyden chamber- and
transendothelial-chemotaxis.12,19-21 Since it has been
shown that eosinophils isolated with MACS, in contrast to the density
gradient centrifugation method involving cell activation with fMLP,
exerted stronger chemotactic response toward
chemoattractants,22 it was not surprising that the cells in
our system migrated well, even toward gradients of fMLP. For these
reasons it is certain that results obtained for SN-induced chemotaxis
on eosinophils in our chemotaxis measurement system are reliable.
Moreover, results indicate that SN, as compared to RANTES which shows a
similar efficacy on eosinophils as the strong chemotactic agonist
C5a,19 is a potent stimulator of eosinophil chemotaxis. In
fact, a specific anti-human SN antibody was able to completely suppress
the chemotactic response to SN, confirming SN as an independent
chemoattractant.
There is considerable literature published on homologous and
heterologous desensitization to one chemoattractant by another but most
previous studies have focused on assays other than chemotaxis. In
eosinophils, contrasting to neutrophils, the chemotactic movements induced by fMLP, C5a, or RANTES were not reduced at any concentration by the presence of one of the other chemoattractants. Also,
postreceptor signaling pathways are independent and not desensitized by
each other, indicating at least three noninterfering receptor-signal transduction pathways for chemotaxis and actin polymerization in
eosinophils.21
Preincubation of the cells with an effective concentration of SN for 10 minutes led to a highly significant inhibition of SN-induced but not
SP-, IL-8-, RANTES-, or fMLP-induced migration indicating
homologous SN receptor downregulation in eosinophils. This result is a
hint to a unique and independent receptor and receptor signaling
mechanism for SN in eosinophils apart from the noninterfering
receptor-signal transduction pathways for chemotaxis mentioned above.
Therefore, signal transduction pathways of SN were further
investigated.
Many studies focused on the intracellular signaling pathways in
eosinophils and described mechanisms involved in superoxide production
and granular secretion23-25 but only few were focused on
eosinophil migration.26-28 Addition of staurosporine to
eosinophils slightly stimulated migration in our study, not
surprisingly, since Schweizer et al26 have reported that
staurosporine increases the F-actin content in eosinophils, and that
PAF-induced chemotaxis and IL-5-induced chemokinesis are independent
of protein kinase A and protein kinase C activation.26 The
latter finding is in accordance with our observations, where
staurosporine failed to influence SN-, SP-, as well as IL-8-induced
chemotaxis. Tyrphostin-23, a selective tyrosine kinase inhibitor,
blocked SP-induced chemotaxis, which is mediated via specific tyrosine
kinase-coupled SP receptors.7 Growth factor-stimulated
chemotaxis of neutrophils can be diminished by WTN, a
phosphatidylinositol-3-kinase (PI3-kinase) and phospholipase D (PLD)
inhibitor, whereas it lacks this effect on neutrophil migration
stimulated with classical chemoattractants.29 In
eosinophils, we obtained similar results because WTN was able to reduce
the chemotactic response toward SN and SP, but not toward IL-8. For affecting cAMP levels in eosinophils we inhibited phosphodiesterase with IBMX, which is reported to inhibit eosinophil's responses with
IC50 values equal to the range of the IC50 values obtained with
rolipram (type IV-selective).30 Moreover, an in vivo study on the selective type IV phosphodiesterase inhibitor T-440 showed higher potency of the drug in eosinophils rather than in
neutrophils.31 Others showed a lack of type III- and type
V-selective inhibitors to suppress the chemotactic responsiveness of
rat eosinophils in vitro28 and guinea pig eosinophils in
vivo.32 To our knowledge, effects of phosphodiesterase
inhibitors on eosinophil functions are described only for PAF,
leukotriene B4, eotaxin, and C5a activation of the
cells.27,28,33 We now observed that IBMX is able to diminish SN-induced migration of eosinophils with no effect on SP or
IL-8 stimulation, suggesting that SN uses signal transduction pathways
involving cyclic AMP. Additionally we show that SP involve tyrosine
kinase and WTN-sensitive enzymes for intracellular signaling in
eosinophil chemotaxis.
In conclusion, SN is a potent stimulator of eosinophil chemotacic
response, which is mediated via a unique and specific signal transduction pathway that is different from what is described so far
and can be affected by phosphodiesterases and WTN-sensitive enzymes,
potentially due to PI3-kinase or PLD inhibition. Furthermore, our
results suggest that activation of the latter and tyrosine kinases is
required for SP-induced chemotaxis of eosinophils. Since
phosphodiesterase IV inhibitors has been successfully used in animal
models for therapy of eosinophil-related diseases,32,34 and
the potent chemotactic activity of SN on eosinophils can be blocked by
phosphodiesterase inhibition, this novel neuropeptide might play a role
in some of these in vivo models.
| |
FOOTNOTES |
Submitted October 30, 1997;
accepted December 10, 1997.
*
Specific binding sites for 125I-BHSN were identified on
human MonoMac 6 cells. Scatchard analysis: single class binding
site with kd = 7.3 nmol/L and
Bmax of 322 fmol/mg protein.
Supported by the Austrian Science Funds (Grant No. 09977 to C.J.W.).
Address reprint requests to Christian J. Wiedermann, MD, Department of
Internal Medicine, University of Innsbruck, Anichstrasse 35, A-6020
Innsbruck, Austria.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be here-by marked
"advertisement" in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
| |
ACKNOWLEDGMENT |
The authors thank R. Fischer-Colbrie, PhD, for providing the anti-SN
antibody and fruitful discussions.
| |
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Abstract
Introduction
Abstract