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ABSTRACT |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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We determined whether neutrophil recruitment induced by the T-lymphocyte cytokine, interleukin-17 (IL-17) is modulated by tachykinins in airways in vivo. Cell recruitment into airways was induced by
either human (h) IL-17 (1 µg) or rat (r) IL-1
(2.5 ng), instilled intratracheally in rats (n = 5 to 7). Six hours after instillation, hIL-17 (3.1 ± 1.2 × 106 cells/ml) and rIL-1 (4.1 ± 0.5 × 106 cells/ml), respectively, induced a significant and selective increase in neutrophil count in bronchoalveolar lavage fluid
(BAL) when compared with vehicle (0.6 ± 0.2 × 106 cells/ml). For hIL-17, this effect was dose-dependent. Inhalation of peptidase inhibitors (phosphoramidon plus captopril) potentiated the effect of
both hIL-17 and rIL-1. Inhalation of a neutral endopeptidase inhibitor (phosphoramidon) alone also
increased the neutrophil count for hIL-17, whereas an angiotensin-converting enzyme inhibitor (captopril) alone did not. A selective neurokinin (NK)-1 receptor antagonist (SR 140333) reduced the
neutrophil count, both with and without phosphoramidon pretreatment. In conclusion, IL-17 selectively recruits neutrophils into rat airways in vivo and this effect is modulated by endogenous tachykinins acting via NK-1 receptors.
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INTRODUCTION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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T-lymphocytes regulate the recruitment of both neutrophilic
and eosinophilic leukocytes into airways (1). For eosinophils, this regulation is in part mediated by secretion of the eosinophil regulatory cytokine, interleukin (IL)-5 (2, 3). However, it
is not clear how T-lymphocytes regulate neutrophil recruitment. It has been hypothesized that this regulation involves proinflammatory cytokines such as tumor necrosis factor (TNF)-
(4), but no study on airways in vivo has actually proven this.
The recently discovered T-lymphocyte cytokine interleukin (IL)-17 may have effects on neutrophil recruitment. IL-17 can be released from activated human peripheral blood CD4+ cells (5). Interestingly, human (h) IL-17 stimulates the secretion of the C-X-C chemokine hIL-8, a neutrophil chemoattractant, in primary, synovial, and skin fibroblasts from humans (5, 6). Also, hIL-17 stimulates the expression of the neutrophil-preferring adhesion molecule, intercellular adhesion molecule-1 in skin fibroblasts (5). A recent study demonstrated specific receptors for IL-17 in the airways (7). Thus, if released into the airways, IL-17 could link the activation of T-lymphocytes to neutrophil recruitment in airways.
Tachykinins, such as substance P (SP) and neurokinin A (NKA) are colocalized in unmyelinated, sensory nerves of the airways (8). These nerves end close to the bronchial, lining epithelium, and endogenous SP and NKA may modulate neutrophil recruitment into the airways (8). However, the role of tachykinins in selective, cytokine-induced neutrophil recruitment into the lower airways is not known.
In this study, we examined whether the T-lymphocyte hIL-17
can recruit neutrophils into lower airways in vivo and we compared its neutrophil recruiting capacity with that of rat (r) IL-1. We also determined the role of endogenous tachykinins in
neutrophil recruitment caused by hIL-17.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals
Pathogen-free male Sprague-Dawley (SD) rats weighting 250 to 300 g were obtained from B&K Universal AB (Stockholm, Sweden). Animals were maintained on a standard laboratory food with water ad libitum. The current experiments were approved by the Comittee for Animal Experiments of Göteborg University (DNo 134/95).
Intratracheal Instillation of hIL-17 and rIL-1
Rats were anaesthetized with 1 mg/kg of a 3:2 mixture of 50 mg/ml
ketamine hydrochloride (Parke-Davis Scandinavia, Stockholm, Sweden) and 20 mg/ml xylazine chloride (Bayer Sverige AB, Gothenburg, Sweden) intramuscularly. The trachea was intubated with a cannula (O.D. 2.76 mm, Portex; Smith Kline Industries, Betchworth, Surrey, UK). Rats were placed in a supine position with the head elevated. Using a micropipette and an intravenous catheter inserted through the intubation cannula, 106 µl of phosphate-buffered saline (PBS) solution containing either various doses (0.01, 0.1 and 1 µg) of recombinant hIL-17 or 2.5 ng of recombinant rIL-1 (R&D Systems Europe
Ltd, Abingdon, UK) or corresponding vehicle was injected and
flushed with 3 ml of air to deliver the solution to the lung. The dose of
rIL-1 was chosen based upon separate dose-response experiments in
our SD rat model (Hoshino and coworkers, unpublished data). Separate experiments showed that the drug solution was distributed evenly
from the trachea to small bronchi, using this intratracheal instillation
procedure. The negative control animals received the vehicle of the
cytokines. This vehicle consisted of sterile PBS with 0.21% bovine serum albumin (BSA)(Grade V; Sigma Chemical Co., St. Louis, MO)
and 0.1 ng lipopolysaccharide (LPS) (Escherechia coli serotype O55:
B5; Sigma Chemical) because each cytokine per se contains a small
amount of LPS (< 0.1 ng/µg of cytokine according to the manufacturer). After intratracheal instillation, the rats were allowed to regain consciousness.
Bronchoalveolar Lavage
Bronchoalveolar lavage fluid (BAL) was obtained 6 h after the intratracheal instillation of cytokines or corresponding vehicle. After receiving 300 mg/kg pentobarbital sodium (Apoteksbolaget, Umeå,
Sweden) intraperitoneally, which is a lethal dose, a tracheal cannula
(10 mm long and 2.7 mm internal diameter) was inserted into the upper cervical trachea through a tracheotomy. BAL was collected in a
plastic tube on ice after gentle, manual instillation and withdrawal of
4 ml of sterile PBS five times using a syringe through the intratracheal
cannula (20 ml total volume). There was no significant difference in
BAL recovery volume between groups. The fluids were centrifuged
(200 × g for 10 min at 4° C), and the cell pellet was resuspended in
washing buffer containing sterile PBS with 0.35% BSA and 0.1% glucose. Total BAL cell counts were determined in a hemocytometer using Türk solution. For differential BAL cell counts, cytospin preparations were stained with May-Giemsa. Differential cell counts were
conducted according to standard morphology criteria using oil immersion microscopy (magnification: ×1,000). Cell counts were carried out
on 300 cells, and the absolute number of each cell type was calculated.
The cell-free BAL was collected and stored at 
80° C.
Peptidase-inhibition versus Neutrophil Recruitment
Induced by hIL-17 or rIL-1
The combination of the selective neutral endopeptidase (NEP) inhibitor phosphoramidon (0.4 mM, 60 breaths; Sigma Chemical Co.) and the selective angiotensin-converting enzyme (ACE) inhibitor captopril (4.6 mM, 60 breaths; Sigma Chemical Co.) or vehicle (0.9% saline, 60 breaths) was inhaled as an aerosol 30 min prior to intratracheal instillation of each cytokine or the corresponding vehicle (12).
In separate experiments, phosphoramidon or captopril or vehicle was inhaled, as described above, prior to intratracheal instillation of hIL-17 or the corresponding vehicle. Aerosols were generated with an ultrasonic nebulizer (Model 2511 PulmoSonic; DeVilbiss Co, Somerset, PA), and were administered intratracheally through a cannula using a ventilator system (Model 50-1718; Harvard Apparatus Ltd., South Natik, MA)
Neurokinin Receptor Antagonism versus Neutrophil Recruitment Induced by hIL-17
The selective NK-1 receptor antagonist, SR 140333 (S)-1-{2-[3-(3,4-dichlorophenyl)-1-(3-isoproxyphenylacetyl)piperidin-3-yl]ethyl}-4-phenyl-1-azoniabicyclo[2.2.2]octane chloride (13) and the selective
NK-2 receptor antagonist, SR 48968 (S)-N-methyl-N[4-(4-acetylamino-4-phenyl piperidino)-2-(3,4-dichlorophenyl)butyl]benzamide (14) were utilized. SR 140333 and SR 48968 were kindly donated by
Dr. Xavier Emonds-Alt (Sanofi Recherche, Montpellier, France). These compounds were stored in ethanol (20° C, 2 mM) and were diluted in saline (0.9%) to a final ethanol concentration of 0.67% for
SR 140333 and 0.35 % for SR 48968. Either 1 mg/kg SR 140333 or 0.31 mg/kg SR 48968 was administered intraperitoneally 30 min prior to
the intraperitoneal instillation of hIL-17 (15). Control animals received the corresponding vehicle (same volume of ethanol in saline).
For both SR 140333 and SR 48968, respectively, the described experiments were repeated in separate rats receiving pretreatment with inhalation of phosphoramidon 30 min prior to the intraperitoneal instillation of hIL-17.
rIL-1 level in BAL
Levels of rIL-1 (pg/ml) in BAL from rats treated with hIL-17 (1 µg)
or the corresponding vehicle were assessed using ELISA (R&D Systems Europe Ltd) for rIL-1.
Data Analysis
Experiments were conducted with a randomized, matched design; animals from the same batch were utilized for intervention and control experiments in parallel during the same experimental day. Data are expressed as mean ± SEM. Statistical differences between groups were evaluated using Student's t test (unpaired one- or two-way) in the case of two groups. Analysis of variance (Kruskal-Wallis followed by Mann-Whitney U-test) was used in the case of more than two treatment groups. The relationship between the dose of IL-17 and the neutrophil count was analyzed using Spearman's rank correlation. A standard statistical package (StatView, Abacus Concept, Berkeley, CA) and a Macintosh computer (Apple Computer Inc, Cupertino, CA) were utilized. A p value less than 0.05 was regarded as significant.
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RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Intratracheal Instillation of hIL-17 and rIL-1
Intratracheal instillation of hIL-17 induced a selective and significant increase of the neutrophil count in BAL (Figure 1A) and this increase was dose-dependent (Figure 2). In contrast, intratracheally administered hIL-17 induced no significant increase in macrophage, eosinophil, or lymphocyte counts in
BAL (Figure 1A). Similar to that of hIL-17, intratracheally instilled rIL-1 induced a selective and significant increase of
the neutrophil count in BAL (Figure 1B). The increase in neutrophil count induced by 1 µg of hIL-17 (6.3 nmol) displayed a
similar order of magnitude as that induced by 2.5 ng of rIL-1
(14.7 pmol).
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Peptidase-inhibition versus Neutrophil Recruitment
Induced by hIL-17 or rIL-1
Inhalation of phosphoramidon plus captopril significantly enhanced the neutrophil count in BAL, for rats receiving hIL-17 or rIL-1 instilled intratracheally (Figure 3). In contrast, the eosinophil count was not enhanced by inhalation of the peptidase inhibitors prior to intratracheally instilled hIL-17. The
eosinophil count in BAL was 0.003 ± 0.002 × 106/ml, using inhalation of vehicle, and 0.001 ± 0.001 × 106/ml, using inhalation of phosphoramidon plus captopril prior to hIL-17 instillation. Correspondingly, the eosinophil count was 0.008 ± 0.008 × 106/ml, using inhlation of vehicle, and 0.004 ± 0.002 × 106/ml,
using inhalation of phosphoramidon plus captopril prior to intratracheal instillation of rIL-1. Inhalation of phosphoramidon alone significantly enhanced the neutrophil count in BAL
(Figure 4), whereas inhalation of captopril did not, in rats receiving intratracheal instillation of hIL-17.
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Selective NK-receptor Antagonism versus Neutrophil Recruitment Induced by hIL-17
Pretreatment intraperitoneally with the selective NK-1 receptor antagonist SR 140333 attenuated the neutrophil count in BAL, in rats given hIL-17 intratracheally (Figure 5A). In contrast, intraperitoneal pretreatment with the selective NK-2 receptor antagonist SR 48968 did not attenuate the neutrophil count in BAL in rats given hIL-17 intratracheally (Figure 5B). The specific effect of SR 140333, but not that of SR 48968, was even more pronounced after pretreatment with phosphoramidon (Figure 6A).
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rIL-1 Level in BAL
Measuring rIL-1 in BAL, we found no significant difference
(p > 0.05, n = 9) for hIL-17- versus vehicle-treated rats (hIL-17: 65.8 ± 7.51 pg/ml, versus vehicle: 63.6 ± 8.02 pg/ml).
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DISCUSSION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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This study shows that intratracheal instillation of hIL-17
causes dose-dependent neutrophil recruitment into airways
and this recruitment is enhanced by selective inhibition of
NEP and it is attenuated by NK-1-receptor antagonism in SD
rats in vivo. The study also shows that the selective neutrophil-recruiting effect of hIL-17 is mimicked by rIL-1, although
hIL-17 per se does not increase rIL-1.
Mucosal biopsies from patients with newly diagnosed asthma display an increased number of neutrophils and lymphocytes (16). A significant number of neutrophils has also been observed in the sputum of asthmatic patients during obstructive exacerbations, with or without infections, indicating a role for neutrophils in acute airway inflammation (17, 18). There is also corresponding evidence of the role of neutrophils in chronic airway inflammation; samples from patients with chronic bronchitis who smoke display an increased number of neutrophils and T-lymphocytes in the vicinity of mucosal glands when compared with asymptomatic smokers (19). Hypothetically, activated neutrophils may induce hypersecretion in bronchial glands via the release of the potent secretagoge neutrophil elastase (20), but little is known about the mechanistic relationship between the T-lymphocytes and neutrophils.
We now demonstrate that the neutrophil recruitment induced by intratracheal instillation of the T-lymphocyte cytokine hIL-17 is dose-dependent and as selective as it is for the
species homologue macrophage cytokine rIL-1 in rat airways
in vivo. It has previously been demonstrated that hIL-1 recruits neutrophil in rat airways and mouse air pouch (21, 22).
Our observation that IL-1 was not increased by IL-17 instilled intratracheally argues against IL-17 recruiting neutrophils via IL-1. Because CD4+ and CD8+ cells constitute the
only known sources of IL-17 (5, 23), our findings indicate
that IL-17 can link the activation of T-lymphocytes to neutrophil recruitment.
On a molar basis, the potency of hIL-17 is weaker than that
of rIL-1 in inducing neutrophil recruitment in rat airways in vivo. Hypothetically, this difference in potency could be attributed to species heterogenity. However, separate experiments (Hoshino and colleagues, unpublished data) have confirmed that mouse (m) IL-17 and hIL-17 are equipotent in the
rat and that mIL-17 and rIL-17 display a 90% amino acid homology and a highly conserved glycosylation site (24). This
does not point out species heterogeneity as an explanation of
why hIL-17 is less potent than rIL-1 in the airways. It is possible that IL-17 is less potent than IL-1 because of its mechanism of action, which may involve release of other neutrophil-recruiting mediators, but this mechanism does not involve
secondary release of IL-1.
We also demonstrated that the neutrophil recruitment induced by hIL-17 is significantly depressed by endogenous
NEP (EC 3.4.24.11, enkephalinase). We did this by showing
that pretreatment with combined inhibition of NEP of ACE
(EC 3.4.15.1, kininase I) as well as inhibition of NEP alone
enhances neutrophil recruitment. In contrast, we found that
inhibition of ACE alone had no such effect. Both NEP and
ACE degrade endogenous peptides and may be important in
regulating various inflammatory responses in the airways (12,
24). Our study therefore indicates that endogenous peptides are involved in modulating the neutrophil response to hIL-17 as well. This modulation may be universal for neutrophil-recruiting cytokines because we found that combined inhibition of NEP of ACE enhanced neutrophil recruitment induced by hIL-17 as well as that induced by rIL-1. In support
of our findings, previous studies have indicated that neutrophil recruitment is depressed by NEP, using stimuli other than
cytokines (11, 27). The fact that NEP is located mainly in the
lining airway epithelium, whereas ACE is located mainly in
vascular endothelium within the airway wall (24, 25, 28), also
makes NEP the more likely candidate of the two for modulation of neutrophil recruitment into the airways. Thus, if secreted in the airways by T-lymphocytes, IL-17 probably releases peptides primarily from nerve endings close to the
lining epithelium, where these peptides can subsequently be
degraded by NEP.
It has previously been reported that NEP, in addition to
ACE, may regulate blood pressure via degradation of SP and
bradykinin (29). To minimize the risk of such indirect, unspecific effects on neutrophil recruitment, we administered the
peptidase inhibitors locally, by inhalation. The results of our
study also provide several arguments against such unspecific
effects. First, the combined pretreatment with inhibitors of
NEP and ACE did not significantly alter the neutrophil count
under baseline conditions (i.e., rats receiving the vehicle of IL-17 alone; see METHODS). Second, the very low eosinophil count
in BAL from rats treated with hIL-17 or rIL-1 was not increased by inhibition of NEP plus ACE. This contrasts to the
neutrophil count and it is unlikely that a significant change in
blood pressure would affect the neutrophil count and leave
other types of cell counts unaltered. Third, in the case of hIL-17,
inhibition of NEP, but not inhibition of ACE, increased neutrophil recruitment similarly to inhibition of NEP plus ACE. If an unspecific mechanism would be the case, then inhibition of ACE, located in vascular endothelium, should cause more
effect than inhibition of NEP. Fourth, a bradykinin receptor
antagonist inhibited neutrophil recruitment induced by IL-1
in a previous study, and tachykinins are known to mediate
bradykinin responses (30).
We also found that a selective NK-1 receptor antagonist attenuates the neutrophil recruitment by hIL-17, whereas a selective NK-2 antagonist does not. This specific effect of NK-1
receptor antagonism was even more evident in rats pretreated
with the NEP inhibitor phosphoramidon, suggesting that the
neutrophil response to hIL-17 is modulated by endogenous
tachykinins acting mainly via NK-1 receptors. In this context,
the dominating tachykinin is likely to be substance P (SP), because NK-1, NK-2, and NK-3 receptors are primarily targeted
by SP, NKA, and NKB, respectively (31, 32). We find it unlikely that the lack of effect of the NK-2 antagonist was due to
a too low dose because we utilized a dose that has clear anti-inflammatory effects in vivo (14, 32). The effect of the NK-1
receptor antagonist also argues against the hypothetical possibility that NEP degrades IL-17 protein per se. Peptidase degradation of rIL-1 appears unlikely as well, because NEP does
not hydrolyze human IL-1 (33).
The inhibitory effect on neutrophil recruitment caused by the NK-1 receptor antagonist was partial (25 to 40%). It is therefore possible that other peptide mediators, in addition to endogenous tachykinins, are involved in modulating the neutrophil response to hIL-17 in airways in vivo. Bradykinin, for example, may play a role in modulating the neutrophil response to hIL-17, because tachykinins are associated with bradykinin-induced airway responses (34, 35).
Although no previous study has focused on cytokine-induced neutrophil recruitment into the lower airways, several previous studies support the idea that endogenous tachykinins (possibly SP) modulate neutrophil recruitment. In rat airways, SP potently increases adhesion and transvascular migration of neutrophils (24). SP also induces neutrophil chemotaxis both in vivo (36) and in vitro for human (37) and rat (38) cells, respectively. In addition, a NK-1 receptor antagonist reduces the number of neutrophils in airways after allergen challenge in sensitized mice (39). In rats, a NK-1 receptor antagonist even blocks neutrophil adhesion (9). Taken together, all these findings are compatible with tachykinins (possibly SP) modulating neutrophil recruitment into the airways by acting on NK-1 receptors.
In conclusion, this study on rats has shown that the T-lymphocyte cytokine IL-17 selectively and dose-dependently can recruit neutrophils into airways in vivo and this effect is modulated by endogenous tachykinins acting mainly on NK-1 receptors. If a similar mechanism exists in human airways, NK-1 receptor antagonists may be effective in treating airway inflammation involving neutrophils.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Anders Lindén, M.D., Ph.D., Lung Pharmacology Group, Guldhedsgatan 10A, S-413 46 Gothenburg, Sweden.
(Received in original form June 2, 1998 and in revised form November 3, 1998).
Acknowledgments: The writers gratefully acknowledge the technical assistance of Carina Malmhäll. They also thank Sanofi Recherche, Montpellier, France for the kind donation of SR 140333 and SR 48968.
Supported by Göteborg University, The Hermann Krefting Foundation against Asthma and Allergy, The Swedish Heart and Lung Foundation, The Swedish Medical Research Council (K97-04X-09-04-8-08A, U1268), The Swedish Medical Society, and The Vårdal Foundation. No support, direct or indirect, was obtained from the tobacco industry. SR 140333 and SR 48968 donated by Sanofi Recherche, Montpellier, France.
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References |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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