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Lung Pharmacology Group, Department of Respiratory Medicine and Allergology, Institute of Internal Medicine, Göteborg University, Gothenburg, Sweden
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The recruitment of neutrophils in the airways involves several cytokines, including the neutrophil activator IL-6 and the neutrophil chemoattractant IL-8 (1, 2, 8, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35). Both IL-6 and IL-8 can be produced by several types of cells present in the airway wall, including airway epithelial and smooth muscle cells, endothelial cells, fibroblasts, and monocytes/macrophages (26, 29, 30, 31, 32, 33, 34, 35). However, the cellular mechanisms that orchestrate the release of IL-6 and IL-8 in the airways are not fully understood.
It is known that subsets of T lymphocytes orchestrate the recruitment of eosinophils in response to allergen in sensitized airways (36). Interestingly, there is also evidence that certain subsets of T lymphocytes orchestrate the recruitment of neutrophils in response to allergen in sensitized airways (36). However, little is known about the molecular mechanism(s) by which subsets of T lymphocytes orchestrate neutrophil recruitment in the airways in response to stimuli other than allergens.
The cytokine IL-17 is a 17-kDa molecule that is produced by CD4+ and CD8+ subsets of T lymphocytes from humans and mice in vitro (37, 38, 39). In a recent study we demonstrated that exogenous human (h)4 IL-17 protein recruits neutrophils in rat airways in vivo, in part via the induced release of a rat correlate to IL-8, macrophage inflammatory protein (MIP)-2 (40, 41). We also demonstrated that the corresponding effect of exogenous hIL-17 on human bronchial epithelial cells in vitro is mediated by induced de novo synthesis and functionally significant release of hIL-8 protein. However, until now it has not been known whether endogenous IL-17 protein is important for the neutrophil recruitment in response to a nonallergic stimuli such as local endotoxin (LPS) exposure in the airways in vivo (8, 42, 43, 44).
For the current study we hypothesized that endogenous IL-17 protein mediates neutrophil recruitment in response to local endotoxin exposure in the airways and that this IL-17 acts in part via the induced release of neutrophil-associated cytokines from cells in the airway wall. We now present evidence supporting this hypothesis, obtained using local exposure to endotoxin from Escherichia coli as a stimulus of neutrophil recruitment in mouse airways in vivo. We also identify inflammatory cells capable of releasing mouse (m)IL-17 protein in response to endotoxin exposure.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We used specific pathogen-free C57BL/6 mice (male, 6–8 wk old, weight range 17–26 g; B&K Universal, Stockholm, Sweden). Mice were kept in individually ventilated racks and received standard laboratory food plus water ad libidum at the Animal Care Facility of Göteborg University (Göteborg, Sweden). The experiments were approved by the Animal Ethics Committee in Göteborg, Sweden (diary numbers 310/98 and 298/01).
Aneasthesia and euthanasia
Before intranasal (IN) or i.p. administration of either endotoxin, cytokines and/or Abs, the mice were transiently anesthetized using CO2 gas (AGA Gas, Göteborg, Sweden). By the end of experiments and before the collection of bronchoalveolar lavage (BAL), blood, and tissue samples, the animals were anesthetized i.p. using a mixture of xylazin (130 mg/kg in 0.1 ml sterile PBS) and ketamine (670 mg/kg in 0.1 ml PBS) (Apoteksbolaget, Göteborg, Sweden). After reaching deep anesthesia, mice were euthanized by opening the chest and bleeding the right ventricle of the heart.
Local endotoxin exposure
Various doses (2–200 µg, depending on experiment, in 25 µl PBS) of endotoxin (LPS, E. coli serotype 055:B5; Sigma-Aldrich, St. Louis, MO) or vehicle (25 µl PBS) were administered IN using a micro pipette (45).
Systemic blockade of IL-17
Twenty-four hours before endotoxin exposure, a specific, monoclonal anti-mIL-17 Ab (anti-IL-17ab; R&D Systems, Abingdon, England) was administered i.p. (3–100 µg of anti-IL-17ab in 0.5 ml of PBS, followed by 0.2 ml of air to ascertain that all Ab solution reached the peritoneal cavity). As control, an isotype Ab (rat (r)IgG2a; BD PharMingen, Heidelberg, Germany) was administered i.p. (100 µg in 0.5 ml of PBS).
Local stimulation with IL-17
Exogenous mIL-17 protein (R&D Systems) was administered IN (3 µg in 25 µl of PBS). This recombinant protein contained <1 ng of endotoxin per mg mIL-17, according to batch analysis by the manufacturer.
Systemic blockade of neutrophil-associated cytokines
Specific, mAbs against mIL-6 and/or MIP-2 (100 µg in 0.5 ml PBS; R&D Systems) and/or corresponding isotype control Abs (rIgG1 for anti-mIL-6 Ab, rIgG2b for anti-MIP-2 Ab) were instilled i.p. 24 h before endotoxin exposure.
Blood samples
Samples of venous blood (0.6 ml) were harvested from the right ventricle of the heart during the euthanasia procedure (described above) by the end of each experiment. Blood smear slides were prepared for each mouse.
Bronchoalveolar lavage
After euthanasia, a tracheotomy was performed and BAL was conducted (2 x 0.25 ml of PBS) via a tracheal cannula. This was followed by gentle aspiration. The recovered BAL suspension was pooled and kept on ice until centrifugation (at 1000 rpm, 10 min, 4°C; using model 5403; Eppendorf-Netheler, Hamburg, Germany). The total number (i.e., concentration) of cells was determined using resuspended cell pellets from BAL suspension. The cell-free BAL fluid supernatant was frozen for later analysis (-84°C).
Cell differential counts in BAL and blood samples
Cell differential counts were performed on cytospin slides prepared from BAL fluid (Cytospin 3; Shandon Life Science, Astmor, U.K.) and on smear slides from blood, using May-Grünwald-Giemsa staining. All slides were evaluated in a microscope (Zeiss Axioplan 2; Zeiss, Jena, Germany) at x1000 magnification. These cell counts were conducted on 400 cells in BAL samples and on 200 cells in blood samples.
Isolation and culture of T lymphocytes and airway macrophages from mice
After euthanasia of mice, we surgically removed the spleen or the lungs and homogenized this tissue. Lungs were perfused with PBS through the pulmonary arteries via the right cardiac ventricle before homogenization. Red blood cells were lysed, and single cells were harvested from the spleen homogenate by filtering them through a 40-µm-cell strainer.
CD3+ lymphocytes were separated using high-gradient magnetic cell separation. Briefly, two methods of selection were used. For positive selection, spleen and lung cells, respectively, were incubated with a monoclonal biotinylated anti-CD3e Ab (clone 145-2C11; BD PharMingen, San Diego) followed by incubation with streptavidin-coupled microbeads (Miltenyi Biotec, Bergisch-Gladbach, Germany). The spleen and lung cells, respectively, were then passed through a column (MACS; Miltenyi Biotec) in a magnetic field, after which the CD3+ lymphocytes were eluated. This procedure resulted in a 95% purity of lymphocytes in the retrieval.
For negative selection of CD3+ spleen lymphocytes, a Pan T cell isolation kit was used according to the manufacturer’s instruction (Miltenyi Biotec). The "non-CD3+ lymphocytes" in spleen homogenate were indirectly magnetically labeled with a mixture of biotin-conjugated mAbs, followed by an anti-biotin mAb conjugated to the microbeads. The unlabeled spleen cells passed through the magnetic field of the column, yielding untouched CD3+ spleen lymphocytes. The purity of these lymphocytes was 88%.
For culture, the CD3+ lymphocytes were seeded (0.5 x 106 cells/well) in a 96-well plate (model 3072; BD Biosciences, Erembodegen, Belgium) in RPMI 1640 supplemented with FCS (10%), penicillin-streptomycin (100 U/ml and 100 µg/ml), sodium pyruvate (1%), and L-glutamine (2 mM) (all from Sigma-Aldrich) with or without airway macrophages.
Airway macrophages were harvested from the same mice as the CD3+ lymphocytes. First, BAL was conducted (4 x 1.0 ml of PBS). Thereafter, centrifugation and resuspension in RPMI 1640 medium (Sigma-Aldrich) followed. BAL cells were then seeded (0.5 x 105/well) into a 96-well plate (above). These cells were incubated (3 h, 5% CO2, 37°C), and the cell medium was then aspirated followed by washing of the cells in RPMI 1640 three times to remove nonadherent cells. This procedure resulted in 87% purity of macrophages among the remaining adherent cells in the retrieval.
Complete supplemented RPMI 1640 medium (above) was added to the cultures. In the experiments on the role of IL-17 in the release of MIP-2 and IL-6 only, a neutralizing anti-mIL-17ab (5 µg/ml; R&D Systems) was then added and incubated for 30 min (46). Finally, the CD3+ lymphocytes, with or without airway macrophages, were exposed to endotoxin (LPS, E. coli serotype 055:B5: 100 ng/ml). Complete RPMI 1640 medium was used as a negative control, and calcium ionophore (CI) A23487 (CI: 1 µg/ml) plus PMA (2 ng/ml) was used as a positive control (all from Sigma-Aldrich). After 20 h of endotoxin exposure, the conditioned media were harvested and frozen (-84°C) for later measurement of IL-17 protein.
Cytokine measurements with enzyme-immunosorbent assay (EIA)
Cellfree BAL fluid supernatants or conditioned media were analyzed using commercially available EIA kits for mIL-6, MIP-2, and IL-17 protein, respectively (R&D Systems). For the measurement of IL-17 in cell-free BAL fluid only, the BAL fluid recovery of 25 mice was pooled for each treatment group. This pooled BAL fluid (10 ml) was then concentrated 60x using ultrafiltration with a 10-kDa cutoff (Centricon Plus-20; Millipore, Bedford, MA). For all cytokines, a concentration below the lowest value of the EIA standard curve was assigned a 0 value.
Detection of IL-17 protein with ELISPOT
Detection of soluble mIL-17 protein released from a coculture of positively selected lung CD3+ cells plus airway macrophages was conducted using ELISPOT assay. Briefly, cell culture plates (M200; ImmunoSpot, Cleveland, OH) were coated overnight at 4°C with a monoclonal anti-mouse capture Ab (clone 50101.111; 5.0 µg/ml; R&D Systems) dissolved in PBS. The plates were then blocked with blocking solution (RPMI 1640 plus 10% FCS plus 100 U/ml penicillin, 100 U/ml streptomycin, all from Sigma-Aldrich).
CD3+ lymphocytes from lung tissue were enriched over a magnetic field as above. The cells were seeded (0.5 x 106 cells/well) in the plates with and without airway macrophages, respectively, in complete medium (RPMI 1640 plus 10% FCS plus 100 U/ml penicillin, 100 µg/ml streptomycin, 100 µg/ml sodium-pyruvate, and 4 mM L-glutamine). One-half of the cultures were stimulated with CI (1 µg/ml) and PMA (2 ng/ml). After 20 h of incubation in 5% CO2 at 37°C, the plates were washed (PBS plus 0.05% Tween 20), and the biotinylated anti-mIL-17 (clone AUS01; 2 µg/ml; R&D Systems) was used to detect the captured extracellular IL-17 protein. Spots were visualized using AV-HPR enzyme and 3-amino-9-ethylcarbazole substrate. The plates were washed in water to stop the reaction. Spots were enumerated using a dissecting microscope at a magnification of x40 (CETI, Antwerpen, Belgium).
Detection of intracellular IL-17 protein with immunohistochemistry (IHC)
IHC staining of intracellular mIL-17 protein was performed in negatively selected spleen CD3+ lymphocytes. The protein release from these cells was blocked using 0.1% GolgiPlug (BD PharMingen) during the last 6 h of culture. The CD3+ lymphocytes were fixed immediately after incubation in 2% formaldehyde, and thereafter cytospin preparations were prepared. The airway macrophage fraction was fixed directly on the culture slides in the same way. The cytospin slides were stored wrapped in aluminum foil at -84°C.
The slides were washed, and endogenous peroxidase was blocked with glucose oxidase solution according to manufacturer’s instructions (Sigma-Aldrich). Dilutions were performed using 0.05% BSA solution in PBS (Sigma-Aldrich), and incubations were performed at room temperature. After blocking unspecific binding using rabbit serum (DAKO, Glostrup, Denmark), the slides were incubated overnight with a monoclonal anti-mIL-17 Ab (BHH01, 10 µg/ml; R&D Systems) or isotype control Ab (rIgG2a, 10 µg/ml; BD PharMingen). After washings, the slides were incubated with rabbit anti-mIgG1-HRP Ab (61-0120; Zymed Laboratories, San Francisco, CA) for 1 h followed by more washing. The Abs were then visualized by the 3,3'-diaminobenzidine-chromogen system (DAKO). After additional washing in distilled water, the preparations were counterstained with Mayer’s hematoxylin (DAKO) and subsequently washed in tap water, dehydrated, and mounted.
Data presentation and statistical analysis
All data are presented as mean (SEM) unless otherwise stated. The Spearman rank correlation was used for correlation analysis of data. Statistical analysis of differences between groups was conducted using the Wilcoxon signed rank test for single, paired comparisons and Mann-Whitney U test for single, unpaired comparisons. A Kruskall-Wallis test preceded the Mann-Whitney U test for multiple comparisons. All p values refer to the Wilcoxon signed rank test or the Mann-Whitney U test. All n values refer to the number of independent experiments for each treatment group, unless otherwise stated.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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IN administration of endotoxin dose dependently increased neutrophils in BAL fluid 24 h after administration (Fig. 1A). According to the dose-response data, 10 µg of endotoxin per mouse should produce a submaximum, reproducible response. Therefore, this dose was used in most subsequent endotoxin exposures.
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Soluble IL-17 protein from T lymphocytes after endotoxin exposure in vitro
As measured with EIA, addition of endotoxin (100 ng/ml) caused a small increase in the concentration of soluble mIL-17 protein in conditioned cell medium from the monoculture of positively selected CD3+ spleen lymphocytes in vitro (Fig. 2A). This was not the case in medium from a monoculture of negatively selected CD3+ spleen lymphocytes (Fig. 2B). However, negatively selected as well as positively selected CD3+ spleen lymphocytes responded to endotoxin (100 ng/ml) when cocultured with airway macrophages, with a clear increase in the concentration of soluble mIL-17 protein (Fig. 2, A and B). For positively selected CD3+ spleen lymphocytes in coculture, this release constituted 107% (17) of the positive control response to CI plus PMA. The corresponding response of negatively selected spleen CD3+ cells in coculture with airway macrophages was 113% (30). The monoculture of airway macrophages did not display any substantial release of soluble mIL-17 protein in the conditioned cell medium after stimulation with CI plus PMA (6.4 (1.5) pg/ml, n = 3).
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IHC staining of intracellular IL-17 protein in negatively selected spleen CD3+ lymphocytes, after coculture with airway macrophages, revealed a higher relative number of IL-17-staining cells after addition of endotoxin than after addition of vehicle (Fig. 3, A and B). Replacing the specific anti-mIL-17ab with an isotype control Ab did not reveal any corresponding unspecific staining of CD3+ spleen lymphocytes (Fig. 3C). In contrast, airway macrophages did not display any specific staining for intracellular mIL-17 protein after coculture with negatively selected CD3+ spleen lymphocytes (Fig. 3, D–F).
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The i.p. administration of a specific anti-mIL-17 Ab dose dependently attenuated the increase in neutrophils in BAL fluid 24 h after administration of endotoxin IN, whereas the isotype control Ab did not (Fig. 4A). This inhibitory effect was selective for neutrophils (Table I). However, the anti-mIL-17 Ab did not cause any corresponding inhibitory effect on the number of neutrophils in BAL fluid (Fig. 4B) 6 h after endotoxin IN. Nor did the anti-mIL-17 Ab produce any substantial effect on the induced increase in neutrophils in blood 24 h after endotoxin IN (Fig. 4C). There was no pronounced difference in the recovery volume of BAL fluid or in the weight of mice for the different treatment groups (data not shown).
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IN administration of exogenous mIL-17 protein markedly increased the number of neutrophils in BAL fluid, from 0.01 (0.00) x 104 neutrophils/ml (vehicle) to 1.79 (0.80) x 104 neutrophils/ml (mIL-17) 12 h after administration, and this effect was statistically significant (p = 0.0005, n = 5–14). In contrast, exogenous mIL-17 did not display any pronounced effect (p > 0.05, n = 5–14) on neutrophils in blood at the same time point (2.05 (0.54) and 2.15 (0.22) x 104 neutrophils/ml after vehicle and mIL-17, respectively).
Neutrophils in BAL fluid and in blood after systemic blockade of neutrophil-associated cytokines
The i.p. administration of either a specific anti-mIL-6 Ab or a specific anti-MIP-2 Ab, or both, markedly reduced the induced increase in neutrophils in BAL fluid (Fig. 5A) harvested 24 h after endotoxin IN. In contrast, these Abs did not exert any corresponding effect on neutrophils in blood (Fig. 5B).
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IN administration of endotoxin markedly increased the concentration of mIL-6 (Fig. 6A) and MIP-2 (Fig. 6B) in cell-free BAL fluid after 24 h. The i.p. administration of a specific anti-mIL-17 Ab before administration of endotoxin IN caused substantial inhibition of this increase in mIL-6 and MIP-2 at 24 h after endotoxin IN (Fig. 6, A and B). In contrast, administration of the anti-mIL-17 Ab i.p. did not cause a corresponding inhibition of mIL-6 (346.7 (143.1) for LPS plus IL-17ab compared with 594.8 (210.1) for LPS plus IgG2a; p > 0.05 and 1.3 (0.5) for the negative control PBS plus IgG2a) or MIP-2 (82.9 (41.8) for LPS plus IL-17ab compared with 174.8 (103.8) for LPS plus IgG2a; p > 0.05 and 3.4 (0.6) for the negative control PBS plus IgG2a) in cellfree BAL fluid (pg/ml) harvested 6 h after administration of endotoxin IN.
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As measured with EIA, blockade with an anti-mIL-17 Ab did not exert any substantial effect on the concentration of either IL-6 (anti-mIL-17 Ab: 4162 (814); and vehicle: 4530 (972) pg/ml) or MIP-2 (anti-mIL-17 Ab: 19525 (6675); and vehicle: 17846 (8300) pg/ml) (p > 0.05, n = 3 for both cytokines) in the conditioned cell medium from the coculture of negatively selected CD3+ spleen lymphocytes plus airway macrophages exposed to endotoxin (100 ng/ml) in vitro.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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It is well known that subsets of T lymphocytes are involved in directing not only cellular but also functional responses to allergen in sensitized airways, leading to the development of bronchial hyperresponsiveness for example (48). Interestingly, there is also evidence that subsets of T lymphocytes are also involved in determining bronchial hyperresponsiveness in nonallergic airways (49). In both cases it appears that at least the CD4+ subset of T lymphocytes plays an important role. Our current in vitro data on lung and spleen T lymphocytes (CD3+) from mice now show that some of these cells are capable of releasing mIL-17 protein in response to endotoxin exposure and, as judged in vitro, this release is substantial (50); the endotoxin-induced IL-17 release from T lymphocytes is comparable to that of the very potent control stimulus CI plus PMA in the positive control group. It appears that this IL-17 release originates from the CD3+ lymphocytes, and this release requires costimulation by APC (airway macrophages). This is because our IHC data on intracellular IL-17 protein show a clear, specific signal in CD3+ lymphocytes, but not in airway macrophages, after these cells were cocultured together in vitro. In support of this, our EIA and ELISPOT data on extracellular IL-17 protein in cell medium show no IL-17 release in the monoculture of airway macrophages, not even after stimulation with the very potent stimulus CI plus PMA. The fact that the monoculture of positively selected CD3+ lymphocytes did display some release of IL-17 protein in direct response to endotoxin exposure is likely to be because of an artifact related to stimulation with CD3+ Abs. Taken together, our in vitro data thus suggest that both T lymphocytes and macrophages can be involved in orchestrating the neutrophil response to endotoxin exposure in the airways through the release of IL-17, even though cellular sources other than T lymphocytes cannot be excluded. In support of T lymphocytes costimulated by airway macrophages being a potential source of IL-17 in the airways in vivo, a recently published study demonstrates an influx of lymphocytes and macrophages precursors (i.e., monocytes) within 6 h after local endotoxin exposure in human airways (51).
For several reasons, it is likely that endogenous IL-17 recruits neutrophils in the airways by stimulating local cells to release neutrophil-associated cytokines in mice in vivo. First, we show that the neutrophil response to local endotoxin exposure in the airways is markedly reduced after systemic administration of a specific Ab against mIL-6 and the mIL-8 correlate MIP-2, respectively, and the combination of these Abs attenuates the neutrophil response in the airways. Second, local endotoxin exposure increases mIL-6 and MIP-2 in the airways in parallel with an increase in neutrophils. Third, systemic administration of a specific Ab against mIL-17 substantially decreases mIL-6 and MIP-2 in the airways 24 h, but not 6 h, after local endotoxin exposure, in parallel with the corresponding effects on neutrophils. Even if there was a trend toward an inhibitory effect of the mIL-17 Ab on mIL-6 and MIP-2, but not on the neutrophils, observed 6 h after endotoxin exposure, this effect was not statistically significant. This particular observation can be explained by a certain time being needed for the endogenously released IL-17 to exert its indirect effect via the induced release of other neutrophil-recruiting cytokines. We also show evidence in vitro that blockade of IL-17 does not affect the mIL-6 or MIP-2 release in conditioned cell medium of an endotoxin-exposed coculture of CD3+ lymphocytes and airway macrophages. This forwards other "nonlymphocyte nonmacrophage" cells as a likely source of the mIL-6 and MIP-2 release caused by IL-17 in airways in vivo. In line with all these findings, it has been shown that hIL-17 stimulates the release not only of IL-8 but also of IL-6 in human bronchial epithelial cells in vitro and that local endotoxin exposure increases both IL-6 and IL-8 in human airways in vivo (26, 51).
In conclusion, our study suggests that endogenous IL-17, presumably released mainly from a subset of T lymphocytes costimulated by airway macrophages, mediates a substantial part of the neutrophil recruitment taking place 24 h after endotoxin exposure in the airways in vivo. Once released in the airways, IL-17 can induce a subsequent release of at least two cytokines known to be of importance for neutrophil recruitment (i.e., MIP-2 and IL-6), probably from local nonlymphocyte, nonmacrophage cells. Indeed, these findings are in line with recent findings published by Ye et al. (52), demonstrating that mice lacking IL-17 receptors are incapable of developing a full neutrophil response to Klebsiella pneumoniae infection in the airways. It thus seems as if IL-17 can constitute a tool for T lymphocytes that orchestrates neutrophil recruitment in mouse airways, and this may be an important mechanism in host defense. If similar mechanisms exist in humans, then IL-17 constitutes a potential target for specific pharmacotherapy against an exaggerated recruitment of neutrophils in inflammatory diseases of the airways and lungs.
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Acknowledgments |
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Footnotes |
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2 M.M. and O.P. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Anders Lindén, Lung Pharmacology Group, Department of Respiratory Medicine and Allergology, Göteborg University, Guldhedsgatan 10A, S-413 46 Gothenburg, Sweden. E-mail address: anders.linden{at}lungall.gu.se
4 Abbreviations used in this paper: h, human; BAL, bronchoalveolar lavage; IN, intranasal; r, rat; m, mouse; MIP, macrophage inflammatory protein; CI, calcium ionophore; EIA, enzyme-immunosorbent assay; IHC, immunohistochemistry.
Received for publication November 14, 2001. Accepted for publication March 10, 2003.
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) or without (
) the presence of airway macrophages from mice. A, Data from positively selected CD3+ lymphocytes. B, Data from negatively selected CD3+ lymphocytes (see Materials and Methods). Data presented as mean with SEM. n = 3–5; *, p < 0.05.
