 on Eosinophil Activation In Vitro
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Abstract |
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Abstract
Introduction
References
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Increased concentrations of tumor necrosis factor-
(TNF-), interleukin (IL)-4, and IL-13 have been
measured in bronchoalveolar lavage fluid (BALF) of patients with asthma following allergen provocation.
In addition, these cytokines have also been reported to activate eosinophils in vitro. Although cytokine interactions have been postulated in the activation of eosinophils, the combined effects of cytokines on eosinophil activation remain poorly understood. Because activation of eosinophils has been regarded as a
crucial event in the pathogenesis of asthmatic inflammation, we tested the hypothesis that IL-4 and IL-13
could enhance the effects of TNF- on eosinophil activation. For this purpose, eosinophils from normal
donors were purified and cultured in the presence of IL-4 or IL-13 and TNF-. Eosinophil survival and
surface expression of CD69 were assessed by flow cytometry. There was a concentration- and time-dependent upregulation in CD69 expression as well as eosinophil survival when eosinophils were incubated with
IL-13, IL-4, or TNF-. However, eosinophil viability and CD69 expression increased synergistically when
eosinophils were incubated with IL-13 or IL-4 in the presence of TNF-. This synergistic effect of IL-4
and IL-13 on CD69 expression was not limited to TNF- but was also observed with IL-5. Our study provides evidence that IL-4 can activate eosinophils in a similar fashion as does IL-13. Furthermore, this
study shows that the addition of IL-4 or IL-13 to TNF- or IL-5 has synergistic effects on eosinophil activation, suggesting that the combined effects of different cytokines present in BALF following allergen
provocation can enhance eosinophil activation in vitro.
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Introduction |
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Abstract
Introduction
References
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Increased numbers of endobronchial eosinophils are a
hallmark of bronchial asthma, and the concept that eosinophils play a crucial role in chronic asthmatic inflammation
is generally accepted. Activation of eosinophils is therefore
regarded as a crucial step in the initiation and maintenance
of asthmatic inflammation as well as other diseases associated with atopy. Eosinophil numbers have been correlated
with airflow obstruction (1) and bronchial hyperreactivity
(2). The precise mechanisms regulating eosinophil activation in vivo remain unclear. Following allergen provocation in allergic asthma, an increase in eosinophils can be
observed in the bronchoalveolar lavage fluid (BALF),
where eosinophil numbers correlate with activated T lymphocytes and interleukin (IL)-5 as well as granulocyte-
macrophage colony-stimulating factor (GM-CSF) concentrations (3). Accordingly, IL-5 and GM-CSF have been implicated in the regulation of eosinophil recruitment and
activation (4). However, a number of other cytokines
can be measured in increased concentrations following allergen provocation. Accordingly, mean concentrations of
191.6 pg/ml of IL-4, 8.3 pg/ml of IL-13, and 44.9 pg/ml of
tumor necrosis factor (TNF)- have been measured in unconcentrated BALF 18 h after allergen challenge (7) and might therefore contribute to the regulation of eosinophil
activation and survival in vivo. Recently, it has been
shown that eosinophil chemotaxis can be stimulated by
IL-4 (8), and eosinophil survival and activation can be enhanced by IL-13 (9). Both cytokines also selectively induce
vascular cell adhesion molecule (VCAM)-1 expression on
endothelial cells in vitro (10, 11) and may promote the antigen-induced, VCAM-1/very late antigen-4-dependent recruitment of eosinophils into tissue (12). TNF- represents another cytokine that has been shown to influence eosinophil activation in vitro (13). TNF- that can also be
measured in increased concentrations in the lungs of patients with intrinsic bronchial asthma (17), as well as in allergic asthma following allergen provocation (3), is secreted by alveolar macrophages and mast cells, but also
eosinophils (18), and has multifunctional properties including the induction of cell adhesion molecule expression, including that of intercellular adhesion molecule (ICAM)-1,
endothelial cell leukocyte adhesion molecule-1, and VCAM
on endothelial cells (22).
On the basis of the observation of the in vivo generation of multiple cytokines associated with activation of
eosinophils in vitro, we compared the effects of IL-4, IL-13, and TNF- on eosinophil activation in vitro. Furthermore, we tested the hypothesis that IL-4 or IL-13 in combination with TNF- might augment eosinophil activation.
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Materials and Methods |
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Reagents, Cytokines, and Antibodies
Percoll was obtained from Pharmacia (Uppsala, Sweden);
phosphate-buffered saline (PBS) and RPMI from Seromed
(Berlin, Germany); fetal calf serum (FCS) from Gibco (Paisley; UK); rhIL-4, rhIL-5, rhIL-13, and rhTNF- from Bioconcept (Umkirch, Germany); L-glutamine, penicillin, streptomycin, ethylenediaminetetraacetic acid (EDTA), and
propidium iodide were purchased from Sigma (Deisenhofen, Germany), phycoerythrin (PE)-conjugated anti-Leu 23 (CD69) from Becton-Dickinson (Heidelberg); PE-conjugated anti-immunoglobulin (Ig)G from Dako (Hamburg);
CD16-microbeads and a magnetic cell separation system (MACS) from Miltenyi Biotec (Bergisch-Gladbach, Germany).
Purification of Eosinophils
Eosinophils were obtained from 100 ml EDTA-blood of
healthy donors. Cells were separated according to a modified procedure initially described by Hansel and coworkers (25). Shortly after this, blood was diluted 1:1 with PBS
and 22-ml aliquots were overlayered onto a 20-ml isotonic
Percoll solution (density 1.080 g/ml) in 50 ml tubes and
centrifuged for 30 min at 1,000 × g and 4°C. Differential cell counts were performed using Kimura stain. After centrifugation, the supernatant was removed and the mononuclear cells at the interface were aspirated. Erythrocytes
and platelets were removed by hypotonic lysis (0.2% NaCl
for 30 s). The granulocytes were washed twice in PBS containing 2% FCS. Eosinophils were separated by negative selection of neutrophils, using the MACS. The pellet was
resuspended in 1 ml PBS/2% FCS, the number of granulocytes was counted, and 5 µl of CD16 microbeads per 1 × 107 neutrophils were added. Cells and microbeads were incubated for 30 min at 4°C with occasional mixing. The cell
suspension was added onto the top of the separation column. Eosinophils were eluted with ice-cold PBS/2% FCS
under magnetic influence. After separation, cells were
washed twice in PBS/2% FCS. The purity of eosinophils
was 
97%, with some contaminating of mononuclear cells,
as assessed by Kimura staining.
Cell Culture
Culture medium consisted of RPMI 1640 supplemented with 10% heat-inactivated FCS, 2 mM L-glutamine, 100 IU/ml penicillin, 100 µg/ml streptomycin, and 2% N-2-hydroxyethylpiperazine-N'-ethane sulfonic acid (Hepes). Eosinophils (1 × 106 cells/ml) were cultured at 37°C in a humidified atmosphere with 5% CO2 either in culture medium alone or in the presence of cytokines. Before immunofluorescence labeling, the cells were washed twice in PBS/2% FCS.
Survival Assay
Survival of cultured eosinophils was assessed with propidium iodide. Cells (5 × 104) were washed once in PBS/2% FCS and resuspended in 100 µl of a propidium iodide solution (0.5 µg/ml dissolved in PBS). The relative proportion of viable to nonviable cells was determined by flow cytometry after analysis of at least 2,000 cells.
Flow Cytometric Analysis of CD69 Cell Surface Antigen
Expression of CD69 on eosinophils was measured as follows: 20 µl of cell suspension (5 × 104 cells) were incubated with 10 µl of PE-conjugated CD69 and PE-conjugated anti-IgG, respectively, for 30 min on ice. The cells were then washed once in PBS/2% FCS and resuspended in 100 µl of a propidium iodide solution (0.5 µg/ml in PBS). Flow cytometry was performed on at least 2,000 cells from each sample with a FACScan (Becton Dickinson, Heidelberg, Germany). To include only viable cells in the analysis, propidium iodide-positive, nonviable cells were excluded by appropriate gating in a separate fluorescence channel (FL3). Furthermore, PE-conjugated anti-CD69-antibodies were measured only on viable, propidium iodide negative cells (channel FL2). Nonspecific fluorescence was determined by incubating cells with mouse IgG of the same isotype but with irrelevant antigen specificity. The specific mean fluorescence (SMF) for each population was determined by subtracting the nonspecific fluorescence from the mean fluorescence measured with anti-CD69 antibody.
Statistical Analysis
Unless stated otherwise, the data in the text and figures are expressed as mean ± SEM. Comparisons between groups were performed using Wilcoxon's signed-rank test for paired samples. Statistical significance was assumed at P < 0.05.
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Results |
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Induction of CD69 Expression on Eosinophils by IL-13 and IL-4
When purified eosinophils were labeled with anti-CD69 antibody, expression of CD69 surface antigen was generally not detectable. However, there was a low-level induction of CD69 expression when isolated blood eosinophils (5 × 104 cells/ml) were cultured for 6 h (2.35 ± 0.81 SMF) in medium (Figure 1). Incubation of purified eosinophils with increasing concentrations of IL-4 or IL-13 (between 1 and 100 ng/ml) for 6 h caused a concentration-dependent increase in CD69 surface expression (Figure 1). In contrast to the effects of IL-4 on CD69 expression, which reached a maximum at 10 ng/ml, there was a linear increase in CD69 expression following incubation of eosinophils with IL-13 over the dose range investigated. CD69 surface expression increased after incubation of eosinophils with 1, 10, and 100 ng/ml IL-13, to 5.1 ± 1.5, 8.03 ± 1.81, and 9.82 ± 2.03 SMF, respectively. In comparison, IL-4 used in the same concentrations increased the CD69 surface expression to 8.18 ± 2.01, 8.93 ± 1.69, and 8.92 ± 1.98 SMF, respectively (Figure 1). The observed differences in CD69 expression following incubation with IL-4 and IL-13 were consistently significantly different when compared with unstimulated control cells (each P < 0.01).
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The time-dependent kinetics of cytokine-induced CD69 expression on eosinophils were studied in a separate set of experiments. For this purpose, eosinophils were incubated in the presence of 10 ng/ml IL-13 or IL-4 for 6 and 24 h, after which CD69 expression was analyzed. Following incubation with IL-13, the SMF for the CD69 expression increased to 6.8 ± 1.29 after 6 h and 4.18 ± 1.06 SMF after 24 h, which was significantly different from control cells (P < 0.01). Similar results were obtained following incubation with IL-4; SMF for CD69 reached 6.87 ± 1.24 after 6 h and 3.99 ± 0.81 after 24 h (P < 0.001 compared with control cells). In contrast, there was only a minor change in the CD69 expression on control eosinophils incubated in medium alone (1.23 ± 0.55 SMF after 6 h and 1.46 ± 0.58 SMF after 24 h) (Figure 2a).
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Coincubation of TNF- with IL-4 and IL-13
Compared with IL-13 or IL-4, the effects of 10 ng/ml TNF-
on CD69 expression were less pronounced (3.57 ± 0.82 SMF after 6 h and 3.61 ± 1.07 SMF after 24 h of incubation), but were still significantly elevated compared with
unstimulated control cells (P < 0.01) (Figure 2a). However, when eosinophils were incubated in the presence of
either IL-4 or IL-13 with TNF-, a synergistic upregulation of CD69 expression was observed. As shown in Figure 2a, CD69 surface expression on eosinophils following incubation with 10 ng/ml of TNF- and 10 ng/ml IL-13 increased to 13.21 ± 2.11 SMF after 6 h of incubation and remained at 9.68 ± 1.99 SMF after 24 h. Almost identical
results for CD69 expression were obtained when IL-4 (10 ng/ml) was used (13.84 ± 2.21 SMF after 6 h incubation
and 10.83 ± 2.37 SMF after 24 h). The observed differences in CD69 expression following coincubation of eosinophils with IL-4 or IL-13 in combination with TNF-
consistently reached statistical significance when compared
with CD69 expression measured after incubation with
IL-4, IL-13, or TNF- alone (each P < 0.01).
In a separate set of experiments, the observed synergistic effects of IL-4 or IL-13 with TNF- on CD69 expression were compared with those of IL-5, a potent activator
of eosinophils. As shown in Figure 2b, incubation of eosinophils with IL-5 alone increased CD69 expression significantly over that of control cells (P < 0.01, n = 11). However, there was a further, statistically significant increase
in CD69 expression when IL-4 or IL-13 was added to IL-5 (Figure 2b, P < 0.01). Figure 3 displays representative histograms of the IL-4- and IL-13-induced CD69 expression
with or without TNF- or IL-5.
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The synergistic effects of IL-4 or IL-13 and TNF- on
CD69 expression were also demonstrated in a concentration-dependent fashion when increasing concentrations of
TNF- ranging from 0.1 to 100 ng/ml were added to either
IL-4 or IL-13 (each 10 ng/ml) (Figure 4). CD69 expression
on cultured eosinophils increased from 1.63 ± 1.13 SMF
for cells incubated in medium alone to 5.86 ± 1.73 SMF
when cells were cultured in the presence of 100 ng/ml TNF-
(P < 0.05). In contrast, CD69 expression was markedly
upregulated when cells were incubated with IL-4 or IL-13
(each 10 ng/ml) (10.32 ± 1.84 SMF for IL-4 and 9.58 ± 2.16 SMF for IL-13). This increase in CD69 expression was
dose-dependently enhanced to 18.88 ± 4.88 SMF for IL-4
and 19.73 ± 4.01 SMF for IL-13 when TNF- (100 ng/ml) was added. This was statistically significant when compared
with cells incubated with IL-4 or IL-13 alone (P < 0.05, except for 0.1 ng/ml TNF-, where P = 0.18) (Figure 4).
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Influence of TNF- on IL-13- and IL-4-enhanced
Eosinophil Survival
To substantiate further the activating effects of IL-4 or
IL-13 and TNF- on cultured eosinophils, cell viability was
measured following incubation of eosinophils (5 × 104/ml)
in RPMI over 4 d in the absence or presence of IL-13 or
IL-4 (10 ng/ml each) alone or in combination with TNF-
(10 ng/ml). Eosinophil viability was assessed by propidium
iodide exclusion measured by flow cytometry. After 4 d in
culture, there were only 15.5 ± 4.0% viable eosinophils
present in culture. In contrast, when eosinophils were cultured in the presence of IL-13 or IL-4 (10 ng/ml each), survival after day 4 was increased to 26.0 ± 5.0% and 24.5 ± 4.6% (each P < 0.001), respectively. In comparison, eosinophil survival following incubation with TNF- alone was 18.9 ± 4.1%, which was not statistically significantly different from cells incubated in medium alone. However, costimulation of eosinophils with IL-13 or IL-4 in the presence
of TNF- (10 ng/ml each) increased survival of eosinophils
after 4 d in culture to 37.1 ± 5.3% and 37.3 ± 5.5% (each
P < 0.001), respectively (Figure 5). Thus, the mean change
in eosinophil survival expressed as percentage of unstimulated control cells was 21.9% for TNF-, 67.7% for IL-13,
and 58.1% for IL-4, whereas the coincubation of IL-13 or
IL-4 in the presence of TNF- increased the mean number of viable cells corrected for the appropriate control by
139.4% and 140.6%, respectively.
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Discussion |
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In this study, we investigated the effects of IL-13, IL-4, and
TNF- on eosinophil survival and CD69 expression. Because eosinophil viability in vitro decreases rapidly in the
absence of eosinophil-activating cytokines, the observed
increase in eosinophil viability following incubation with
cytokines added to cell cultures is suggestive of eosinophil-activating properties. Similarly, induction of CD69 expression on eosinophils has been reported as an indication of eosinophil activation (26). Therefore, our results, which
show an increase in eosinophil viability as well as CD69
expression on cultured eosinophils, enlarge on previous
observations in which we have reported that IL-13 can increase eosinophil survival and CD69 expression in vitro
(9) by demonstrating similar results for IL-4. Therefore, to
the best of our knowledge, this is the first report showing
that IL-4 can directly activate normal eosinophils and our
findings challenge a recent report in which eosinophil survival was enhanced following incubation with IL-13 but
not with IL-4 (27). The reasons for these differences remain unclear. In a different study, an increase in eosinophil chemotaxis has been reported for eosinophils from
patients with atopic dermatitis following incubation with
IL-4, which, however, was not observed with eosinophils
from normal donors (8). With respect to eosinophil viability and CD69 expression as markers for eosinophil activation, we were not able to substantiate these differential
findings for IL-4 and IL-13. Thus, in our hands, IL-4 as well
as IL-13, both of which have been implicated in the regulation of IgE synthesis (28), were able to induce eosinophil activation and could thus influence the humoral as well
as the cellular arm of allergic hypersensitivity reactions.
TNF-, another cytokine present in elevated concentrations following allergen provocation in allergic asthma,
has been shown to increase expression of ICAM-1 on cultured eosinophils from normal donors (13, 14). Furthermore, incubation of eosinophils from normal donors induced CD4 (16) and the release of reactive oxygen species
(15). Here, we report that incubation of eosinophils with
TNF- has a weak effect on eosinophil survival as well as CD69 expression. These effects of TNF- on eosinophils
were consistently weaker than those of IL-4 and IL-13.
Interestingly, when eosinophils were incubated with a
combination of either IL-4 or IL-13 and TNF-, there was
a marked, synergistic upregulation of eosinophil activation
as measured by CD69 expression. This increase in eosinophil activation compared favorably with the effects of IL-5,
and we were able to show an additional effect of IL-4 or
IL-13 to that of IL-5. Although the increase in CD69 expression by eosinophils following incubation with IL-5 was
significantly higher than that observed following stimulation with IL-4 or IL-13 and TNF-, our results demonstrate that IL-4 and IL-13 can further enhance CD69 expression even in the presence of a potent activator of
eosinophil function such as IL-5. In addition, eosinophil
survival was enhanced when IL-4 or IL-13 was incubated
with TNF-, supporting the hypothesis that TNF- can enhance eosinophil activation by IL-4 and IL-13. Similar effects have not been reported previously for eosinophils.
A synergistic effect of IL-13 and TNF- has recently
been shown for the induction of VCAM-1 on endothelial
cells in vitro (31, 32). Similar results have been obtained
for IL-4 (33). Because VCAM-1 appears to be crucial for
the selective recruitment of eosinophils and lymphocytes
to the site of inflammation in allergic diseases (12), and
can be upregulated synergistically by IL-4 or IL-13 and
TNF-, our results provide evidence that the combination
of IL-4 or IL-13 with TNF- also has direct activating effects on eosinophils.
IL-13, as well as IL-4 and TNF-, can be found in elevated concentrations following allergen provocation in allergic asthma (3, 34). It has been proposed that these
cytokines are produced locally in the bronchoalveolar
compartment by several cell types following allergen provocation (34, 36). Therefore, our results suggest that
different cytokines present in elevated concentrations in
BALF following allergen provocation, especially IL-4, IL-13, and TNF-, can contribute synergistically to activate
eosinophils. Even though these effects might not reach the
magnitude of the classic eosinophilopoietins IL-3, IL-5,
and GM-CSF, our results provide evidence that the combination of other cytokines might also contribute to the activation of eosinophils in allergic asthma.
In this study, we have shown that there is no difference
in the effects of IL-13 and IL-4 on human eosinophils from
normal donors. Because IL-13 and IL-4 share common receptor subunits, it can be speculated that the effects are
mediated by similar receptor-dependent pathways. In contrast to our findings, differential effects for IL-4 and IL-13
have been reported for IL-1Ra production by neutrophils
(39). Although in this study IL-4 synergized with TNF- to
induce IL-1Ra production by human neutrophils, IL-13 did not modulate TNF--induced IL-1Ra production (39).
Thus, although the effects of IL-4 or IL-13 in combination
with TNF- are almost identical with respect to eosinophil
activation and endothelial cell adhesion molecule expression, differential effects of these cytokines might be operant on other cell populations.
In conclusion, we provide evidence that IL-4 and IL-13
have similar effects on eosinophil activation, and that these
effects can be synergistically enhanced by TNF-. Because
these cytokines have been measured in increased concentrations following allergen provocation in asthma, it can be
speculated that these cytokines could contribute to the orchestration of eosinophil inflammation in allergic asthma.
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Footnotes |
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Address correspondence to: Dr. rer. nat. Werner Luttmann, Department of Pneumology, Medical University Clinics, Hugstetter Str. 55, 79106 Freiburg, Germany. E-mail: LUTTMANN{at}PNM1.UKL.UNI-FREIBURG.DE
(Received in original form February 9, 1998 and in revised form June 17, 1998).
Abbreviations: bronchoalveolar lavage fluid, BALF; fetal calf serum, FCS; granulocyte-macrophage colony-stimulating factor, GM-CSF; immunoglobulin, Ig; interleukin, IL; phosphate-buffered saline, PBS; phycoerythrin, PE; specific mean fluorescence, SMF; recombinant human, rh; tumor necrosis factor-, TNF-; vascular cell adhesion molecule-1, VCAM-1.
Acknowledgments: The authors thank Ms. S. Bock for her expert technical assistance. This work was supported by a grant from the Forschungskommission der Universitätsklinik Freiburg and from the Bundesministerium für Bildung, Wissenschaft, Forschung, und Technologie (FKZ 01 GC 9701/7).
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Abstract
Introduction
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