1 Institute for Immunology, 2 Medical Policlinic, Klinikum Innenstadt, and 3 Institute for Prophylaxis and Epidemiology of Cardiovascular Disease, University of Munich, 80336 Munich, Germany
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ABSTRACT |
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Strenuous, anaerobic exercise leads to an increase
of leukocytes that are mobilized from the marginal pool. We have
analyzed in human peripheral blood the effect of exercise on the number of CD14+CD16+ monocytes as determined by
two-color immunofluorescence and flow cytometry. We show herein that
this type of monocyte responds with a dramatic up to 4.8-fold increase.
Mobilization does not occur after 1 min at 100 or 200 W but 1 min at
400 W leads to a twofold increase of the
CD14+CD16+ monocytes immediately after
exercise. The numbers remain high at 5 min and gradually decrease to
reach the initial level at 20 min postexercise. After 20 min of rest,
the CD14+CD16+ monocytes can be mobilized again
by a second exercise. The CD14+CD16+ monocytes
appear to be mobilized from the marginal pool where they preferentially
home because of a higher expression of adhesion molecules like CD11d
and very late antigen-4. Exercise goes along with an increase
of catecholamines, and mobilization of the
CD14+CD16+ monocytes can be substantially
reduced by treatment of donors with the -adrenergic receptor blocker
propranolol. Mobilization of CD14+CD16+
monocytes by a catecholamine-dependent mechanism may contribute to the
increase of these cells in various clinical conditions.
glucocorticoid; marginal pool; stress
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INTRODUCTION |
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WITH THE USE OF CD14 and CD16 antibodies, human monocytes can been divided into two populations. The majority of cells is CD14 strongly positive (CD14++) and CD16 negative, and it represents what previously had been addressed as monocytes. Cells expressing CD14 at low levels together with the CD16 molecule, i.e., the CD14+CD16+ monocytes, usually comprise 10% of all monocytes (21, 29). These cells have distinct properties like a high expression of major histocompatibility complex class II and a lower level of CD11b and CD33 when compared with the CD14++ monocytes. With regard to cytokine production, CD14+CD16+ monocytes are efficient producers of the proinflammatory tumor necrosis factor, but they produce no or only little of the anti-inflammatory interleukin-10 (8). We therefore have addressed these cells as proinflammatory monocytes. This designation fits well with the finding that these cells are strongly elevated in inflammatory diseases like bacterial infections (18), including sepsis (3, 5). Also the CD14+CD16+ monocytes were found to be increased in patients postmajor cardiac surgery, patients that showed features of system inflammation without infection (7).
On the other hand, Gabriel et al. (10) reported that brief periods of exercise will increase low CD14 monocytes by a factor of 2. We have analyzed this observation in detail to elucidate the mechanism of increase. We could demonstrate an average 3.5-fold increase in the number of CD14+CD16+ monocytes by 1 min of excessive exercise. These data show that, under resting conditions, the majority (>75%) of the CD14+CD16+ monocytes are not in peripheral blood, but they reside in the marginal pool.
We hypothesized that the exercise-induced increase is mediated by adrenal hormones. In fact, our blocking studies show that mobilization of the CD14+CD16+ monocytes is mediated in part by catecholamines. The rapid mobilization of these cells into the central pool under conditions of stress may serve to provide a large population of active cells for defense at sites of injury and infection.
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MATERIALS AND METHODS |
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Volunteers.
Volunteer participants for the study were recruited from laboratory
staff and from the students of the University of Munich. The
participants were apparently healthy males, aged 32.1 ± 7.6 yr.
For studies involving blockade of -adrenergic receptors, participants were subject to a medical examination, including electrocardiogram, and written informed consent was obtained from eligible subjects. For treatment with high-dose glucocorticoids, volunteers were subjected to a medical examination, including clinical
chemistry for liver and kidney function and blood differential. After
written informed consent, glucocorticoids, i.e., 250 mg methylprednisolone (Urbason solubile; Hoechst-Marion-Roussel, Bad
Soden, Germany), were administered intravenously over a 15-min period
on three consecutive days. The study was cleared by the Ethics
Committee of the Medical Faculty, University of Munich. Volunteers did
not take any medication in the preceding 4 wk.
Forms of exercise. For the first type of exercise employed in our study, participants were asked to run at the highest possible speed from the basement to the roof in a stairway consisting of 129 stairs with a total height of 21.3 m. The average time required for the task was 36 s (range 35-37 s). The calculated work ranged from 426 to 506 W depending on the body weight of the participant. Blood was drawn before and immediately after the exercise.
For a graded and defined workload, we used a home trainer bike (Ergo-bike; Daum-Electronic, Veitsbronn, Germany) equipped with an eddy current brake for selection of different levels of exercise intensity. Duration of exercise ranged from 45 s to 2 min at 100, 200, or 400 W. For continuous sampling, participants received a permanent venous access (Venflow 2; Ohmeda, Helsingborg, Sweden) that was kept open by slow infusion of a balanced salt solution. Blood was drawn before and at 1, 5, 10, and 20 min after the exercise. For the study of blockade ofLeukocyte analysis. Two-milliliter EDTA-blood samples were taken. The total leukocyte count was determined with a cell dyne counter (Abbott, Wiesbaden, Germany). For determination of monocyte populations, 100-µl blood samples were washed one time with PBS and then admixed with the CD14 antibody My-4 conjugated to FITC (no. 6603511; Coulter Electronics, Krefeld, Germany) and with the CD16 antibody B73.1 conjugated to phycoerythrin (no. 347617; Becton Dickinson, Heidelberg, Germany) at saturating concentrations. After incubation for 20 min on ice, the erythrocytes were lysed, and cells were analyzed using a fluorescence-activated cell-sorter (FACS, Becton Dickinson). Compensation was adjusted using the two control stains. With scatter gates around leukocytes, we acquired 5,000 CD14+CD16+ monocytes plus CD14++ monocytes according to the green/yellow analysis. Percentages of the CD14+CD16+ monocytes and the CD14++ monocytes were calculated from the two-color plot. Absolute number of monocytes per microliter of blood was calculated based on the cell dyne number and the FACS scatter gate for all leukocytes.
For three-color immunofluorescence, whole blood samples were stained with two different combinations. For detection of CD11d, anti-CD11d (antibody 217L, kindly provided by W. Michael Gallatin and Darcey Clark, ICOS, Bothell, WA), or the respective isotype, control was employed for a first incubation on ice for 20 min. After cells were washed, goat anti-mouse-Ig-FITC (no. M35001; Medac, Hamburg, Germany) was added for 20 min. Next, mouse IgG (no. M-9269; Sigma, Munich, Germany) was added at 50 µg/ml, followed by addition of anti-CD14 antibody My-4 conjugated to phycoerythrin (no. 6603262; Coulter) plus anti-CD16 antibody conjugated to the energy-transfer complex PC-5 (no. 1851; Coulter/Immunotech). After a final 15-min incubation, erythrocytes were lysed. For detection of very late antigen-4 (VLA-4) and CD62L, the reagents anti-VLA-4 (no. 0764; Coulter-Immunotech, Hamburg, Germany) and anti-CD62L (no. 347440; Becton Dickinson) or the respective isotype control was employed for a first incubation on ice for 20 min and then cells were washed. Goat anti-mouse-Ig-Tricolor (no. 35006; Medac) was added for 20 min. Next, mouse IgG (no. M-9269; Sigma) was added at 50 µg/ml, followed by addition of anti-CD14 My-4-FITC and anti CD16-phycoerythrin. After a final 15-min incubation, erythrocytes were lysed. In FACS analysis for both types of staining, gates were set around the two monocyte populations in the two-color plot for CD14 and CD16, and the signals for the third marker were analyzed in single-parameter histograms. Here the specific median fluorescence intensity was calculated by subtracting the median for the isotype control from the median for the specific antibody. With the type of data processing used herein, an increase of the fluorescence intensity by 77 channels reflects a doubling of antigen expression.Lactate.
Blood was drawn in a sodium-heparin vacutainer (Becton Dickinson) and
centrifuged immediately at 4°C, and plasma was stored without delay
at 20°C for not more than 4 wk. Lactate concentration was
determined with a commercially available test kit based on an enzymatic
reaction on an autoanalyzer (TDx; Abbott).
Catecholamines.
Plasma catecholamines were determined in blood samples collected in
vials containing EGTA (1.8 mg/ml final) and reduced glutathione (2.4 mg/ml final). Samples were chilled on ice immediately, centrifuged in
the cold, and stored at 80°C until analysis. An established method
(26) with some modifications was employed. This involved addition of an internal standard (dihydroxybenzylamine) and adsorption to aluminum oxide followed by reverse-phase HPLC and electrochemical detection.
Statistics. For statistical analysis of paired data, the Wilcoxon test was employed. For analysis of time course data, the Bonferroni-Holm test for multiple data points was used.
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RESULTS |
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Mobilization of
CD14+CD16+
monocytes by an upstairs run.
Staining of whole blood samples with CD14 and CD16 antibodies allows
for detection of two monocyte populations. One population is strongly
positive for CD14 and lacks CD16 (Fig.
1A). These cells are
the classical monocytes. A second cell population
coexpresses the CD14 antigen at a low density together with the
CD16 antigen. These double positive cells usually account for 10% of
all monocytes and for 50.3 ± 19.5 cells/µl blood in apparently
healthy donors (n = 10).
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Effect of graded workload on mobilization of
CD14+CD16+
monocytes.
Next, we asked what extent of exercise is required for the increase of
the CD14+CD16+ monocytes to occur. For this,
participants exercised on a home trainer bike for 1 min at 100 W
followed by 20 min of rest. They then exercised for 1 min at 200 W, and
after another 20 min of rest they exercised for 1 min at 400 W. Both
the exercise at 100 and at 200 W did not result in a significant
increase in the number of CD14+CD16+ monocytes
(Fig. 3). An exercise
for 1 min at 400 W, however, resulted in a 2.1-fold increase of these
cells. This increase was evident immediately after the exercise,
persisted for 5 min, and declined to the initial level after 20 min
(Fig. 3). The increase of monocytes in response to exercise was quite
specific to the CD14+CD16+ monocytes since the
classical CD14++ monocytes showed only a moderate 1.3-fold
increase (Fig. 3, bottom).
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Effect of repeated exercise on mobilization of
CD14+CD16+
monocytes.
We next analyzed the effect of extending the time of exercise on the
increase of CD14+CD16+ monocyte numbers. Donors
exercised on the bike for 1 min at 400 W, and after 20 min of rest they
exercised for 2 min at 400 W. As shown in Fig.
4, the average 2.1-fold increase after 1 min at 400 W is exceeded by a 2.8-fold increase of the
CD14+CD16+ monocytes after 2 min of exercise.
In addition to demonstrating an increased mobilization when increasing
the duration of the exercise, these data also show that the cells that
are mobilized after the first exercise disappear with rest and then can
be mobilized once again.
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Expression of adhesion molecules by monocyte populations.
Adhesion molecules may be involved in localization of cells to a
compartment like the marginal pool. We therefore analyzed adhesion
molecules on the CD14+CD16+ monocytes compared
with the CD14++ cells. Expression of CD11d was clearly
higher on the CD14+CD16+ monocytes as was VLA-4
(2.7- and 3.4-fold, respectively). At the same time, expression of
CD62L was virtually absent from these cells (Fig.
5). Additional integrin molecules that
were found to be upregulated in the CD14+CD16+
monocytes were CD11a and CD11c (Table
1). By contrast, as noted earlier
(28), CD11b was substantially lower, and CD18, the common -chain for CD11a-d, showed a similar level of expression for the
CD14+CD16+ monocytes and the CD14++
cells. Also, in addition to CD62L, the CD15 and CD15s markers were
found to be almost absent in the CD14+CD16+
monocytes (Table 1).
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Role of catecholamines in mobilization of
CD14+CD16+
monocytes.
Excessive exercise is associated with the release of stress hormones
like catecholamines. We have determined the levels of both epinephrine
and norepinephrine in blood of donors before and after 1 min of
exercise at 400 W. As can be seen in Table 2, both hormones were increased
severalfold immediately after exercise.
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Effect of glucocorticoids on mobilization of
CD14+CD16+
monocytes.
Previous studies have shown that high-dose therapy with glucocorticoids
will selectively deplete the CD14+CD16+
monocytes (6). Depletion of these cells in the central
pool could be due to a shift into the marginal pool. We have therefore treated healthy volunteers with methylprednisolone at 250 mg/day for
three consecutive days. Twenty-four hours before the first and 24 h after the last dose, the volunteers were subjected to a maximum
exercise on the home trainer bike at 400 W. The first exercise led to a
3.5-fold increase from 33 to 109 cells/µl, i.e., 348% (Fig.
8). The 3-day treatment with
glucocorticoids reduced the number of
CD14+CD16+ monocytes to 8 cells/µl. Exercise
on day 4 also led to a substantial enhancement of cell
numbers by a factor of 3.5, but the maximum level achieved was only
98% of the starting level (Fig. 8).
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DISCUSSION |
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The existence of distinct monocyte populations in human blood is now well established (27). In the present report, we have analyzed the mobilization of monocytes by anaerobic exercise, and we demonstrate a dramatic increase (average 3.5-fold) of the CD14+CD16+ blood monocyte subpopulation within seconds of an upstairs run. This type of exercise, although constant with respect to altitude to be covered, is not very well controlled with respect to work load. Also, it is not very well suited for continuous monitoring of parameters. We have therefore used graded levels of exercise on a home trainer bike. Here we could show that a 200-W exercise for 1 min is not sufficient for a significant mobilization of the CD14+CD16+ monocytes. Rather, 400 W for 1 min are required. After 20 min of rest, the CD14+CD16+ monocytes can be mobilized again by a second round of exercise at 400 W for 2 min. This indicates that the CD14+CD16+ monocytes are mobilized from a dynamic compartment.
Similar observations have been made for neutrophils and for lymphocytes (17). Among the latter, the natural killer (NK) cells show the most pronounced increase (9, 12). These cells are considered to be mobilized from the marginal pool, a pool that has been shown in experimental animals to contain granulocytes, NK cells, and monocytes (14). We suggest that the CD14+CD16+ monocytes recruited after excessive exercise stem from this marginal pool.
The assignment of the cells to the marginal pool can, however, not be demonstrated directly in this system. Here distribution analysis with tagged cells might give direct evidence. Direct demonstration of the marginal pool can, however, only be achieved in an animal model, where the central pool can be defined by bleeding and the marginal pool by extensive perfusion of the vasculature (14).
The pig has recently been demonstrated as a useful animal model, since here a homologue of the CD14+CD16+ monocytes, i.e., CD163+ cells, has been identified (23). Hence, the pig model may be employed for the study of the CD14+CD16+ homologue in the marginal pool.
Our findings show that mobilization from the marginal pool mainly applies to the CD14+CD16+ monocytes while the CD14++ cells are hardly affected. What then is the basis of this selectivity?
One possibility is the higher expression of adhesion molecules on the
CD14+CD16+ monocytes. These cells do show
clearly higher levels of CD11d and VLA-4. VLA-4 is an integrin that
mediates rolling on and adhesion to vascular cell adhesion molecule
(VCAM)-1 on endothelial cells (1, 16). CD11d
is a recently identified 2-integrin that can interact
with endothelial intercellular adhesion molecule-3 (22,
25) but also with VCAM-1 (11). The question
is whether such interactions can occur with resting endothelial cells.
It is evident, however, that rolling of leukocytes does occur on endothelium in vivo in the absence of inflammation (15,
19). Our concept that the
CD14+CD16+ monocytes preferentially localize to
the marginal pool is also supported by the finding that these cells
fail to express CD62L. Palecanda et al. (20), on the basis
of cross-linking studies, have suggested that leukocytes, when rolling
on endothelial cells, will shed the L-selectin, leading to the presence
of soluble serum L-selectin in the absence of inflammation. Other
selectins still may be involved in the interaction of the
CD14+CD16+ monocytes with endothelium, since
these cells do have a higher expression of
P-selectin-glycoprotein-ligand-1 that may allow for interaction with
P-selectin on endothelium.
The finding that the monocytes with a higher expression of adhesion molecules are found mainly in the marginal pool is very similar to findings in the rat. Here the frequency of cells with high leukocyte-function antigen-1 expression was low in the central pool and very high in the marginal pool (14). When adhesion molecules, in fact, mediate localization to the marginal pool, the question is how cell attachment to endothelial cells can change so rapidly. Here changes in affinity of the adhesion molecules on the leukocytes are a likely explanation (4, 13).
Such an affinity decrease may be brought about by catecholamines. We
have shown herein that catecholamines rapidly increase after excessive
exercise. Furthermore, blockade of -adrenergic receptors reduced
mobilization of the CD14+CD16+ monocytes or
even prevented it in some donors. One might argue that
-blockade
will reduce the intensity of work since catecholamines cannot stimulate
energy supply appropriately. In our experiments, the donors exercised,
however, at a submaximal level with a fixed work load before and after
the
-blockade. Hence, the reduction of
CD14+CD16+ monocytes appears to be a direct
effect of
-blockade at the level of the leukocyte. A role for
catecholamines has been clearly demonstrated also for the mobilization
of NK cells after epinephrine infusion (24). Also,
mobilization of NK cells after psychological stress was successfully
blocked by propranolol (2). When looking at the effect of
-propranolol on catecholamine levels, we noted in preliminary
experiments with three donors an increase of the basal level of
norepinephrine from 64 ± 36 to 109 ± 48 pg/ml, whereas
exercise led to a similar increase before (364 ± 257 pg/ml) and
after the
-blockade (261 ± 192 pg/ml).
We failed to demonstrate a blockade of
CD14+CD16+ monocyte mobilization in two of
eight donors. Albeit less pronounced compared with the six donors with
a propranolol suppression of CD14+CD16+
monocyte mobilization, the CD16+ NK cells in these subjects
were also decreased by propranolol treatment in these two donors (data
not shown). Hence, it is clear that the -blocker did work in these
donors. Therefore, it is possible that in these donors mobilization is
independent of catecholamines.
The depletion of the CD14+CD16+ monocytes by glucocorticoids as reported earlier (6) has been confirmed in this study. This depletion could be due to a shift of the cells into the marginal pool. If this is true, then exercise-induced mobilization should result in similarly high levels of CD14+CD16+ monocytes both before and after glucocorticoid treatment. We found, however, that the average mobilization after glucocorticoid treatment only reached the basal level of CD14+CD16+ monocyte numbers. This then indicates that glucocorticoids do not shift these cells into the marginal pool. Rather they deplete the cells in both the central and the marginal pool. Still one can argue that glucocorticoids will shift the CD14+CD16+ monocytes into the marginal pool in a fashion that renders them resistant to mobilization, i.e., the cells might be sticking tightly to the endothelium. To analyze this possibility, in situ analysis in an animal model is required.
Taken together, the data herein show that CD14+CD16+ monocytes are selectively mobilized from the marginal pool in a rapid catecholamine-dependent fashion.
The CD14+CD16+ monocytes have been shown to increase in clinical conditions like sepsis, human immunodeficiency infection, and postsurgical systemic inflammatory syndrome and in patients with atherogenic lipid profile (27). This increase was interpreted to reflect a net increase of the cells in blood, but based on the current findings such increases in number could also be due to a shift from the marginal pool into the central pool.
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ACKNOWLEDGEMENTS |
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We acknowledge the generous provision of anti-CD11d antibodies by ICOS (Bothell, WA). We also thank M. Blumenstein (Munich, Germany) for helpful discussion and H. Gabriel (Jema, Germany) for critically reading the manuscript.
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FOOTNOTES |
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This work was supported by grants from the Ernst and Berta Grimmke-Foundation (Düsseldorf, Germany), from Deutsche Forschungs-gemeinschaft (SFB 217, A6), from the Graduierten-Kolleg "Infektion und Immunität" at the University of Munich, and from Hoechst-Marion-Roussel (Bad Soden, Germany).
The data presented herein are part of the thesis of B. Steppich.
Address for reprint requests and other correspondence: H. W. L. Ziegler-Heitbrock, GSF-National Research Center, Institute for Inhalation Biology, Cooperation Group Aerosols in Medicine, Robert-Koch-Allee 6, 82131 Gauting, Germany (E-mail: ziegler{at}gmx.de).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Received 22 June 1999; accepted in final form 20 March 2000.
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Hybridoma
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