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Vol. 83, Issue 5, 1492-1498, 1997
1- and
1+2-receptor blockade
suppress the natural killer cell response to head-up tilt in humans
Departments of Infectious Diseases and Anesthesia, Copenhagen Muscle Research Center, Rigshospitalet, University of Copenhagen, DK-2200 Copenhagen N; and Danish Armed Forces Health Services, Jægersborg, DK-2820 Gentofte, Denmark
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Klokker, M., N. H. Secher, P. Madsen, M. Pedersen, and B. K. Pedersen. Adrenergic 
1-
and 1+2-receptor blockade suppress the natural killer cell response to head-up tilt in humans. J. Appl. Physiol. 83(5):
1492-1498, 1997.
To evaluate stress-induced changes in blood
leukocytes with emphasis on the natural killer (NK) cells, eight male
volunteers were followed during three trials of head-up tilt with
adrenergic 1- (metoprolol) and
1+2- (propranolol) blockade and
with saline (control) infusions. The 1- and
1+2-receptor blockade did not
affect the appearance of presyncopal symptoms, but the head-up tilt
induced a transient lymphocytosis that was abolished by
1+2-receptor blockade but not
by 1-receptor blockade. Head-up
tilt also resulted in delayed neutrophilia, which was insensitive to
-receptor blockade. Lymphocyte subset analysis revealed that the
head-up tilt resulted in a twofold increase in the percentage and
absolute number of CD3
/CD16+
and
CD3/CD56+
NK cells in peripheral blood and that this increase was partially blocked by metoprolol and abolished by propranolol. The NK
cell activity on a per NK cell basis did not change during head-up tilt, indicating that the cytotoxic capability of NK cells recruited to
circulation is unchanged. The data suggest that the head-up tilt-induced lymphocytosis was due mainly to
CD16+ and
CD56+ NK cells and that their
recruitment to the blood was inhibited by
1- and especially
1+2-receptor blockade. Thus
stress-induced recruitment of lymphocytes, and of NK cells in
particular, is mediated by epinephrine through activation of
-receptors on the lymphocytes.
aviation medicine; catecholamines; gravity; leukocytes; lymphocytes; lymphocyte subsets; neutrophils; T cells
INTRODUCTION THE IMMUNE SYSTEM is influenced by thermal and
traumatic injury (4), surgery (26, 37), acute myocardial infarction (17), and even jet lag (18) and spaceflight (32, 35). Isolated physical stressors have been investigated in humans during exercise (30), hypoxia (19), hyperthermia (10, 12), head-up tilt (20),
and various forms of stress that induce similar changes in the cellular
immune system (8). The underlying mechanism is probably
multifactorial and may be mediated in part by hormones (28).
This study focuses on the possible roles of adrenergic Natural killer (NK) cells are a heterogenous population of
lymphocytes that mediate non-major-histocompatibility-restricted cytotoxicity. NK cells do not express CD3 (denoted CD3 METHODS Eight healthy men [age 26 (range 22-31) yr, weight 75 (67-85) kg, and height 179 (176-183) cm] volunteered as
subjects after they gave informed consent to participate the study,
which was approved by the Ethics Committee of Copenhagen (EC reference
no. KF V 92210). The subjects were not specially trained
for the purpose of head-up tilt and did not perform any regular sport
activities. Subjects arrived in the laboratory at 8 AM, were
postabsorptive for 10 h, and were allowed to drink only
water. Infectious diseases within 10 days before the
experiment or any history of cardiac and pulmonary disease excluded the
subject.
Experiments were performed on a tilt table with a bicycle saddle and
without support for the feet. After 30 min of supine rest, intravenous
infusion of isotonic saline was started at 15 ml/h. After another 30 min of supine rest, head-up tilt to an angle of 50° was performed
over 5 min (starting at time = 0 min), and the subject remained in this
position until the onset of PS. With the occurrence of PS, the subject
was immediately returned to the supine position (23). On other days,
A catheter (1.0 mm ID; 20 gauge) was inserted in the brachial artery of
the nondominant arm for blood pressure and sampling of blood and was
flushed with saline (3 ml/h). Arterial pressure was measured with a
transducer (Bentley Laboratories, Uden, Holland) fastened to the
subject at heart level in the midaxillary line and connected to a
monitor (Simonsen & Weel, Copenhagen, Denmark). A venous catheter at
the wrist was used for the administration of test or placebo
substances. A bolus (0.13 mg/kg of metoprolol or propranolol) was
injected over 3 min, and subsequently a constant dose (0.10 mg kg of
metoprolol or propranolol) was administered by a pump (Injectomat 50, Fresenius Medicintechnik, Bad Humburg, Germany). A two-lead
electrocardiogram was used to record heart rate. Arterial
blood samples for immunological studies were drawn just before head-up
tilt, at appearance of PS, after a further 10 min, and again after 120 min of recovery (4 × 60 ml).
-receptors on
lymphocytes in stress-induced immunomodulation. -Receptor blockade
during exercise influences exercise performance. For the study of
sympathoadrenergic blockade, we have, therefore, chosen a stress model
that does not require active physical performance. Head-up tilt is an
experimental model that is used to induce central hypovolemia as a
model of "functional hemorrhage" in humans. Experiments with
head-up tilt are reproducible, noninvasive, and acceptable for the
volunteers. Also, head-up tilt can be considered to complement physical exercise in revealing mechanisms of importance regarding the
influence of stress on the cellular immune system.
),
but the majority of human NK cell activity is mediated by the CD16+,
CD56+, or
CD16+/CD56+
cells (expressing CD16 and/or CD56 on cell surface) (27). Through multiple linear regression, it has been recently shown that it is
especially the percentage of CD16+
cells that influences the NK cell activity in normal donors (39). We
have previously described increased concentrations of lymphocytes and
of NK cells in blood during head-up tilt (20). During the first phase
of the head-up tilt (the normotensive phase), the concentrations of
plasma norepinephrine, -endorphin, cortisol, and adrenocorticotropic
hormone increase, whereas the plasma concentration of epinephrine
increases at the onset of presyncopal symptoms (PS; nausea, dizziness,
and a flushing sensation) with reduced heart rate and blood pressure
(33). These hormones have immunomodulatory effects and could
mediate the head-up tilt-related immune changes (20). Based
on infusion studies showing that epinephrine mimics the effect of
cycling on NK cells (16, 36), we hypothesized that adrenergic
-receptor blockade would abolish the stress-induced recruitment of
lymphocytes and especially of the NK cells to the blood. Therefore, we
evaluated the influence of metoprolol
(1-receptor blockade) and
propranolol (1+2-receptor
blockade) on immunocompetent cells during head-up tilt-provoked PS.
Fig. 1.
Effects of 1- and
1+2-blockade during head-up
tilt compared with control on neutrophil (
) and lymphocyte (
)
concentrations. Blood samples were collected before, during head-up
tilt at appearance of presyncopal symptoms (PS), 10 min after PS and
return to supine position (PS+10), and 120 min after return to supine
(PS+120). A: control head-up tilt.
B: adrenergic
1-receptor blockade.
C: adrenergic
1+2-receptor blockade. Values
are means ± SE of 8 men. Statistically significant differences were
determined by analysis of variance (ANOVA) and Tukey's honestly
significant difference (HSD) post hoc test based on the ANOVA.
* Significant difference between denoted value and preceding
value, P 
0.01. § Significant difference between value at PS during
1- or
1+2-blockade and value at PS in
control trial, P 0.001.
[View Larger Version of this Image (12K GIF file)]
Fig. 2.
Effects of 1- and
1+2-blockade during head-up
tilt compared with control on
CD3/CD16+
() and
CD3/CD56+
() natural killer (NK) cell concentrations. Values are means ± SE of 8 men. Statistically significant differences were determined by
ANOVA and Tukey's HSD post hoc test based on the ANOVA.
* Significant difference between denoted value and preceding
value, P 0.001. § Significant difference between value at PS during
1- or
1+2-blockade and value at PS in
control trial, P 0.001.
[View Larger Version of this Image (12K GIF file)]
Table 1.
Effects of 1- and
1+2-blockade during head-up tilt
compared with control on percentage of CD3+ (pan
T), CD4+ (T helper), CD8+ (T
cytotoxic), CD14+ (monocytes), CD19+
(B lymphocytes), and CD16+ and
CD56+ (NK) cells
Control
1-Blockade
1+2-Blockade
Before
PS
PS + 10
PS + 120
Before
PS
PS + 10
PS + 120
Before
PS
PS + 10
PS + 120
CD3+
71.7 ± 2.3
60.8 ± 3.2
70.0 ± 1.9
64.7 ± 3.0
72.5 ± 3.8
72.4 ± 3.1
77.2 ± 0.9
70.8 ± 2.1
72.8 ± 3.4
72.8 ± 3.1
73.0 ± 2.7
69.6 ± 2.7
CD4+
42.3 ± 1.5
37.2 ± 1.2
39.8 ± 2.7
37.4 ± 2.6
44.9 ± 2.2
35.2 ± 2.7*
45.8 ± 5.0
40.4 ± 3.9
41.5 ± 4.4
45.7 ± 1.8
45.6 ± 2.9
44.4 ± 3.1
CD8+
24.9 ± 3.9
30.0 ± 3.8
26.0 ± 4.8
24.5 ± 3.7
20.4 ± 3.1
26.0 ± 3.8
31.8 ± 6.0
22.8 ± 3.0
20.8 ± 3.7
26.9 ± 4.1
21.6 ± 3.0
24.2 ± 2.9
CD14+
14.9 ± 2.5
11.7 ± 1.7
13.9 ± 2.1
14.2 ± 2.3
13.9 ± 3.4
10.6 ± 1.8
8.3 ± 2.0
13.9 ± 3.1
14.1 ± 3.3
13.6 ± 2.3
12.2 ± 2.9
16.3 ± 3.6
CD3
/ CD16+ 8.9 ± 1.5
20.2 ± 4.0*
7.7 ± 1.9
6.5 ± 2.0
3.0 ± 0.6
7.1 ± 1.6
4.9 ± 0.8
6.3 ± 1.1
5.1 ± 2.1
5.2 ± 1.6
4.0 ± 1.3
7.2 ± 2.4
CD19+
29.1 ± 9.0
14.7 ± 5.0
9.7 ± 4.0
20.4 ± 6.5
11.0 ± 3.3
14.2 ± 3.7
17.4 ± 3.9
21.6 ± 5.7
18.5 ± 5.2
14.7 ± 3.3
18.1 ± 5.6
15.3 ± 4.8
CD3
/ CD56+ 9.5 ± 2.2
22.6 ± 4.6*
9.1 ± 2.0
7.8 ± 2.5
4.4 ± 1.3
10.1 ± 2.5
4.9 ± 1.6
7.0 ± 2.2
7.5 ± 2.5
6.9 ± 2.0
6.0 ± 2.1
8.6 ± 2.7
Values are means ± SE given in % of 8 men. A more precise
estimation of natural killer (NK) cells was determined
(CD3
/CD16+ and
CD3/CD56+ cells). Blood samples were
collected before, during head-up tilt at appearance of presyncopal
symptoms (PS), 10 min after PS and return to supine position
(PS + 10), and 120 min after (PS + 120). Statistically
significant differences were determined by analysis of variance (ANOVA)
and Tukey's honestly significant difference (HSD) post hoc test based
on the ANOVA.
*
Significant difference between value during head-up
tilt at appearance of PS compared with initial and subsequent values, P 0.05.
Significant difference between value at PS
during 1- or 1+2-blockade and value at PS
in control trial, P 0.05.
Fig. 3.
Effects of 1- and
1+2-blockade during head-up
tilt compared with control on NK cell activity (, effector-target
cell ratio = 100:1; , effector-target cell ratio = 50:1). Values are means ± SE of 8 men. Statistically significant differences were determined by ANOVA and Tukey's HSD post hoc test based on the ANOVA.
* Significant difference between -blockade during PS and preceding values, P 0.01. * Significant difference between -blockade and placebo pooled
values during PS and preceding values, P 0.01 and
P 0.05, respectively.
[View Larger Version of this Image (13K GIF file)]
1- and
1+2-receptor blockade were
performed by intravenous infusion of metoprolol (1 mg/ml; Seloken,
Astra Hässle, Albertslund, Denmark) or propranolol (1 mg/ml;
Inderal, Zeneca, Copenhagen, Denmark), respectively. The infusion was
started after 30 min of supine rest. The three trials were carried out
in random order and separated by >2 wk.
|
|
/CD16+
cells and LU10 × 107
CD3/CD56+
cells (39).
Cell-surface marker analysis by flow cytometry.
BMNC subset concentrations were determined according to cell surface
molecules by using monoclonal antibodies (CD markers). Lymphocytes were
differentiated according to surface molecules: CD3 (pan T cells), CD4
(T helper cells), CD8 (T cytotoxic cells), CD14 (monocytes), CD19 (B
lymphocytes), and CD16 and CD56 (NK cells). The fluorescein
isothiocyanate (FITC)- and phycoerythrin (PE)-conjugated monoclonal
antibodies anti-Leu2 (CD8), anti-Leu3 (CD4), anti-LeuM3 (CD14),
anti-CD19 (CD19), anti-Leu4 (CD3), anti-Leu11 (CD16), and anti-CD56
(CD56) (Becton Dickinson, Mountain View, CA, and Dakopatts, Glostrup,
Denmark) were used. The two latter were applied simultaneously with the
use of anti-Leu4 (CD3) for determination of
CD3/CD16+
and
CD3/CD56+
NK cells. Cells were incubated with PE- (Becton Dickinson) and FITC-conjugated (Dakopatts) mouse immunoglobulin G1 and G2, which were
used as negative controls. The BMNC (1 × 106) were washed twice in
phosphate-buffered saline (PBS) with 2% fetal calf serum (FCS) and
resuspended in 100 µl PBS containing 2% FCS and 10 µl of the
monoclonal antibody. After incubation on ice for 45 min, the cells were
washed twice in a balanced electrolyte solution. Labeled cells were
analyzed by flow cytometry by using a fluorescent-activated cell sorter
(Becton Dickinson).
Cell concentrations.
Lymphocyte and neutrophil concentrations were determined by using a
cell counter (model H.1, Technicon).
Statistics.
Analysis of variance (ANOVA) was used to evaluate changes with time and
trials (model: dependent variable = constant + subject + trial + time + trial × time; Systat, Evanston, IL). If proven significant (P 0.05), Tukey's
honestly significant difference (HSD) post hoc test based on ANOVA
categorical variables trial and time and interaction product trial × time were performed. Logarithmic transformation
of LU10 data was performed to allow ANOVA calculation.
P 0.05 was considered statistically
significant. The calculated probability values referred to in text and
Figs. 1, 2, 3 are true for both the ANOVA and Tukey's HSD tests. The data in Figs. 1, 2, 3 and Tables 1 and 2 are given as means ± SE. Initial power calculations revealed that to detect
changes in NK cell activity of >10% activity [
= 0.10; type
I error, 
= 0.05; type II error, = 0.20 
power = 80%.
Based on previous studies (20) estimated SD = ~10% standardized difference (2/SD) = 2.0], the sample
size was found to be approximately eight subjects in three groups of
continuous data in the ANOVA. Justifications for this sample size
include the fact that the subject group was homogenous and that the
test persons served as their own controls.
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RESULTS
During control head-up tilt, PS appeared after 21.6 ± 3.1 (SE) min
and after 20.6 ± 5.4 and 16.3 ± 4.9 min with
1- and
1+2-receptor blockade,
respectively, with no significant differences between trials. Infusions
with metoprolol and propranolol were not associated with any side
effects. The 1- and
1+2-receptor blockade did not
affect the bradycardic-hypotensive reaction to head-up tilt (mean
arterial pressure = 55 ± 4 and 51 ± 4 mmHg, respectively, compared with 49 ± 3 mmHg in the control head-up tilt). The only cardiovascular finding was an abolished head-up tilt-induced increase in heart rate to 57 ± 2 and 55 ± 3 beats/min during
1- and
1+2-receptor blockade,
respectively, compared with 66 ± 4 beats/min in the control trial.
No significant differences were found between pre-head-up tilt values
of dependent variables of any trial. Except for
1+2-receptor blockade, the
lymphocyte concentration increased during head-up tilt and returned to
the pre-head-up tilt value 10 min after PS (P < 0.01). During head-up tilt with
1+2-receptor blockade, no
changes in lymphocyte concentration could be demonstrated, and this was
in contrast to the lymphocyte concentration at the appearance of PS in
the control trial (P < 0.001; Fig.
1). The neutrophils increased during head-up tilt
(P < 0.01) and increased further
after 120 min of recovery (P < 0.001), and this was not influenced by
1- or
1+2-receptor blockade.
The concentration and percentage of
CD3/CD16+
and
CD3/CD56+
NK cells increased during head-up tilt
(P < 0.01), but the recruitment of
NK cells to the blood was reduced during
1-receptor blockade and
completely abolished by
1+2-receptor blockade
(P < 0.01 compared with control;
Fig. 2, Table 1). Head-up tilt had only a
minor influence on other BMNC subpopulations, and -receptor blockade
did not influence the changes in these subpopulations. The NK cell
activity increased during head-up tilt
(P < 0.05), and this increase tended
to be less pronounced during 1-
or 1+2-receptor blockade, but
there was no significant difference (effector-target cell ratios = 50:1
and 100:1 are shown in Fig. 3; effector-target cell
ratio = 25:1 is not shown). The cytotoxicity on a per
cell basis, LU10 × 107 BMNC, was borderline
significantly elevated during PS in all trials
(P = 0.093), whereas in
1+2-receptor blockade all observations not distinguishing between the time were reduced compared
with the control (P < 0.01). No
changes in LU10 × 107
CD3/CD56+
or LU10 × 107
CD3/CD56+
NK cells were found (Table
2).
The hemoglobin concentrations were 8.8 ± 0.1, 8.9 ± 0.1, and
8.9 ± 0.1 × 103
mol/l before and 9.3 ± 0.2, 9.4 ± 0.1, and 9.3 ± 0.1 × 103
mol/l during head-up tilt in the placebo and
1- and
1+2-receptor blockade trials,
respectively, with no significant differences between the trials.
DISCUSSION
This study confirmed that head-up tilt induces neutrocytosis and
lymphocytosis (20). The increased lymphocyte concentration was due
mainly to recruitment of NK cells to the blood, and, accordingly, the
NK cell activity (lysis per fixed number of BMNC) increased during
head-up tilt. The study demonstrates that adrenergic -receptor blockade inhibits the head-up tilt-induced lymphocytosis and abolishes the increase in number and percentage of NK cells. Also, it may partly
block the NK cell activity.
1+2-Receptor blockade with
propranolol inhibits exercise-induced lymphocytosis (2). In numerous
species, the expression of adrenergic -receptors on T, B, and NK
cells provides the molecular basis for these cells to be targets for
catecholamine signaling (21). -Receptors on lymphocytes are linked
intracellularly to the adenyl cyclase system (5), and the -receptor
density changes in concert with lymphocyte activation and
differentiation (1). Dynamic exercise upregulates the adrenergic
-receptor density, especially on NK cells (22). In humans, a single
epinephrine injection induces a transient increase in the number of
circulating blood lymphocytes and monocytes (36) and reduces the
response to T-cell mitogens (6). The finding that
epinephrine infusion is capable of mimicking the effect of cycling,
especially with respect to recruitment of cells mediating NK and
lymphokine-activated killer cell activity (13, 36, 38) is compatible
with the finding that exercise induces upregulation of adrenergic
-receptors on NK cells but not on other lymphocyte subsets (22).
There is evidence that the sympathetic nervous system may be involved in the control of cellular immunity in the spleen (14, 21). The murine
splenic NK cell activity is enhanced by splenic denervation (31) and is
suppressed by exposure to norepinephrine or an agonist (7).
Furthermore, electrical stimulation of splenic nerve results in
suppression of the splenic NK cell activity, which was blocked by
injection of a peripherally acting adrenergic -receptor blocking agent (15). The finding of an effect of adrenergic -blockade on the
NK cells in the peripheral blood in humans corresponds to the finding
on murine splenic NK cells. This may reflect the fact
that during stress NK cells are partly recruited to the peripheral blood from the spleen. However, infusion of epinephrine (34) and
exercise (9) do cause lymphocytosis, and based on these studies the
spleen plays only a minor role in stress-induced lymphocytosis. However, another recent study in splenectomized subjects suggests that
the spleen accounts for one-third of the lymphocytosis in exercise
(25). Other possible sites from which cell mobilization may occur
include the lymphoid organs and the bone marrow.
The present study showed that the heart rate decreased during both
1- and
1+2-adrenergic blockade.
Although heart rate and associated hemodynamic changes may directly
influence the number of NK cells that are recruited to the blood, this
is not likely to be the most important mechanism of action, especially because 1+2-adrenergic blockade
inhibited the mobilization of NK cells. However, the finding that
2-receptor agonists, but not
1-agonists, induce selective
detachment of NK cells from endothelial cells (3) and that
1+2 more than
1-receptor antagonists
inhibited the mobilization of NK cells to the blood, lends support to
the hypothesis that catecholamines, via
2-adrenergic receptors, can
induce recruitment of NK cells from the marginating to the circulating
pool, by changing the adhesive interactions between NK cells and
endothelial cells. The finding that adrenergic -receptor blockade
did not significantly inhibit the increase in NK cell activity may be
due to an insufficient number of volunteers and large interindividual
variation, because there was a tendency toward a lower increase in NK
cell activity during 1+2- receptor blockade (Table 2, Fig. 3). The NK cell activity on a per cell
basis did not change significantly during and after head-up tilt. This
indicates that the cytotoxic capability of the NK cells recruited to
the circulation is unchanged.
1+2-Receptor blockade had an
inhibiting effect on the NK cell activity on a per cell basis,
indicating that 1+2-receptor
blockade did not just inhibit the recruitment of NK cells to
circulation but inhibited the function of the individual cell. This may
be mediated through the adenyl cyclase system (5).
-Receptor blockade did not abolish the head-up-tilt-induced
neutrocytosis, which is in accordance with the finding that infusion of
epinephrine does not induce neutrocytosis to the same extent as does
exercise (3). However, during exercise, growth hormone and cortisol are
known to cause marked neutrocytosis (11, 24), and our hypothesis is
that epinephrine and cortisol, but in head-up tilt probably not growth
hormone (unpublished observations), mediate the acute stress effect on
neutrophils (8), and, therefore, -receptor blockade did not inhibit
head-up tilt-related neutrocytosis.
Although no cardiovascular changes occurred during adrenergic
1- and
1+2-receptor blockade except
for an abolished head-up tilt-induced increase in heart rate, they did
suppress the stress response of NK cells. The present
study and most other studies focusing on mechanisms of NK activation
during stress (28) are limited to young healthy men, and there is an
absence of data on other population segments (women and middle-aged and elderly individuals). However, the available results indicate that the
epinephrine mediates the recruitment of NK cells from the marginating
pool in blood vessels during stress through activation of -receptors
on BMNC.
ACKNOWLEDGEMENTS
The excellent technical assistance of Ruth Rousing, Hanne Villumsen, Elise Møller, Lars Brogaard, and Anne Asanovski is acknowledged. Anders F. Johnsen and Viggo Lemche, the Danish Defence Research Establishment, and Henrik Ullum are thanked for valuable statistical discussions.
FOOTNOTES
Address for reprint requests: M. Klokker, Dept. of Infectious Diseases, M 7641, Rigshospitalet, Tagensvej 20, DK-2200 Copenhagen N, Denmark (E-mail: Klokker{at}dk-online.dk).
Received 22 May 1996; accepted in final form 26 June 1997.
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