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and IL-6 secretion in the spleen
* Laboratory of Neuroendocrinoimmunology, Department of Internal Medicine I;
Institute for Medical Microbiology; and the
§ Institute of Pathology/Immunology, University of Regensburg, 93042 Regensburg, Germany
1Correspondence: Laboratory of Neuroendocrinoimmunology, Department of Internal Medicine I, University of Regensburg, Franz Josef Strauss Allee 11, 93042 Regensburg, Germany. E-mail: rainer.straub{at}klinik.uni-regensburg.de
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONCONCLUSIONSREFERENCES |
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is necessary to overcome infection. We now report in a
superfusion model, using mouse spleen slices, that although local
Pseudomonas aeruginosa increased splenic TNF- and
IL-6 secretion severalfold over basal levels, electrically released
neurotransmitters attenuated cytokine secretion to similar basal level
as under bacteria-free conditions. Bacteria reversed noradrenergic
inhibitory effector mechanisms: Under bacteria-free conditions, TNF-
secretion was very low and IL-6 secretion was mainly inhibited by
2-adrenoreceptor ligation. In the presence of bacteria, TNF- and
IL-6 secretion were high and IL-6 secretion was mainly inhibited by
ß-adrenoreceptor ligation. The - to ß-adrenoswitch of IL-6
inhibition in the presence of bacteria was mediated by the prior
adrenergic regulation of TNF-. In vivo, chemical
abrogation of sympathetic inhibition reduced accumulation of bacteria
in the spleen, which depended at least in part on TNF-. This
suggests that activation of the sympathetic nervous system may be a
forerunner for accumulation of bacteria in tissue and consecutively
sepsis due to intensified inhibition of TNF- secretion.—Straub,
R. H., Linde, H.-J., Männel, D. N., Schölmerich,
J., Falk, W. A bacteria-induced switch of sympathetic effector
mechanisms augments local inhibition of TNF- and IL-6 secretion in
the spleen.
Key Words: Pseudomonas aeruginosa • macrophage • tumor necrosis factor • interleukin 6 • norepinephrine • adrenoreceptor
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONCONCLUSIONSREFERENCES |
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or thermal injury (2)
or in patients after abdominal trauma (3
, 4)
. The local
infection may sometimes result in a systemic response that depends on
the cytokines produced at the site of infection. Cytokines such as
interleukin 1 (IL-1), IL-6, and tumor necrosis factor (TNF-)
stimulate the hypothalamus via endings of peripheral sensory nerves,
through the endothelium of the brain vasculature, directly in brain
regions with a weak blood–brain barrier and possibly by permeating
immune cells (5)
. This response is accompanied by
stimulation of the hypothalamus-pituitary-adrenal (HPA) axis
(6)
and an activation of the hypothalamus-autonomic
nervous system (HANS) axis with elevated nerve firing rates at
sympathetic nerves to lymphoid organs (7
, 8)
. Both
systemically released cortisol (9)
and locally released
sympathetic neurotransmitters (10)
are effector mechanisms
to inhibit excessive cytokine secretion at the site of infection. A
strong inhibition of local TNF- secretion may be harmful because
TNF- could be necessary to overcome the local infection. It was
recently shown that chemical sympathectomy enhanced nonspecific immune
responses to the intracellular pathogen Listeria
monocytogenes in splenic macrophages (11)
, which
indicates that sympathetic inhibition of the local immune response may
be deleterious. Furthermore, it was demonstrated that norepinephrine
(NE) infusion resulted in significantly higher numbers of bacterial
colony-forming units (CFU) in liver and lung of rabbits as compared to
control animals (12)
. Thus, it would be important to know
more about the local regulation of TNF- and IL-6 secretion by the
sympathetic nervous system in infected lymphoid tissue. There may be
fine-tuning of overall effects of the HANS axis by microenvironmental
factors such as bacteria in peripheral tissue. Our previous studies
demonstrated functional interaction between autonomic nerves and
macrophages in the spleen, which depended on microenvironmental factors
such as cortisol (13
, 14)
.
In this study, we first characterized bacterial growth in explanted
tissue slices and investigated secretion of TNF- and IL-6 making use
of a superfusion model (13)
. To study the role of NE for
the secretion of TNF- and IL-6 from the tissue slices, we induced
release of sympathetic neurotransmitters by electrical stimulation in
the absence or presence of Pseudomonas aeruginosa
(13)
. Although local bacteria increased splenic TNF-
and IL-6 secretion severalfold over basal levels, electrically released
sympathetic neurotransmitters attenuated cytokine secretion to the same
basal level similar to bacteria-free conditions. These facts and the
studies mentioned (11
, 12)
prompted us to investigate the
effect of chemical sympathectomy on accumulation of bacteria in the
spleen after intraperitoneal (i.p.) injection of Pseudomonas
aeruginosa. We now report that chemical sympathectomy can markedly
reduce bacteria accumulation and that this effect reflects, at least in
part, its action on TNF- secretion.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONCONCLUSIONSREFERENCES |
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Superfusion protocol and standardization of different slices
Spleen slices were transferred to minisuperfusion chambers with
a volume of 80 µl and equipped with two perforated gold disc
electrodes forming the bottom and top of each chamber, respectively
(13)
. Superfusion was performed for 8 h at a
temperature of 37°C and a flow rate of 66 µl/min (one slice per
chamber, 24 chambers in parallel). In some experiments we collected
superfusion medium every hour for 15 min (64 1 ml) to determine
cytokine levels in the superfusate; in experiments to modulate cytokine
secretion, a different protocol was used: during the first 4 h of
the superfusion period, all slices were superfused with culture medium
without any additional drugs or electrical stimulation (ES). Between
the 225th and 240th min, superfusate was collected to determine
IL-64.h [pg/ml; enzyme-linked immunoassay
(ELISA) technique, see below]. During the second part of the
superfusion period (4th–8th h), drug, ES, or both were applied to
modulate IL-6 secretion. Between the 465th and 480th min superfusate
was collected to determine IL-68.h. Since
spontaneous IL-6 secretion at 4 and 8 h correlated closely
(16)
, IL-64.h was used to
standardize the IL-6 secreting capacity of the different slices. The
dimensionless ratio 
(modulation index) = 100 x
(IL-68.h/IL-64.h) was used
to standardize the IL-6 secretion of each slice at 8 h
(17)
. This technique was the best method and was found to
be superior to standardization using the leukocyte count of the slice,
wet weight, dry weight, and volume of the slice (14
, 16
, 17)
.
Experiments with adrenergic antagonists and electrical
stimulation, and adrenergic agonists
To indirectly study the effect of electrically released
endogenous NE (13
, 16
, 17)
, propranolol hydrochloride
(ß1,2-adrenergic receptor antagonist; Sigma) and phentolamine
(1,2-adrenergic antagonist; Sigma) were used in the indicated
concentrations. The dilutions of the drugs were prepared immediately
before the experiments. In experiments to study transmitter effects,
drugs were added at 240 min until the end of superfusion. After a drug
equilibration period of 20 min between the 240th and the 260th min,
slices were electrically stimulated using five trains of monophasic
rectangular pulses (2 ms, 1 Hz, 43 mA, 2000 pulses; ref
13
) at 260, 305, 350, 395, and 440 min.
To study the effects of adrenergic agonists NE (Sigma),
p-aminoclonidine (2-adrenergic agonist; RBI, Natick,
Mass.), and isoproterenol (ß1,2-adrenergic agonist, Sigma) were used.
In all experiments, the substances were added between the 4th and the
8th h of superfusion without additional ES.
Experiments with the monoclonal neutralizing anti-TNF- antibody
V1qH8
Since it is believed that TNF- secretion precedes IL-6
secretion, the significance of TNF- secretion for IL-6 secretion was
characterized using the monoclonal anti-TNF- antibody V1qH8
(18)
. In these experiments, purified V1qH8 mAb was used
(subclone of V1q, ref 19
) throughout the experiment. To
study aspects of TNF--modulated IL-6 secretion TNFRI/II(-/-),
animals were used (animals described above). Purified rat IgG (Sigma)
was used as antibody control.
Determination of number of bacterial CFU in blood and spleen of
infected mice
NMRI mice were injected i.p. with 107 CFU
of Pseudomonas aeruginosa (bacteria in midlogarithmic growth
as described above). This number of bacterial CFU was found to induce a
significant accumulation of bacteria in the spleen within 7 h,
which was not observed with smaller numbers of bacterial CFU such as
106 or 105. Similar numbers
of bacterial CFU were used in another study (20)
. Mice
were killed 7 h after infection by CO2
inhalation, bled by heart puncture, and their spleens were recovered,
carefully washed five times in saline, and homogenized. Bacterial
counts were determined by plating 10-fold serial dilutions of blood or
homogenized spleens on Mueller-Hinton agar plates. Bacterial CFU were
counted 36 h later. All animal care and experimentation were
conducted under official permission from the Regierung der Oberpfalz,
Regensburg.
Sympathetic denervation
Chemical sympathectomy was performed in NMRI mice using
6-hydroxydopamine (6OH-DA, Sigma). 6OH-DA was dissolved in sterile
saline and injected i.p. at 250 mg/kg body weight 5 days prior to
injection of bacteria. Control animals received the respective vehicle.
Cytokine determination
Murine IL-6 and TNF- in superfusate fractions were determined
by sandwich ELISAs making use of specific antibody pairs (Endogen,
Boston, Mass.). Sensitivity was < 8 pg/ml and < 15 pg/ml,
respectively. For both ELISAs, intra- and interassay coefficient of
variation were below 10%.
Presentation of the data and statistical analysis
All data are given as mean ± SE;
n = number of observations; one observation = one
slice. Using 24 chambers, we were able to investigate 24 slices in one
experiment of one mouse. In one experiment with an antagonist and
additional ES four different conditions were investigated:
1) 6 control slices without drug or ES, 2) six
slices with drug only, 3) six slices with ES only, and
4) six slices with drug and ES. In an experiment with an
exogenous agonist, two different conditions were investigated:
1) 12 control slices and 2) 12 slices with an
indicated agonist concentration. Since average of one experiment
varied from mouse to mouse, the effects are demonstrated in percent of
the control ( of the control is 100%) of each mouse. Wilcoxon
signed rank test (SPSS for Windows V8.0.0, SPSS Inc., Chicago, Ill.)
was used to compare the control vs. drug-induced effects and
P<0.05 was the significance level.
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RESULTS AND DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONCONCLUSIONSREFERENCES |
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and
strong inhibition of IL-6 secretion, which depends partly on
-adrenergic inhibition (14
, 16
, 17)
. Two earlier
studies suggested that spontaneous IL-6 secretion is inhibited by a
tonic neuronal and hormonal influence (14
, 21)
. To compare
the electrically induced inhibition of IL-6 secretion under different
bacterial conditions, superfusion experiments without bacteria and with
bacteria were carried out. Under bacteria-free conditions, spleen
slices spontaneously released IL-6 (Fig. 1A
), which increased severalfold in the presence of bacteria
(Fig. 1B
). Under the same conditions, spleen slices
spontaneously released endogenous norepinephrine, which led to a
superfusate concentration of approx. 10-9 M
(data not shown). Electrically released neurotransmitters (identical
electrical stimulus) inhibited different levels of IL-6 secretion at
4 h to a similarly low level at 8 h irrespective of the
presence of bacteria (Fig. 1A, B
). This indicates that
neurotransmitter-induced inhibition of IL-6 secretion is optimized at
the local site when bacteria are present.
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Influence of endogenous NE on IL-6 secretion in the presence and
absence of bacteria
To investigate the effect of electrically released endogenous NE
on IL-6 secretion, specific -adrenergic and ß-adrenergic
antagonists were used to block NE effects in the presence and absence
of bacteria. Under bacteria-free conditions, electrical inhibition of
IL-6 secretion was attenuated by the -adrenergic antagonist
phentolamine, which indicated that endogenous NE inhibited IL-6
secretion via -adrenoreceptors (Fig. 2A
, open bars). In the presence of bacteria, however, the
-adrenergic antagonist phentolamine further decreased electrically
inhibited IL-6 secretion (Fig. 2A
, cross-hatched bars). This
additional inhibition was significant at 10-7 M
phentolamine, but there was no difference between phentolamine at
10-7 M and 10-6 M (Fig. 2A
, cross-hatched bars). This indicates a complete change of
the -adrenergic regulation of splenic IL-6 secretion under the
different conditions with and without bacteria.
|
To study the effect of electrically released endogenous NE via
ß-adrenergic ligation, the following experiments were carried out
under conditions with and without bacteria. Electrical inhibition of
IL-6 secretion was not affected by the ß-adrenergic antagonist
propranolol under bacteria-free conditions (Fig. 2B
, open
bars) confirming an earlier study (16)
. However, in the
presence of bacteria, propranolol at 10-7 and
10-6 M attenuated the electrically induced
effect (Fig. 2B
, cross-hatched bars). This indicates a
change of the ß-adrenergic regulation of splenic IL-6 secretion under
the different conditions with and without bacteria.
In conclusion, electrically released endogenous NE inhibited IL-6
secretion via -adrenoreceptors under conditions without bacteria,
whereas NE inhibited IL-6 secretion via ß-adrenoreceptors under
bacteria-rich conditions. We call this phenomenon the - to
ß-adrenoswitch of NE-induced inhibition of
splenic IL-6 secretion.
Influence of TNF- secretion on IL-6 secretion in the presence
and absence of bacteria
To study the importance of prior TNF- secretion for the
subsequent IL-6 secretion, the following experiments were initiated. In
the absence of bacteria, TNF- concentration was very low, which was
significantly changed in the presence of bacteria (Fig. 3A
). However, no clear peak response was detected, which
suggests that the growing number of bacteria continuously stimulate
TNF- secretion in these slices (Fig. 3A
). To characterize
the importance of TNF- for the subsequent secretion of IL-6, we used
the anti-TNF- mAb V1qH8 (Fig. 3B
). Both spontaneous and
bacteria-induced IL-6 secretion were at least in part dependent on
TNF- production because neutralization by the anti-TNF- mAb V1qH8
significantly reduced IL-6 secretion (Fig. 3B
). The effect
of V1qH8 mAb was much more pronounced in spleen slices with bacteria
present (Fig. 3B
). This indicates that prior TNF-
secretion is important for the subsequent IL-6 secretion, which is much
more pronounced under conditions with bacteria as compared to
conditions without bacteria.
|
The inhibition of IL-6 secretion via -adrenoreceptors in a
bacteria-free milieu and ß-adrenoreceptors in the presence of
bacteria depends on the differential adrenergic regulation of prior
TNF- secretion
As mentioned above, electrically released endogenous NE inhibited
IL-6 secretion via -adrenoreceptors when bacteria were absent,
whereas NE inhibited IL-6 secretion via ß-adrenoreceptors under
bacteria-rich conditions (= - to ß-adrenoswitch). To study the
importance of prior TNF- secretion for the - to ß-adrenoswitch
of inhibition of IL-6 secretion, the following experiments were carried
out using the neutralizing anti-TNF- mAb V1qH8 and TNFRI/II(-/-)
animals.
In the first series of experiments the effect of the electrically
released endogenous neurotransmitter NE was tested by means of specific
antagonists. In the presence of bacteria, V1qH8 mAb reversed the effect
of phentolamine (cross-hatched bars in Fig. 4A
; compare with Fig. 2A
) and abolished the effect
of propranolol (cross-hatched bars in Fig. 4B
; compare with
Fig. 2B
) in experiments with electrical field stimulation.
This indicates that prior TNF- secretion is responsible for the -
to ß-adrenoswitch of IL-6 inhibition when conditions are changed from
medium without bacteria to medium with bacteria.
|
Similar results should be obtained when the respective exogenous
agonists instead of the antagonists (+ endogenous NE) were used.
Application of high concentrations of norepinephrine (=stimulation of
ß-adrenoreceptors) and the ß-adrenergic agonist isoproterenol
confirmed the above results for electrically released endogenous NE
(Fig. 5A, B
): Under conditions with bacteria present, IL-6 secretion
was inhibited via ß-adrenoreceptors, which was reversed using the
anti-TNF- antibody (Fig. 5A, B
). Under the same
conditions (bacteria + anti-TNF- mAb), isoproterenol at
10-5 M even increased IL-6 secretion
(P<0.01, Fig. 5B
). These experiments indicate
that prior TNF secretion is responsible for the ß-adrenergically
induced inhibition of IL-6 secretion under conditions with bacteria. To
study the importance of 2-adrenergic effects, we used the respective
agonist p-aminoclonidine, demonstrating a significant shift
of the response curve to higher concentrations in the presence of
bacteria that was reversed by V1qH8 mAb (Fig. 5C
). A rat
control antibody had no effect (data not shown). These experiments
clearly indicate that the differential noradrenergic inhibition of IL-6
secretion depends on prior TNF- production due to bacterial stimuli
in the tissue. The effects of bacterial growth were not mimicked by 10
µg/ml lipopolysaccharide (LPS) (Salmonella typhimurium,
optimum stimulatory concentration; ref 14
) in the
superfusion medium (data not shown). This demonstrates that the
bacterial component LPS is not the critical stimulus for TNF-
effects under these conditions as compared to growth of the entire
viable bacterium. Other factors such as stimulation by bacterial DNA
may be more important (22)
.
|
To corroborate the results obtained with V1qH8 mAb, TNFRI/II(-/-)
mice and the respective control animals were used. In the presence of
bacteria in TNFRI/II(-/-) mice, propranolol was without effect on the
result of electrical stimulation (Fig. 6A
, right half), which indicates that endogenous NE in these
mice does not modulate IL-6 secretion via ß-adrenergic pathways.
However, phentolamine 10-7 M completely
abrogated the electrical inhibition of IL-6 secretion (Fig. 6A
, right half). Thus, complete loss of signaling through
the TNF receptor is accompanied by a strong -adrenergic inhibition
of IL-6 secretion. This -adrenergic inhibition was much more marked
in experiments with spleen slices of TNFRI/II(-/-) mice as compared
to spleen slices of NMRI mice under bacteria-free conditions (compare
Fig. 2A
, open bars, and Fig. 6A
, right half).
This may indicate that IL-6 secretion is under small TNF control in
NMRI mice even under sterile conditions, which has been demonstrated in
experiments with V1qH8 mAb in NMRI mice (Fig. 3B
, open
bars). In experiments with TNFRI/II(+/+) mice, propranolol attenuated
the electrically induced inhibition (Fig. 6A
, left half) as
it did in normal NMRI mice (Fig. 2B
). Phentolamine at
10-7 M tended to increase the electrically
induced inhibition of IL-6 secretion in TNFR(+/+) mice (Fig. 6A
, left half), which did not reach the level demonstrated
in NMRI mice under the same bacterial conditions (Fig. 2A
).
Furthermore, the electrically induced inhibition was significantly
stronger in TNFRI/II(+/+) mice than in TNFRI/II(-/-) mice (Fig. 6A
), which suggests that a major part of IL-6 inhibition in
the presence of bacteria depends on ß-adrenergic mechanisms. These
studies were further substantiated by use of exogenous NE in optimum
concentration (as shown in Fig. 5A
) to stimulate
ß-adrenoreceptors (Fig. 6B
). In the presence of bacteria,
NE at 10-5 M inhibited IL-6 secretion in
TNFRI/II (+/+) mice (Fig. 6B
, left bar), whereas NE at
10-5 M stimulated IL-6 secretion in
TNFRI/II(-/-) mice (Fig. 6B
, center bar), as was found in
NMRI mice (Fig. 5A
). The stimulatory effect of NE was
completely abrogated with the optimum concentrations of additional
phentolamine 10-7 M plus propranolol
10-6 M (Fig. 6B
, right bar). In
conclusion, the differential modulation of IL-6 secretion under various
conditions with and without bacteria depended on the prior induction of
TNF- secretion by these bacteria.
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Attenuation of bacteria accumulation in the spleen by sympathetic
denervation
As mentioned above, inhibition of IL-6 secretion was optimized
under conditions with bacteria as compared to conditions without
bacteria. We have further shown that under conditions with bacteria,
ß-adrenergically induced inhibition of IL-6 secretion depends on
prior TNF secretion. Under conditions with bacteria, optimization of
cytokine inhibition may be positive to decrease extensive secretion of
these potentially harmful mediators. However, an exaggerated
sympathetic inhibition of locally released cytokines, particularly
TNF-, may be deleterious during bacteremia. Thus, we investigated
whether sympathetic denervation changed the local growth of bacteria in
the spleen of NMRI mice. Sympathectomy with 6OH-DA significantly
decreased accumulation of bacteria in the spleen whereas no changes
were found in the blood (P<0.01,
Fig. 7
). Administration of the anti-TNF- mAb V1qH8 increased local
accumulation of bacteria (Fig. 7)
. Furthermore, V1qH8 mAb significantly
increased CFU per milliliter blood under control conditions and in
denervated animals (Fig. 7)
. This indicates that the sympathetic
nervous system is responsible for higher bacterial burden in the
splenic tissue. Sympathetic inhibition of locally produced TNF seems to
be a likely factor for this effect.
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CONCLUSIONS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONCONCLUSIONSREFERENCES |
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. The regulation of IL-6 and TNF-
production is different with respect to cyclic AMP (cAMP; Fig. 8
): Thus, we would like to propose the following model: elevated
intracellular cAMP concentration increases IL-6 secretion
(23)
but decreases TNF- secretion
(24
25
26)
. Since NE stimulates cAMP production via
ß-adrenergic pathways and inhibits cAMP via 2-adrenergic pathways,
cAMP may be the key mediator for these different effects of NE on IL-6
and TNF- secretion (Fig. 8)
. Under bacteria-free conditions, TNF-
plays a minor role (Fig. 3B
, Fig. 8
, left panel) and IL-6
secretion is inhibited by 2-adrenergic stimulation (Fig. 2A
and Fig. 5C
, Fig. 8
, left panel). In the
presence of bacteria, TNF- production is stimulated (Fig. 3A
) and secretion of IL-6 becomes controlled by TNF-
(Fig. 3B
, Fig. 8
, right panel). In this situation IL-6
secretion is stimulated by -adrenergic ligation (Fig. 2A
,
Fig. 8
, right panel) and strongly inhibited by ß-adrenergic
stimulation (Fig. 2B
and 5A,B
, Fig. 8
, right
panel). Thus, inhibition of IL-6 secretion has undergone an - to
ß-adrenoswitch from conditions without bacteria to conditions with
bacteria (Fig. 8)
. What does this mean in a more general context ?
|
If bacteria invade the tissue, immune cells are stimulated by bacterial
products to release cytokines such as TNF-, IL-1, IL-6, or
chemokines. Normally such a response is locally controlled and bacteria
are eradicated. If proinflammatory and anti-inflammatory signals become
unbalanced, an overshooting immune response could lead to the release
of cytokines into the circulation. As a response to circulating
cytokines, the HPA axis (6)
and the sympathetic nervous
system (7)
become activated. Both the HPA axis and
sympathetic nervous system are negative feedback regulatory systems to
dampen the excessive immune response at the local site of infection
(9)
. However, if the inhibition is too strong, macrophage
function may be suppressed, allowing increased local bacterial growth
and leading to high concentrations of cortisol and NE at the site of
infection.
Other important factors may lead to local immunosuppression.
1) Cortisol may increase NE in the nerve endings because the
production of NE is up-regulated by glucocorticoids (27)
.
2) Cortisol up-regulates the number of ß-adrenoreceptors
(28
29
30)
. High concentrations of NE and a high number of
ß-adrenoreceptors leads to an increase of cAMP concentration and
subsequent inhibition of TNF- production (24
25
26)
.
3) It was demonstrated in thymocytes (31)
and
bronchial cells (31
, 32)
that cortisol and pathways that
stimulate cAMP response element binding protein (CREB) may synergize.
4) TNF- or LPS by up-regulation of regulators of
G-protein signaling selectively inhibit signaling through
Gi/o and Gq
(33
, 34)
. Thus, TNF- itself preferentially leads to
activation of the GS pathway (33)
and increases adenylate cyclase responsiveness (35)
. All
these actions result in a potent inhibitory net effect of the
sympathetic nervous system at the local infection site, particularly in
the presence of cortisol. We demonstrated that under bacteria-free
conditions TNF- secretion was very low and IL-6 secretion was mainly
inhibited by 2-adrenoreceptor ligation (preference of the
Gi/o pathway). In the presence of bacteria,
TNF- and IL-6 secretion were high and IL-6 secretion was mainly
inhibited by ß-adrenoreceptor ligation (preference of the
GS pathway). This switch from -adrenergic
to ß-adrenergic inhibition of IL-6 was mediated by bacteria-induced
TNF- secretion. The - to ß-adrenoswitch is an important element
for NE-induced inhibition of extensive TNF- secretion (via
GS, cAMP, and CREB). However, an overshooting
negative feedback response can generate general immunodepression, which
may cause a severe systemic problem during sepsis (36
, 37)
. In addition, high concentrations of norepinephrine at the
local site of infection may augment bacterial growth
(38
39
40)
. Thus, elevated local NE and cortisol levels
would beneficially inhibit excessive cytokine secretion but could also
be harmful due to decreased immunocompetence and support of
bacterial growth.
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ACKNOWLEDGMENTS |
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Received for publication May 18, 1999.
Revision received January 19, 2000.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONCONCLUSIONSREFERENCES |
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-
-
-) of 104 CFU of
Pseudomonas aeruginosa/ml medium. TNF-
··). In experiments with bacteria, 104 CFU
of Pseudomonas aeruginosa/ml medium were used throughout
the entire superfusion period. For superfusion protocol (12 slices from
at least three different mice per drug, concentration and condition)
and IL-6 determination, see legend to Fig. 3
