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production:
roles of tumor necrosis factor-
and IL-10
1 Laboratory of Surgical Metabolism, Department of Surgery, Cornell University Medical College, New York, New York 10021; and 2 Department of Internal Medicine, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
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ABSTRACT |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Epinephrine has
been found to inhibit the production of the proinflammatory cytokine
tumor necrosis factor (TNF)-
and to enhance the production of
anti-inflammatory cytokine interleukin (IL)-10. To determine the effect
of epinephrine on IL-1
production, the following experiments were
performed: 1) blood obtained from subjects at 4-21 h after the start of a continuous infusion of epinephrine (30 ng · kg
1 · min1)
produced less IL-1 after ex vivo stimulation with lipopolysaccharide (LPS), compared with blood drawn from subjects infused with saline; 2) in whole blood in vitro,
epinephrine caused a dose-dependent decrease in LPS-induced IL-1
production, which was likely mediated via adrenergic receptors; and
3) inhibition of TNF and enhancement of IL-10 both contributed to epinephrine-induced inhibition of IL-1
production. Epinephrine, either endogenously produced or administered
as a component of sepsis treatment, may attenuate excessive activity of
proinflammatory cytokines early in the course of systemic infection.
adenosine 3',5'-cyclic monophosphate; lipopolysaccharide; cytokines; adrenergic receptors ; interleukin-1; interleukin-10
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INTRODUCTION |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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INTERLEUKIN (IL)-1 is a multifunctional cytokine that
can exert effects on nearly every cell type (6). IL-1 is
the designation for two polypeptides (IL-1 and IL-1), each
encoded by a separate gene on chromosome 2. Although most IL-1
remains in the cytosol of cells, IL-1 is the predominant type of
IL-1 that can be found in the extracellular environment during disease.
IL-1 has been implicated as a significant mediator of septic shock.
IL-1 can be detected in baboons infused with a lethal dose of live
Escherichia coli and in a subset of
patients with sepsis (2, 11, 13), and administration of IL-1 to baboons
or humans reproduces the major features of sepsis (9, 20). Moreover,
neutralization of endogenous IL-1 activity in animal models of lethal
endotoxemia or bacteremia by infusion of recombinant IL-1 receptor
antagonist has a strong protective effect (10, 21).
In recent years it has become clear that catecholamines can influence
the production of cytokines. Epinephrine has been found to inhibit the
production of the proinflammatory cytokine tumor necrosis factor
(TNF)- by mononuclear cells or whole blood stimulated with
lipopolysaccharide (LPS) in vitro, while simultaneously enhancing the
production of the anti-inflammatory cytokine IL-10 (25, 29, 30).
Accordingly, infusion of epinephrine in healthy humans exposed to an
intravenous dose of LPS is associated with reduced TNF and increased
IL-10 plasma concentrations (30). Hence, epinephrine may
have a net anti-inflammatory effect on the cytokine network.
Knowledge of the effect of epinephrine on IL-1 production is limited.
Such knowledge may not only have implications for the understanding of
endogenous catecholamine effects during acute systemic infection but
also for the therapeutic use of these hormones in patients with septic
shock. It is difficult to determine the effect of epinephrine on
LPS-induced IL-1 synthesis in humans in vivo, because in the widely
adopted model of human endotoxemia, IL-1 is not released to the
circulation in significant quantities (30, 31). Therefore, in the
present study we sought to study this epinephrine effect under
conditions that mimic the human in vivo situation as closely as
possible, i.e., the IL-1 production capacity of whole blood was
determined ex vivo before and during a continuous infusion of
epinephrine in healthy humans in vivo. In addition, because
epinephrine-induced inhibition of TNF and enhancement of IL-10
production found earlier in this model may influence IL-1 production
(5, 8, 11, 30), we examined the roles of these cytokines in the
observed epinephrine effect.
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MATERIALS AND METHODS |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Study design and subjects.
There were 18 male subjects, aged 28 ± 1 (SE) yr, admitted to the
Adult Clinical Research Center of the New York Hospital-Cornell University Medical Center after documentation of good health by history, physical examination, and hematological and biochemical screening. The study was approved by the Institutional Review Board,
and written informed consent was obtained from all subjects before
enrollment in the study. Subjects were randomized to receive either a
constant intravenous infusion of epinephrine (Parke-Davis, Morris
Plains, NJ; 30 ng · kg1 · min1;
n = 8), starting at 9 AM or an
equivalent volume of normal saline (n = 10). Venous blood samples for whole blood stimulation were obtained
before the start of the infusion and at 4, 8, and 21 h thereafter.
Blood was collected aseptically with a sterile collecting system
consisting of a butterfly needle connected to a syringe (Becton
Dickinson, Rutherford, NJ). Anticoagulation was obtained with sterile
heparin (Elkins-Sinn, Cherry Hill, NJ; 10 U/ml blood final
concentration).
Whole blood stimulation.
Whole blood was stimulated for 24 h at 37°C with LPS (10 ng/ml
final concentration; E. coli serotype
0127:B8; Sigma Chemical, St. Louis, MO) in sterile polypropylene tubes
(Becton Dickinson) as described previously (30). After the incubation,
plasma was prepared by centrifugation and stored at 
70°C
until assays were performed. IL-1 levels were expressed as nanogram
per 109 monocytes, because
monocyte counts changed during infusion of epinephrine (30) and
monocytes are the major source of IL-1 (3).
70°C until assays were performed.
Assay.
IL-1 was measured by enzyme-linked immunosorbent assay as described
previously (18, 30).
Statistical analysis. All values are given as means ± SE. Serial data were compared by analysis of variance (ANOVA). Paired samples were compared with the Wilcoxon test for matched samples. P < 0.05 was considered to represent a statistically significant difference.
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RESULTS |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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LPS-induced IL-1 production by whole blood ex vivo
during epinephrine infusion.
During infusion of saline, plasma epinephrine concentrations and
monocyte counts did not change and remained normal (30). In addition,
LPS-induced IL-1 production by whole blood was similar at all time
points evaluated, indicating that there was no circadian rythmn that
influenced LPS responsiveness of whole blood (Fig. 1). In subjects receiving a constant
infusion of epinephrine, plasma epinephrine concentrations reached
a plateau of 1,037 ± 179 pg/ml, whereas monocyte counts
modestly increased (30). Epinephrine significantly attenuated
LPS-induced IL-1 production in whole blood
(P < 0.05 vs. saline infusion). This
effect was noted within 4 h after initiation of epinephrine infusion
and persisted throughout the 21-h observation period (Fig. 1).
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Epinephrine inhibits IL-1 production via effect on
-adrenergic receptor.
Next, we studied the mechanisms by which epinephrine inhibits IL-1
production in whole blood in vitro. Incubation of whole blood with LPS
(10 ng/ml) caused an increase in IL-1 concentrations, peaking after
16 h (data not shown). Therefore, in subsequent experiments we used
this incubation period. Epinephrine caused a dose-dependent inhibition
of IL-1 production by whole blood incubated with LPS (Fig.
2, top).
Because epinephrine binds to both - and -adrenergic receptors, we
next assessed which adrenergic receptor was involved in the effects of
epinephrine on IL-1 production. For this purpose, we incubated whole
blood with LPS (10 ng/ml) in the presence or absence of epinephrine
(106 M), the -adrenergic
receptor antagonist phentolamine
(105 M), and/or the
-receptor antagonist propranolol
(105 M). Blockade of
-receptors by phentolamine did not influence the epinephrine
inhibition of IL-1 production. By contrast, propranolol completely
prevented this effect (Fig. 2,
bottom). To confirm that
-adrenergic receptor stimulation mediates the reduction of
LPS-induced IL-1 production, we next incubated whole blood with LPS
and specific - or -adrenergic agonists. As depicted in Fig.
3, isoproterenol (-receptor agonist) was
a potent inhibitor of LPS-induced IL-1 release. By contrast,
phenylephrine (-receptor agonist) did not influence IL-1 levels
(Fig. 3).
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DBcAMP inhibits IL-1 production.
Because adrenergic stimulation is known to result in an elevation of
intracellular adenosine 3',5'-cyclic monophosphate (cAMP) levels (25, 32), we were interested to determine the effect of DBcAMP
on IL-1 production. Addition of DBcAMP caused a dose-dependent decrease in IL-1 levels in LPS-stimulated whole blood (Fig.
4).
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Inhibition of TNF production contributes to inhibition of
IL-1 production by epinephrine.
It has been demonstrated that the production of IL-1 during
gram-negative bacteremia in vivo is partly dependent on TNF production (11). Inhibition of TNF production by epinephrine (30) could therefore
contribute to epinephrine-induced inhibition of IL-1 production. To
evaluate this possibility, we incubated whole blood with LPS (10 ng/ml)
in the presence or absence of epinephrine (106 M), a neutralizing
anti-TNF MAb (25 µg/ml), or an equivalent amount of an irrelevant
isotype-matched control MAb (Table 1). Anti-TNF inhibited LPS-induced IL-1 production, indicating that TNF
is partially responsible for LPS-induced IL-1 production in whole
blood. Furthermore, in the presence of anti-TNF, epinephrine did not
influence the production of IL-1 anymore. These data suggested that
the inhibiting effect of epinephrine on IL-1 production is dependent
on the concurrent inhibiting effect of epinephrine on TNF production.
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Potentiation of IL-10 production contributes to inhibition
IL-1 production by epinephrine.
IL-10 is known to inhibit LPS-induced IL-1 production (5, 8). It was
therefore possible that epinephrine inhibits LPS-induced IL-1
production in whole blood at least in part by enhancing the release of
IL-10 (30). To test this hypothesis we incubated whole blood with LPS
(10 ng/ml) in the presence or absence of epinephrine
(106 M), a
neutralizing anti-IL-10 MAb (25 µg/ml), or an equivalent amount of an
irrelevant isotype-matched control MAb. Anti-IL-10 potentiated
LPS-induced IL-1 production (Table 1). In the presence of
anti-IL-10, epinephrine did not inhibit IL-1 production. Hence these
results suggested that the inhibiting effect of epinephrine on IL-1
production is dependent on the concurrent enhancing effect of
epinephrine on IL-10 production.
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DISCUSSION |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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The primary objective of the present study was to examine the effect of
epinephrine on IL-1 production in humans. Because the dose of LPS
that can be given safely to normal humans in vivo is too low to induce
a detectable IL-1 response (30, 31), we chose to investigate the
IL-1 production capacity of whole blood obtained from humans infused
with epinephrine. The dose of epinephrine sought to resemble two
clinically relevant situations, i.e., plasma concentrations of
epinephrine were in the same range as those reported in patients with
septic shock (12, 30), and the rate and dose at which epinephrine were
infused were in the same range as the rate and dose at which this
hormone is initiated as part of the treatment of septic patients (15).
It is demonstrated that epinephrine infusion was associated with a
decreased production of IL-1 by LPS-stimulated whole blood, an
effect that lasted for at least 21 h after the start of the infusion.
The mechanisms by which epinephrine influenced IL-1 production was
investigated further in whole blood in vitro. We chose to study
epinephrine effects in whole blood, rather than in cultures of isolated
cells, because the use of whole blood eliminates possible artifacts
that may be associated with isolation of cells, such as
adherence-induced expression of TNF (14). In addition, the effect of a
hormone on cytokine production can be investigated in whole blood under
conditions with a physiological endocrine background and in the
presence of all blood components, which is likely to be of more
relevance for the in vivo situation (4, 29, 30). It should be noted
that the concentrations of epinephrine needed in whole blood in vitro
were much higher than epinephrine concentrations achieved during the in
vivo experiments. Similar epinephrine concentrations were used by our
and other groups in in vitro studies examining the effect of this
hormone on cytokine production (25, 30). Possibly, epinephrine levels
added in vitro rapidly declined due to oxidation. Nonetheless, in whole blood, epinephrine inhibited LPS-induced IL-1 production by an exclusive effect on adrenergic receptors. Indeed, adrenergic blockade by propranolol completely prevented the effect of epinephrine on
IL-1 production, and specific receptor adrenergic stimulation reproduced the effect of epinephrine. By contrast, neither the -receptor antagonist phentolamine nor specific
-adrenergic stimulation influenced IL-1 levels.
Elevation of intracellular cAMP levels is a well-described postreceptor
effect of adrenergic stimulation (25, 32). The inhibition of TNF
production by -adrenergic agents has been linked to an
increase in intracellular cAMP concentrations (1, 25, 28, 32). The
effect of -adrenergic stimulation on cAMP levels is transient;
whereas incubation of mononuclear cells with epinephrine or the
-agonist isoproterenol for 2 h led to a rise in intracellular cAMP
concentrations, incubation for 24 h resulted in a decrease in cAMP
levels (25). LPS-induced production of TNF paralleled this biphasic
change in cAMP levels, i.e., preexposure of mononuclear cells to
epinephrine for 3 h reduced TNF synthesis, whereas preincubation with
epinephrine for 24 h enhanced TNF synthesis (25). Therefore, in the
present study we wished to assess the cytokine production capacity of
whole blood after various durations of epinephrine infusions. However,
as was found earlier for the sustained ability of epinephrine to
inhibit LPS-induced TNF production in vivo and ex vivo (30), IL-1
production was diminished even after exposure to epinephrine for 21 h.
In our study, elevation of intracellular cAMP levels by DBcAMP resulted
in a dose-dependent inhibition of LPS-induced IL-1 production by
whole blood, providing further evidence that epinephrine mediates its
effect on IL-1 synthesis via -adrenergic stimulation. The effect
of increased intracellular cAMP on IL-1 (both IL-1 and IL-1)
production by isolated cells or cell lines is controversial (1, 7, 16,
17, 22, 23, 27, 28). Elevation of cAMP by various agents has been
reported either to enhance or not to influence IL-1 mRNA levels (16,
17, 23, 28), and either to enhance, reduce, or not to influence IL-1
protein secretion (1, 7, 16, 17, 22, 23, 27, 28). To our knowledge, our
study is the first to study the effect of elevated cAMP levels on
IL-1 production in whole blood cultures. It is conceivable that
conflicting data on the effect of cAMP on IL-1 production may be
related to differences in experimental conditions and/or stimuli to induce IL-1 synthesis. With respect to the latter
possibility it is interesting to note that in one study elevated cAMP
concentrations inhibited monocytic IL-1 production induced by LPS
but enhanced IL-1 production stimulated by phorbol 12-myristate
13-acetate (16).
The present study did not investigate the effect of epinephrine on IL-1 gene transcription and translation. Also, we did not address the effect of epinephrine on intracellular vs. extracellular IL-1 levels, a relevant issue considering the fact that the majority of IL-1 produced by mononuclear cells is retained intracellularly (6).
The production of IL-1 induced by LPS is partly dependent on TNF (11 and the present study). Because epinephrine inhibits LPS-induced TNF
production (25, 29, 30), we hypothesized that the inhibition of IL-1
production by epinephrine could in part be secondary to reduced TNF
levels. Therefore, to eliminate the effect of reduced TNF
concentrations in the presence of epinephrine, experiments
with a neutralizing anti-TNF MAb were performed. In the presence of
anti-TNF, epinephrine failed to influence IL-1 concentrations in
LPS-stimulated whole blood. Furthermore, because IL-10 inhibits
LPS-induced IL-1 production (5, 8) and epinephrine enhances IL-10
release in LPS-stimulated whole blood (29, 30), we argued that the
epinephrine-induced inhibition of IL-1 release could have been
caused by increased IL-10 levels. We indeed found that anti-IL-10
enhances LPS-induced IL-1 production and that in the presence of
anti-IL-10 epinephrine did not affect IL-1 levels. Hence these
experiments suggest that epinephrine attenuates IL-1 production in
whole blood indirectly via inhibition of TNF and potentiation of IL-10
production.
The systemic inflammatory response syndrome associated with sepsis
involves both activation of the immune and the neuroendocrine system.
Evidence is accumulating that after an acute infectious challenge
epinephrine, either given exogenously or produced endogenously, has
anti-inflammatory effects on the cytokine network by inhibiting the
release of TNF and enhancing the release of IL-10 (19, 24, 26, 30). We
here show that epinephrine inhibits the production of potent
proinflammatory cytokine IL-1, providing further support for the
notion that epinephrine may act to dampen excessive proinflammatory effects of cytokines during the early phases of systemic infection.
Perspectives
Systemic infection leads to the activation of multiple host mediator systems. It has become clear that inflammatory responses that originally were considered to occur independently may influence each other. Activation of the cytokine network plays an important role in the immunological consequences of sepsis. Enhanced release of catecholamines in the early phases after an acute injury has attracted much attention from investigators examining the role of stress hormones in the metabolic changes observed in injured patients. By now it is evident that bidirectional interactions exist between the cytokine network and catecholamines. In this study we show that epinephrine inhibits the production of one of the major proinflammatory cytokines IL-1. Taken together with previous studies, the picture emerges that stress hormones, traditionally considered important for the host metabolic response to infection, may play a significant role in the host immune response to infection.| |
ACKNOWLEDGEMENTS |
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This work was supported by National Institute of General Medical Sciences Grant GM-34695.
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FOOTNOTES |
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Address for reprint requests: S. F. Lowry, Univ. of Medicine & Dentistry of New Jersey, Robert Wood Johnson Medical School, Dept. of Surgery, One Robert Wood Johnson Place CN19, New Brunswick, NJ 08903-0019.
Received 24 February 1997; accepted in final form 18 August 1997.
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Abstract
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Materials & Methods
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References
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 H. Macarthur, T. C. Westfall, D. P. Riley, T. P. Misko, and D. Salvemini Inactivation of catecholamines by superoxide gives new insights on the pathogenesis of septic shock PNAS, August 15, 2000; 97(17): 9753 - 9758. [Abstract] [Full Text] [PDF]
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 I. Matsumoto, A. Niijima, Y. Oomura, K. Sasaki, K. Tsuchiya, and T. Aikawa Acidic fibroblast growth factor activates adrenomedullary secretion and sympathetic outflow in rats Am J Physiol Regulatory Integrative Comp Physiol, October 1, 1998; 275(4): R1003 - R1012. [Abstract] [Full Text] [PDF]
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 M. J. Schultz, P. Speelman, S. Zaat, S. J. H. van Deventer, and T. van der Poll Erythromycin Inhibits Tumor Necrosis Factor Alpha and Interleukin 6 Production Induced by Heat-Killed Streptococcus pneumoniae in Whole Blood Antimicrob. Agents Chemother., July 1, 1998; 42(7): 1605 - 1609. [Abstract] [Full Text]
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