Laboratory of Surgical Metabolism, Department of Surgery, New York Hospital Cornell Medical Center, New York, New York 10021; and Division of Surgical Sciences, University of Medicine and Dentristry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey 08903
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ABSTRACT |
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Postinjury deficits in monocyte tumor necrosis
factor receptors (moTNFR) activity may alter beneficial functions
during an inflammatory response. Several counter-regulatory hormones
elicited during inflammation may modulate tumor necrosis factor (TNF)
activity, but little is known about their influence on moTNFR. Also,
catecholamines inhibit TNF production, but the adrenoreceptor mechanism
of this effect has not been fully clarified. To determine the effect of catecholamines and corticosteroids on moTNFR, whole blood was coincubated for up to 8 (moTNFR) or 24 h (cytokines) in the presence of
lipopolysaccharide (100 ng/ml) and
1) epinephrine (Epi,
106 M), dexamethasone (Dex,
10
6 M) or both (EpiDex,
10
6 M) to assess the
expression of total moTNFR, moTNFR-I, and moTNFR-II. 2) Epi and norepinephrine (EpiNE,
10
6 M) and the
1+2-,
1+2-,
1-, or
2-adrenergic antagonists were
used to assess the role of such adrenoreceptors on total moTNFR and TNF
production, and
N6,2'-O-dibutyryl
adenosine 3',5'-cyclic monophosphate (DBcAMP) alone or in
combination with the phosphodiesterase inhibitor Ro-20-1724/000, to study the cAMP-dependent pathway on total moTNFR. We found that Epi
upregulated total moTNFR and moTNFR-II. Dex did not significantly influence total moTNFR or moTNFR-II. Also, EpiNE increased total moTNFR
and inhibited TNF by a
2-dependent mechanism. DBcAMP
(10
5 M) modestly enhanced
total moTNFR. This suggests a common mechanism for acutely enhancing
moTNFR and attenuation of soluble TNF appearance during conditions of
severe stress.
epinephrine; dexamethasone; adenosine 3',5'-cyclic monophosphate; cytokines; lipopolysaccharide; tumor necrosis factor
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INTRODUCTION |
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DESPITE EVIDENCE that an overwhelming inflammatory response to sepsis (29) or severe trauma (21) may induce organ damage, the pattern of organ failure later in the course of systemic inflammatory syndrome is characterized by fluctuating levels of soluble proinflammatory cytokines (12) along with a decreased presence of cell-associated tumor necrosis factor receptors (TNFRs) (5). This deficit in monocyte cell surface TNFR activity is associated with a poor outcome (5).
Two distinct TNFRs have been characterized, differing both in their molecular weight (55 kDa for TNFR-I, 75 kDa for TNFR-II) and in their relative expression in human cell lines. Both receptors belong to a family of cell surface proteins, including the receptors for nerve growth factor, Fas antigen, BP-50, OX-40, and CD-27, each of which exhibits a characteristic repeating extracellular cysteine motif (27). Monocytes, neutrophils, and activated lymphocytes express both TNFRs (35), the density of TNFR-II being higher than TNFR-I in resting peripheral blood monocytes and in activated T cells (6). TNFR-I shares an intracytoplasmic sequence with Fas (CD-95), a transmembrane receptor that transduces signals leading to programmed cell death (apoptosis) (26). Recent data suggest that only cells cotransfected with both TNFR-I and TNFR-II exhibit TNF-dependent apoptosis and that increased expression of TNFR-II promotes this process (30). Hence, the adequacy as well as the pattern of TNFR expression may be critical for the endogenous regulation of inflammatory cell turnover.
A loss of monocyte TNFRs (moTNFRs) occurs during both experimental (10) and clinical endotoxemia (31). This postinjury deficit of membrane-associated receptors may serve to attenuate the acute effects of inflammatory cytokine products. Nevertheless, a postinjury maintenance or restoration of these membrane TNFRs actually is associated with eventual survival (5).
After severe injury, concurrent increased levels of counter-regulatory
hormones, including both cortisol (2) and catecholamines (32), modulate
various components of the cytokine cascade during sepsis. We have
demonstrated in vitro and in vivo (32) that catecholamines inhibit TNF
production during concomitant lipopolysaccharide (LPS) stimulation
through -adrenoreceptor activation. Nevertheless, it
is unknown whether catecholamines and/or corticosteroids may influence the expression of moTNFR after LPS exposure. Furthermore, the
specific role of
-receptor subtypes on
catecholamine-elicited TNF inhibition remains unclear.
The purpose of this study was to determine whether catecholamines
and/or corticosteroids may influence the appearance of moTNFR in LPS-stimulated whole blood and, if so, to determine which type of
moTNFR is involved and to clarify the mechanisms of this effect. We
also further dissected the role of
1- and
2-adrenoreceptors on
catecholamine-elicited TNF downregulation.
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MATERIALS AND METHODS |
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Whole blood assays. Blood from healthy adults was collected aseptically using a sterile collecting system consisting of a butterfly (Butterfly, Abbott Laboratories, North Chicago, IL) connected to a needle (Becton-Dickinson, Rutherford, NJ) in a 10-ml tube containing EDTA-K3 (vacutainer, Becton-Dickinson, Franklin Lakes, NJ) or in sterile heparin-prefilled (heparin sodium, 10 U/ml blood final concentration, Elkins-Sinn, Cherry Hill, NJ) 50-ml conical tubes (Sarstedt) for TNFR and cytokine assessment, respectively. Whole blood for moTNFR assays was collected in EDTA tubes to avoid heparin-mediated release of TNFR (17). We studied the hormonal influences on cytokine production and moTNFR in LPS-stimulated whole blood because this in vitro model produces similar cytokine release kinetics to that observed in isolated peripheral blood mononuclear cell (PBMC) systems (8). Previous experiments demonstrated that the fluorescence signal of moTNFR remained stable for up to 12 h of incubation in the absence of LPS and that the temporal pattern of moTNFR downregulation after LPS incubation was similar to that observed in vivo (31).
To assess the influence of counter-regulatory hormones on whole blood moTNFR and TNF production, blood was diluted 1:1 in sterile RPMI-1640 supplemented with L-glutamine (Bio Whittaker, Walkersville, MA) and incubated in 5-ml sterile polypropylene tubes (Falcon, VWR, West Chester, PA) for up to 8 (moTNFR) or 24 h (TNF) at 37°C and 5% of CO2, in the presence or absence of LPS (100 ng/ml final concentration; Escherichia coli serotype 0127:B8, Sigma Chemical, St. Louis, MO) or 0.9% NaCl as a control (Abbott Laboratories). Previous dose response and time sequence experiments in the presence of LPS (100 ng/ml) showed maximal total moTNFR upregulation by epinephrine (Epi), norepinephrine (NE), and dexamethasone (Dex) at 10MoTNFR measurements. Monocyte-associated TNFR (total moTNFR) were determined as previously described (31). Briefly, erythrocytes in 400 µl of blood underwent lysis with bicarbonate-buffered (pH 7.2) 0.826% ammonium chloride solution. Leukocytes were recovered by centrifugation, washed with cold phosphate-buffered saline (PBS) containing 0.1% sodium azide and stained with 1 µg/ml biotinylated TNF. After incubation on ice for 15 min, cells were washed with cold PBS containing 0.1% sodium azide and stained with 0.5 µg/ml of streptavidin R-phycoerythrin (PE) (Caltag Laboratories, South San Francisco, CA) for 15 min on ice. Leukocytes were then washed twice with PBS containing 0.1% sodium azide and resuspended for fluorescence-activated cell sorter (FACS) analysis. Nonspecific staining was assessed by incubating only with PE-conjugate streptavidin. This method gave a background identical to that obtained when leukocytes were incubated with 100-fold excess unlabeled human TNF, as previously reported (5).
Expression of moTNFR-I (CD-120b) and moTNFR-II (CD-120a) receptors was determined using specific antibodies directed against either the TNFR-I receptor (htr-20), or the TNFR-II receptor (utr-4), both kindly donated by Dr. M. Brockhaus (F. Hoffmann-La Roche, Basel, Switzerland). Htr-20 and utr-4 are noninhibitory, nonagonist antibodies that do not interfere with the binding of TNF to its receptors (3). In experiments in which htr-20 and utr-4 were used, erythrocytes in 400-µl aliquots of blood were lysed and leukocytes were incubated with either htr-20, utr-4, or mouse immunoglobulin G1 (MOPC-21, Sigma Chemical; all 50 µl of a 20 µg/ml solution) for 45 min on ice. After being washed with PBS, leukocytes were then stained with F(ab')2 fragment of PE-conjugated sheep anti-mouse antibody (Sigma Chemical; 50 µl of 14 µg/ml) for 30 min on ice. Thereafter, leukocytes were washed twice with cold PBS and resuspended for FACS analysis. The flow cytometer photomultiplier gain was standardized using PE-conjugated beads (Calibrite, Becton-Dickinson Immunocytometry Systems, San Jose, CA). Mean channel fluorescence (MCF) at >570 nm was assessed for forward and side angle light scatter-gated monocytes. Data was presented as absolute MCF units that represent the difference between MCF intensities of specifically and nonspecifically stained cells.Assays. Levels of TNF (CLB, Amsterdam, the Netherlands) immunoactivity were measured in plasma supernatants using specific enzyme-linked immunosorbent assay. The sensitivity of this immunoassay was 4 pg/ml. Cytokine levels are expressed as nanograms per 106 PBMCs. Leukocyte counts and differentials were determined in K3-EDTA anticoagulated blood using FACS.
Statistical analysis. Data are summarized as means ± SE. Data were analyzed by one- or two-way analysis of variance. When variables did not follow a normal distribution, nonparametric analysis such as the Friedman test and Wilcoxon's sum rank test were employed. P < 0.05 was considered to represent a statistically significant difference. Statistical analysis was done by employing the statistical package Statview 4.02 (Abacus Concepts, Berkeley, CA) for Apple Macintosh.
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RESULTS |
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After 8 h of incubation, neither Dex nor EpiNE significantly influenced the expression of moTNFR in the absence of LPS (78 ± 7, 79 ± 9, and 103 ± 12 MCF in saline, Dex, and EpiNE, respectively. P = 0.2, n = 5). The levels of TNF in non-LPS-stimulated whole blood for all whole blood experiments were 0.004 ± 0.001 ng/106 PBMC.
Epi increases total moTNFR by selective upregulation of moTNFR-II in
LPS-stimulated whole blood.
To investigate the effect of catecholamines and corticosteroids over
time on total moTNFR, moTNFR-I, and moTNFR-II, whole blood was
incubated in the presence of LPS alone or in combination with Epi
(106 M), Dex
(10
6 M), EpiDex
(10
6 M), or saline as a
control, and sequentially assayed for total moTNFR, htr-20
(moTNFR-I), and utr-4 (moTNFR-II) at baseline and 30, 60, 180, and 360 min afterward and analyzed by FACS. We found that total
moTNFR, moTNFR-I, and moTNFR-II were significantly diminished within 30 min after LPS exposure in all treatment groups (P < 0.001; Fig.
1, top,
middle, and
bottom, respectively). None of the
hormone regimens prevented this diminution of TNF receptors. After 360 min, the Epi-treated group demonstrated a significant reappearance of
both total moTNFR (81 ± 17 vs. 28 ± 6 MCF in Epi and LPS,
respectively, P < 0.05, n = 3; Fig. 1,
top) and moTNFR-II (110 ± 8 vs.
54 ± 6 MCF in Epi and LPS, respectively,
P < 0.05; Fig. 1,
bottom). No effect was observed on
moTNFR-I with Epi treatment (3.9 ± 0.5 vs. 5.3 ± 0.8 in Epi and
LPS, respectively, P = 0.5; Fig. 1,
middle). Dex did not significantly
influence the reappearance or modify the effect of Epi on moTNFR in
LPS-stimulated whole blood (Fig. 1,
top,
middle, and
bottom).
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Catecholamines increase total moTNFR and inhibit TNF production
through 2-adrenoreceptor
activation.
We investigated the role of the different adrenoreceptors on the
expression of total moTNFR and TNF production by incubating whole blood
over 8 (total moTNFR) or 24 h (TNF) in the presence or in the absence
of LPS alone (100 ng/ml) or in combination with EpiNE
(10
6 M), with and without
1+2-,
1+2-,
1-, and
2-adrenergic antagonists. We
found that EpiNE increased total moTNFR appearance (47 ± 13 and
142 ± 32 MCF in LPS and LPS + EpiNE, respectively, P < 0.05, n = 5). This effect was completely
abrogated by propranolol (142 ± 32 and 44 ± 6 MCF in LPS + EpiNE without and with propranolol, respectively,
P < 0.05). In addition, the specific
2-antagonist, ICI-118,551, blocked the salutary effect of EpiNE on
LPS-induced downregulation of total moTNFR in a dose-dependent manner
(P < 0.05; Fig.
2, top).
We also documented that EpiNE significantly attenuated LPS-elicited TNF
production (2.4 ± 0.3 and 0.8 ± 0.2 ng/106 PBMC in LPS and LPS + EpiNE, respectively, P < 0.05), and this effect was substantially abrogated by propranolol
(0.8 ± 0.2 and 1.9 ± 0.4 ng/106 PBMC in LPS + EpiNE without
and with propranolol, respectively, P
<0.05). Blockade with the
2-antagonist ICI-118,551
revealed similar results [0.8 ± 0.2 vs. 1.8 ± 0.4 ng/106 PBMC in LPS + EpiNE without
and with
2-antagonist
(10
5 M), respectively,
P <0.05]. The
1-antagonist metoprolol did not
alter the Epi effect on TNF production (0.8 ± 0.2 vs. 1.0 ± 0.3 ng/106 PBMC in LPS + EpiNE without
and with metoprolol, respectively, P = 0.6; Fig. 2 bottom).
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cAMP agonists partially mimic the effect of Epi on total moTNFR
expression.
To further investigate the intracellular pathway specific to these
adrenergic influences on total moTNFR, whole blood was coincubated over
8 h in the presence of LPS alone or in combination with DBcAMP, the
selective type IV phosphodiesterase inhibitor Ro-20, or a combination
of both. DBcAMP only partially mimicked the above noted and
2 effect, because this compound
significantly enhanced the LPS-elicited total moTNFR (32 ± 5 vs. 51 ± 6 MCF in LPS and LPS + DBcAMP, respectively.
P < 0.05, n = 8). Ro-20 alone did not influence
total moTNFR when coincubated with LPS, nor did this agent
significantly enhance the effect of DBcAMP [51 ± 6 vs. 58 ± 5 MCF in LPS + DBcAMP with and without Ro-20 (10
6 M), respectively (Fig.
3)].
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DISCUSSION |
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This study demonstrates that
2-adrenoreceptor activation not
only causes inhibition of TNF production in LPS-stimulated whole blood
but also fosters the restoration of moTNFRs under such circumstances. Epi enhanced moTNFR by a selective increase in the type II TNFR. This
catecholamine-elicited effect was essentially prevented by a
2-antagonist. Furthermore, we
observed that this influence on moTNFR upregulation was at least
partially independent of TNF ligand as Dex-suppressed TNF production
(results not shown) without significantly influencing either the
initial or subsequent moTNFR responses to LPS upregulation.
A TNF--converting enzyme has recently been cloned (20). This
membrane-bound disintegrin metalloproteinase (MMP) processes the TNF
membrane-bound precursor of 26 kDa into the soluble and mature form of
16 kDa. Furthermore, it has been demonstrated that the transmembrane
receptors TNFR-II (p75) (36) and Fas ligand (14) may shed by a
metalloproteinase-dependent mechanism. Furthermore, experiments in
vitro have demonstrated that Epi downregulates soluble TNF through
posttranscriptional mechanisms (23). Epi might increase moTNFR
appearance and decrease TNF (26 kDa) shedding by modulating MMP
activity. It has been demonstrated that cAMP agonists decrease MMP
activity by inhibiting their synthesis (9) or by enhancing the tissue
metalloproteinase inhibitor, thioinosinic acid I (25).
The effect of TNF inhibition through
2-adrenoreceptor activation is
in contrast to a previous report suggesting an increased TNF response
after catecholamine incubation (24). In that study mouse macrophages
were coincubated in the presence of UK-14304, a specific
2-adrenergic agonist. It is
possible that macrophages display a different adrenoreceptor phenotype
compared with human monocytes. Along this line, a loss of
-receptor
function during the maturation of human monocytes to macrophages has
been demonstrated (1). Hence, a selective
-stimulation eliciting a
calcium-dependent protein kinase activation may enhance transcriptional
factors induced by proinflammatory cytokines. The present data are also in contrast to previous studies of TNF inhibition through
1-activation (33). Because the
main difference between both studies is the agonist employed, it is
possible that, by incubating NE alone (a predominant
2- and
1-agonist) and excluding Epi,
the influence of the
2-receptor
might be overlooked. Both
-receptors stimulate adenyl cyclase and
increase cAMP levels (16). Nevertheless, because
1 is more resistant than
2 to both short- and long-term desensitization (19), an increased density of
2-receptors in human monocytes
(34) may account for the effect documented in the present study.
Epi may also enhance moTNFR synthesis, as has been demonstrated for cAMP agonists that increase TNFR-II mRNA in leukemic cells (18). In the present study we found that DBcAMP only partially reproduced the EpiNE effect. One possibility for this discrepancy is that catecholamines, by specifically binding to the receptor-G protein complex, may sustain more biologically active levels of cAMP (13) or that the adrenergic agonist-Gs complex elicits moTNFR upregulation by a cAMP-independent mechanism (7). Another possibility for this different response could be that, in this whole blood model, DBcAMP might be further metabolized to adenosine and dibutyrate. There is general agreement that the soluble compound DBcAMP is capable of permeating the cell membrane and mimics that action of endogenous cAMP (4). However, we cannot rule out that the effect on moTNFR might also be triggered by adenosine through a type 1 purinergic (P1, subclass A2) receptor activation (11), as the complex adenosine-A2 may also activate cAMP-dependent protein kinase (15). Nevertheless, a similar effect on TNFR upregulation has been observed by employing 8-bromo cAMP, a compound that is not metabolized to other potentially active second messengers (22). Furthermore, the differences in activity between Epi and DBcAMP could not be explained by a decreased half-life of the soluble cAMP agonist, because the combination of DBcAMP with the phosphodiesterase inhibitor Ro-20 did not significantly increase the effect over that of DBcAMP alone.
In summary, this study shows that
2-activation increases the
recovery of monocyte TNF binding capacity after LPS stimulation. This
occurs via a type-II TNF receptor enhancement. Although the maximum
effect was observed in response to Epi concentrations above the
physiological range, these findings do suggest the potential for this
mechanism during inflammatory conditions. Although it remains to be
determined whether severe stress conditions are sufficient to elicit
this response in vivo, it is tempting to speculate that exogenous
administration of catecholamines might be of therapeutic benefit for
maintenance or restoration of immune cell receptor status. The
biological relevance of this study is supported by the observations
that, in critically ill patients, levels of proinflammatory cytokines
correlate poorly with clinical outcome, whereas monocyte and
granulocyte TNFR levels appear to acutely reflect the ultimate
prognosis of patients with severe sepsis (5). This deficit in monocyte-
or granulocyte-associated receptors might inhibit TNF and/or
FasL-mediated apoptosis and thereby perpetuate a dysfunctional
inflammatory cell population. Also, a concomitant decreased presence of
cell associated TNF might interfere with cell-to-cell paracrine
signaling and the necessary immunomodulatory effects of such activity.
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ACKNOWLEDGEMENTS |
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We extend our gratitude to Lynn Wood Keogh in the preparation of the manuscript and Lan Nguyen for technical assistance.
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FOOTNOTES |
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This work was supported by United States National Institute of General Medical Sciences grants GM-34695 and T 32 GM-08466. Xavier Guirao is the recipient of postdoctoral grants no. 95/5260, no. 96/5364, and no. 97/5360 from Fondo de Investigaciones de la Seguridad Social, FIS, Ministry of Health, Spain.
Present address of X. Guirao: Dept. of Surgery, Hospital de Figueres, C/Rector Arolas, s/n, 1700 Figueres, Girona, Spain.
Address for reprint requests: S. F. Lowry, Chairman of Dept. of Surgery, Univ. of Medicine & Dentistry of New Jersey-Robert Wood Johnson Medical School, One Robert Wood Johnson Place-CN 19, New Brunswick, NJ 08903-0019.
Received 24 March 1997; accepted in final form 17 September 1997.
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