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*
Department of Hematology and Oncology, University of Regensburg, Regensburg, Germany;
Beatson Institute for Cancer Research, Glasgow, United Kingdom; and
Institute for Immunlogy and Cell Biology, University of Stuttgart, Stuttgart, Germany
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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(mTNF) expressed on PBMC and, in addition, by
TNF-independent soluble factors that trigger apoptosis in EC.
Neutralizing anti-TNF mAb completely blocked coculture-mediated
apoptosis, despite the fact that there should have been additional
soluble cell death factors. This led to the hypothesis that a reverse
signal is transmitted from the TNF receptor on EC to monocytes (MO) via
mTNF that prevents the production of soluble apoptotic factors. Here we
have tested this hypothesis. The results support the idea of a
bidirectional cross-talk between MO and EC. Peripheral blood MO,
MO-derived macrophages (M
), or the monocytic cell line Mono Mac 6
were preincubated with human microvascular EC that constitutively
express TNF receptor type I (TNF-R1) and subsequently stimulated with
LPS. Cell-free supernatants of these preparations no longer induced EC
apoptosis. The preincubation of MO/M with TNF-reactive agents, such
as mAb and soluble receptors, also blocked the production of death
factors, providing further evidence for reverse signaling via mTNF.
Finally, we show that reverse signaling through mTNF mediated LPS
resistance in MO/M as indicated by the down-regulation of
LPS-induced soluble TNF and IL-6 as well as IL-1 and
IL-10. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Such a reverse signaling of membrane-bound members of the TNF ligand (L) superfamily has been reported for the CD30L (4), CD40L (5), CD95L (FasL) (6), and CD137L (7). In the present report, we provide evidence, to our knowledge for the first time on the basis of functional studies, for a reverse signaling by TNF itself that ultimately leads to the desensitization of MO against bacterial endotoxin.
These data argue for an active role of the vascular endothelium in regulating cytotoxic responses by inducing anergy in immune effector cells via TNF receptor-mTNF bidirectional signaling processes.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The human dermal microvascular EC line CDC/EU.-HMEC-1 (further
referred to as EC) was kindly provided by the Centers for Disease
Control and Prevention (Atlanta, GA) and has been established as
previously described (8). EC (passages 25–35) were
cultured in MCDB131 medium, supplemented with 15% FCS, 1 µg/ml
hydrocortisone (Sigma, Deisenhofen, Germany), 10 ng/ml epidermal growth
factor (Collaborative Biochemical Products, Bedford, MA), and
antibiotics. PBMC were derived from heparinized (Novo Nordisk, Mainz,
Germany) blood of healthy human blood donors according to a standard
protocol using Ficoll hypaque (Pharmacia, Freiburg, Germany) density
gradient centrifugation and subjected to elutriation. Preparation of MO
and MO-derived macrophages (M) were performed as described
previously (9). The monocytic cell line Mono Mac 6 was
kindly provided by Dr. H.W.L. Ziegler-Heitbrock (University of Munich,
Munich, Germany) (10). All experiments presented have been
performed with all three types of monocytic cells. Therefore, we
collectively named them MO/M. All cell culture reagents have been
purchased by Life Technologies (Karlsruhe, Germany) unless stated
otherwise. Cytokines, endotoxin, and (monoclonal) Abs were obtained
from the following sources or described in the following references:
human recombinant TNF- (Knoll AG, Ludwigshafen, Germany), LPS
(serotype 026:B6 from Escherichia coli; Sigma), ELISA kit
for IL-6 (PharMingen, Hamburg, Germany), anti-TNF- mAbs MAK195
and MAK199 (Knoll AG) (11), and T1, as well as
anti-TNF receptor TR60 mAb H398 (12), anti-TNF
receptor TR80 Ab fragments (M80Fab), and mAb 80 M2 (13).
For inhibition/stimulation studies, these Abs were used at a
concentration of 20 µg/ml. The optimal Ab dose was determined by
dose-response experiments (not shown).
Apoptosis assays
A total of 1 x 105/plate EC were
seeded in 35-mm petri dishes (Nunc, Wiesbaden, Germany) and cocultured
with SN of differently treated MO/M for 48 h. MO/M were
either left untreated or incubated in the presence of LPS (10 ng/ml)
for 4 h, washed, and subsequently incubated another 4 h
before SN were collected. To monitor EC apoptosis, the cells were fixed
with methanol/acetone (1:1) for 2 min, washed once in PBS, and stained
with 4,6-diamidino-2-phenylindole (DAPI) (0.5 µg/ml; Sigma) dissolved
in 20% glycerin/PBS. Samples were mounted and subjected to microscopic
analysis. Nuclear condensation as revealed by DAPI staining in the
absence of trypan blue uptake is considered characteristic of apoptosis
as opposed to necrosis (14, 15). The quantitative analysis
included counting the number of apoptotic relative to all identifiable
cells from at least 10 microscopic fields with an average of 70 cells
per field.
An alternative method for detecting apoptosis in human EC was performed as previously described (16) using flow cytometry. Apoptotic cells were identified by a characteristic side scatter image distinct from that of nonapoptotic cells. All results presented in this report were reproduced with this specific method. For the sake of clarity, these results are not displayed here.
ELISA
TNF- in the SN of MO/M was determined by the ELISA
sandwich technique. Briefly, 96-well plates were coated with the
anti-TNF- mAb MAK199, subsequently (hyper)incubated with the
relevant cell culture SN or titrated TNF- standards, respectively.
Development was performed with a biotinylated anti-TNF- mAb
(MAK195) and a peroxidase conjugate according to a standard protocol.
The ELISA for the detection of IL-6, IL-1, and IL-10 in the SN of
MO/M was performed exactly according to the manufacturer’s
instructions.
Statistical analysis
The significance of differences between experimental values was
assessed by means of the Student’s t test. Analysis of the
differences between EC apoptosis inducing vs noninducing SN of MO/M
revealed values of p < 0.001 in all cases. Statistical
analysis of the ELISA results are, where applicable, presented in the
legends to the tables.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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with EC abrogates the production of
LPS-induced EC death factors
All experiments presented below have been performed with
elutriated MO, M, and the monocytic cell line Mono Mac 6. For
simplicity, these different cells are collectively named MO/M
throughout the manuscript. As the experiments involved a series of
incubation and washing steps, the experimental design is illustrated in
panel a of each figure for clarity.
To investigate the hypothesis of a bidrectional cross-talk between EC
and MO/M, MO/M were first seeded for 30 min on an EC monolayer
and subsequently stimulated with LPS (10 ng/ml) for 4 h. MO/M
were then washed three times to remove all reagents and incubated for
another 4 h. Then, SN of these cells were collected and
investigated for their ability to induce EC programmed cell death (Fig. 1
a). In addition, EC were
pretreated with a TNF receptor type I neutralizing mAb
(anti-TNF-R1) for 30 min. Fig. 1b shows that SN derived
from LPS-treated MO/M strongly induced apoptosis in EC (bar
2). In contrast, MO/M that had been preexposed to EC no longer
secreted EC death factors (bar 3). This suppression could be
abrogated by pretreatment of EC with anti-TNF-R1 (bar
4). Supernatants from untreated MO/M did not induce EC
programmed cell death, which confirms previously published observations
(3). These experiments indicate that the cross-talk is
mediated by the interaction of mTNF expressed by activated MO/M and
TNF receptors that are constitutively expressed by EC.
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was provided by the observation that preincubation of EC with soluble
TNF completely blocked the negative signal transmitted by EC (data not
shown), obviously due to the competition in engaging the receptor
binding sites.
Anti-TNF monoclonal Fab inhibit the appearance of
apoptosis-inducing capacity in the SN of LPS-stimulated MO/M
These data clearly indicated that EC are able to generate a
negative regulatory signal toward MO/M that is TNF receptor
dependent and prevents the expression of EC death factors. To confirm
the direct involvement of MO/M mTNF, monocytic cells were
preincubated with anti-TNF mAb Fab for 30 min to engage mTNF before
LPS challenge (Fig. 2a). It is
important to note that Fab have been used to prevent binding of the Abs
to the monocytic Fc receptors. As depicted in Fig. 2b, both
the (Fab')2 as well as the Fab of the
TNF-specific mAbs MAK195 and T1 prevented the production of
apoptosis-inducing SN in MO/M (bars 5 and
6). The completeness of this blockade strongly supports a
central role for mTNF in the initiation of reverse signaling. The fact
that also the monovalent Fab could inhibit the production of cytotoxic
factors further suggests that oligomerization of mTNF may not be
necessary to elicit this response.
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response to LPS (data not shown).
Soluble TNF receptors induce reverse signaling in MO/M
To conclusively prove that reverse signaling proceeds via mTNF, we
used soluble TNF receptor (TNF-R1, TNF-R2) fusion constructs, where the
respective extracellular domain is linked to the Fc part of a human
IgG1 Ab (Fig. 3a). It is
important to note that monocytic cells lack a receptor for IgG1 Fc.
MO/M were pretreated for 30 min with either soluble TNF-R1-Fc or
TNF-R2-Fc. Both constructs were able to suppress the apoptosis-inducing
capacity in SN of LPS-stimulated MO/M (Fig. 3b,
bars 7 and 8).
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These data strongly suggest a role of MO/M-derived mTNF in
regulation of cytotoxic factor production. However, they do not fully
exclude that these effects are due to a paracrine or even autocrine
interaction between mTNF and TNF receptors on the surface of MO/M.
To test this possibility, MO/M were preincubated with
receptor-neutralizing TNF-R1- and TNF-R2-specific Abs before SN were
prepared as described for
Figs. 1–3
. The production of LPS-induced
death factors could not be prevented by this treatment, further
supporting the concept of reverse signaling through mTNF (Fig. 4, a and b).
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, including
genuine TNF-receptors, soluble TNF receptor constructs, Abs, or Ab
fragments, prevented the expression of LPS-induced cytotoxic factors,
suggesting a reverse signaling pathway. Reverse signaling through mTNF inhibits release of soluble TNF induced by LPS
To further elucidate the nature of the reverse signaling by mTNF,
we investigated LPS responses of MO/M other than the production of
EC death factors. One key response mediator of LPS challenge is the
production of soluble TNF that is rapidly induced after LPS addition.
The presence of soluble TNF in SN, prepared as described for Fig. 2, was measured by ELISA. Briefly, elutriated MO and Teflon-grown M
were either left untreated or incubated with LPS for 6 h in the
presence or absence of a previous preincubation with
the anti-TNF mAb 195F. Pretreatment with anti-TNF alone served as a
control. In both cases, anti-TNF had vigorously been washed before
collection of the SN for ELISA analysis.
Table I demonstrates that stimulation of
mTNF by the mAb 195F led to an almost complete down-regulation of
soluble TNF production after LPS challenge (p
< 0.001) in MO. In M, TNF levels after LPS were found to be 8735
pg/ml (±2530). Preincubation of M with anti-TNF down-regulated
the release of soluble TNF to 1183 pg/ml (±1480; p =
0.01); reverse signaling alone (anti-TNF) did not influence TNF
release.
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to become resistant to LPS-induced inflammatory
responses. Reverse signaling via mTNF inhibits the LPS-induced release of IL-6
IL-6 is one of the primary acute-phase proteins that are released
upon LPS stimulation. To answer the question whether LPS resistance or
unresponsiveness induced by reverse signaling of mTNF also affects
other inflammatory mediators, SN of MO/M were analyzed for IL-6
production 2, 6, and 24 h after LPS stimulation using a standard
ELISA technique. A representative experiment is shown in Table II. Reverse signaling via mTNF partially
down-regulated the LPS-induced IL-6 release by 50–80% at all time
points tested. IL-6 release varied considerably among different blood
donors, so that statistical analysis was not applicable. It remains to
be elucidated why inhibition of LPS-induced IL-6 release was
incomplete. One can speculate that LPS may also trigger intracellular
signal transduction pathways independent of a control by mTNF reverse
signaling.
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To gain more information about the nature of the LPS resistance or
anergy that is induced by reverse signaling through mTNF, we also
tested the influence of mTNF stimulation on the LPS-induced release of
IL-1 and IL-10. The monocytic cell line Mono Mac 6 (see Ref.
10) was treated as given, and SN of these cells were
analyzed 6 h (IL-1) and 24 h (IL-10) posttreatment,
respectively. Interestingly, an immediate LPS challenge could not fully
be blocked by mTNF reverse signaling (Table III, anti-TNF/LPS), whereas a 2-h
delay between the mTNF stimulus and LPS challenge (Table III,
anti-TNF/2h/LPS) almost fully abrogated the LPS-induced release of
both cytokines. It remains to be elucidated why mTNF reverse signaling
influenced IL-1 and IL-10 secretion mediated by LPS in an apparently
different way like soluble TNF and the EC death factors, but one can
speculate that mTNF is able to transmit different downstream signals
that take different amounts of time until they can block incoming LPS
signals.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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by various means
elicits a negative regulatory signal that induces monocytic cells to
become resistant to inflammatory responses triggered by LPS. Three
functional parameters strongly support the notion of this bidirectional
cross-talk between EC and MO/M. First, EC expressing TNF receptor
type I (TNF-R1) prevent the expression of endothelial death factors
that are released by monocytic cells upon LPS stimulation. Second,
soluble TNF as a prime response mediator of LPS activation is
completely down-regulated through the engagement of mTNF. Third, the
release of IL-6, an LPS-triggered acute-phase response protein, is
partially blocked by mTNF reverse signaling. Finally, a later mTNF
signal can block IL-1 and IL-10 release mediated by LPS.
It is currently under investigation in our laboratory to delineate the
scope and extent of the mTNF-induced LPS resistance. An interesting
question is, for example, to assess the potential of mTNF to, for
example, restore the IL-12 production in MO/M that is suppressed by
LPS (18).
Indirect effects of mTNF with the TNF receptors on MO/M could be
ruled out by a number of control experiments. Here, the probably most
convincing evidence was that neutralizing TNF receptor Abs (Fig. 4)
failed to prevent the production of death factors by MO/M in
response to LPS stimulation. In addition, we assured that LPS
resistance was not caused by shedding of the primary monocytic LPS
receptor CD14. Flow cytometric analyses of LPS-treated MO/M showed
that CD14 expression was not affected by reverse signaling (data not
shown).
The final molecular proof of principle for a reverse signaling by mTNF
is certainly to use cells from TNF knockout mice
(19). It is the subject of ongoing studies in our
laboratory to transfect MO/M from TNF knockout mice with either
wild-type mTNF or a mutant lacking the cytoplasmic domain. If the
latter mutant is no longer able to provide resistance to LPS-mediated
responses, it must be due to intracellular signal transduction
emanating from mTNF.
There is accumulating evidence in the literature for reverse signaling by members of the TNF/nerve growth factor family. Cross-linking of CD30L on freshly isolated neutrophils increases IL-8 production by these cells (4). The engagement of CD40L can influence Ig production in B lymphocytes, depending on the density of CD40L (5). In addition, reverse signaling through the FasL is required for an optimal proliferation and cytotoxic activity of T lymphocytes (6). Finally, CD137 (ILA/4-1BB) has been recognized as a novel and potent MO activation factor by signaling via CD137L (7).
To our knowledge, we show for the first time on a functional basis that
also mTNF itself is able to transmit reverse signals. A first report on
an active role for mTNF as a costimulatory molecule revealed that
anti-TNF up-regulated anti-CD3-induced IFN-
mRNA expression,
whereas IL-4 mRNA expression was blocked (20). Work is in
progress in our and in other laboratories to elucidate intracellular
signal transduction mechanisms associated with reverse signaling of the
TNF family. It is important to note in this context that also Fab
induced reverse signaling of mTNF (Fig. 2). This suggests that
cross-linking of mTNF, in contrast to other TNF-like ligands, may not
be mandatory for signal transduction. With regard to downstream
signals, Watts et al. provide evidence that casein kinase I
phosphorylates the cytoplasmic domain of mTNF at a consensus sequence
that is conserved among members of the TNF family (21). In
addition, a phosphorylation site of mTNF at serine residues could be
identified (22). While these studies show that the
cytoplasmic portion of mTNF is a target for signal transduction
molecules, they do not yield information on the mechanism of signaling.
However, as phosphorylation sites often serve as docking sites for
adapter proteins and initiate the assembly of signaling complexes, it
is worthwhile to investigate whether mTNF uses classical signal
transduction pathways. With the help of activation-specific Abs and
kinase assays, one can identify several components that might be
involved in reverse signaling.
Along these lines, we have investigated whether the LPS resistance
phenomenon could be explained by the mTNF reverse signaling interfering
with NF-
B activation in response to LPS stimulation. But preliminary
results from our group argue against an effect of mTNF on NF-B
activation, as determined by Western blot analysis of the
phosphorylation and degradation of the NF-B inhibitor I-B (data
not shown).
mTNF has been demonstrated to have some unique properties that are not shared with the soluble form of this cytokine. (2, 17, 23, 24). The observation that mTNF also can transmit reverse signals may have considerable implications for the therapeutic or prophylactic interference with TNF-triggered inflammation. A negative regulatory signal inducing LPS resistance could be of benefit for the control of undesired activation processes triggered by TNF. Success in the treatment of transplant patients with neutralizing TNF Abs (25) may also in part be explained by suppression of macrophage activation due to reverse signaling.
It will be interesting to investigate whether cells other than MO/M
are able to transmit similar reverse TNF signals, e.g., EC, which are
known to constitutively express mTNF (2).
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Acknowledgments |
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differentiation. The expert technical
assistance of Silvia Haffner is gratefully acknowledged. |
Footnotes |
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2 Address correspondence and reprint requests to Dr. Günther Eissner, Department of Hematology and Oncology, University of Regensburg, Franz-Josef-Strauss-Allee 11, D-93053 Regensburg, Germany.
3 Abbreviations used in this paper: EC, endothelial cell; mTNF, transmembrane TNF-; MO, monocyte; M, macrophage; SN, supernatant; L, ligand.
Received for publication December 20, 1999. Accepted for publication April 3, 2000.
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