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J Biol Chem, Vol. 274, Issue 12, 7611-7614, March 19, 1999
B
through Interleukin-1 Signaling Mediators in Cultured Human Dermal
Endothelial Cells and Mononuclear Phagocytes*
,
,,,**
From the Bacterial lipopolysaccharide
(LPS)-mediated immune responses, including activation of monocytes,
macrophages, and endothelial cells, play an important role in the
pathogenesis of Gram-negative bacteria-induced sepsis syndrome.
Activation of NF- Lipopolysaccharide
(LPS),1 or endotoxin, is the
major component of the outer surface of Gram-negative bacteria. LPS is
a potent activator of cells of the immune and inflammatory systems,
including macrophages, monocytes, and endothelial cells, and
contributes to systemic changes known as septic shock (1, 2).
LPS-induced activation of monocytes/macrophages is mediated through a
cell surface receptor glycoprotein, known as membrane CD14 (mCD14). The
binding of LPS to mCD14 is enhanced by LPS-binding protein, a plasma
protein (3). On the other hand, vascular endothelial cells do not
express mCD14 and respond to LPS only in the presence of soluble CD14
(4-6).
We (7) and others (8-12) have shown that protein tyrosine
phosphorylation and activation of ERK1, ERK2, p38 mitogen-activated protein kinase, and c-Jun N-terminal kinase appear to be important for
LPS-induced cellular activation. LPS rapidly induces nuclear factor- The toll gene controls dorsoventral pattern formation during the early
embryonic development of Drosophila melanogaster (18). Toll
initiates a signaling pathway homologous to the mammalian NF- It is known that the IL-1 signaling pathway in mammals is strikingly
similar to the toll signaling pathway in Drosophila
(19-22). The molecular events linking the IL-1 receptor (IL-1R)
signaling complex to the induction of NF- In this study, we tested the hypothesis that LPS activates NF- Cell Culture--
Human THP-1 cells (from ATCC) were cultured in
RPMI medium with 10% fetal calf serum. The immortalized human dermal
endothelial cells (generous gift of Dr. Candal of the Center for
Disease Control, Atlanta) were cultured in MCDB-131 medium with 10%
heat-inactivated fetal bovine serum, 2 mM glutamine, and
100 µg/ml penicillin and streptomycin in 6-well plates.
Expression Vectors and Transfection of THP-1 Cells--
Dominant
negative expression vectors of MyD88, IRAK, IRAK2, TRAF2, TRAF6, and
NIK have been characterized and described before (30, 32, 33). Cells
were used for transfection with FuGene 6 Transfection Reagent
(Boehringer Mannheim) following the manufacturer's instructions in
RPMI with 10% serum. Reporter genes pCMV- Transfection of Human Dermal Endothelial Cells--
Transfection
was carried out using the same method described above. The amount of
NF- Reverse Transcription-Polymerase Chain Reaction (RT-PCR)
Analysis--
Total RNA was isolated from HDMEC and THP-1 cells using
a Qiagen kit (Valencia, CA) and treated with RNase-free DNase I. For RT
reaction, the SuperScriptTM Preamplification system (Life
Technologies, Inc.) was applied. PCR amplification was performed with
Taq polymerase (Qiagen, Valencia, CA) for 28 cycles at
95 °C for 40 s, 54 °C for 40 s, and 72 °C for 1 min.
PCR primers for TLR2 were 5'-GCCAAAGTCTTGATTGATTGG and
5'-TTGAAGTTCTCCAGCTCCTG. PCR primers for TLR4 were
5'-TGGATACGTTTCCTTATAAG and 5'-GAAATGGAGGCACCCCTTC. GAPDH primers were
obtained from CLONTECH.
Immunostaining and Immunoblotting--
Smeared THP-1 cell and
cultured HDMEC on slides were fixed with acetone for 5 min and then
stained with rabbit anti-TLR2 and TLR-4 antibody (1:100) and rabbit IgG
following the instructions on a DACO immunostaining kit. The anti-TLR2
and anti-TLR4 antisera were raised against synthetic peptides
(extracellular domains of TLR2 and TLR4) by BABCO (Richmond, CA). The
sequence of the synthetic peptide for TLR2 was a 27-amino acid peptide,
starting at amino acid residue 277 of the mature hTLR2
(FRASDNDRVIDPGKVETLTIRRLHIPR), whereas the peptide for TLR4 was a
23-amino acid peptide, starting at amino acid 201 of mature hTLR4
(FKEIRHKLTLRNNFDLSLNVMKT). Following immunoperoxidase staining, the
representative fields were photographed.
THP-1 and HDMEC cells were lysed in Laemmli buffer and separated with a
10% SDS-PAGE gel. The protein was then transferred onto a
polyvinylidene difluoride membrane, and then the membrane was probed
with anti-TLR2, anti-TLR4 antibodies, and prebleeds corresponding to
each antibody (1:2,000). After incubation with horseradish
peroxidase-conjugated goat anti-rabbit antibody, the membrane was
developed with an enhanced chemiluminescence ECL detection kit.
A series of defense mechanisms are triggered in vertebrates and
invertebrates in response to Gram-negative bacterial infections by
sensing the presence of LPS (1-3). LPS-induced signal relay is thought
to be initiated following its binding to specific cellular receptors
which then triggers intracellular signaling pathways leading to the
activation of NF- To investigate the potential involvement of IL-1 and TNF signal
transducers in LPS signaling in two LPS-responsive cell types, HDMEC
and THP-1 cells, we cotransfected dominant negative constructs of
various components of the NF- A mutant version of MyD88 ( Division of Pediatric Infectious Diseases, Division of Cardiology and the Burns and Allen
Research Institute, Cedars-Sinai Medical Center and UCLA School of
Medicine, Los Angeles, California 90048, § Tularik Inc.,
South San Francisco, California 98080, and the ¶ Department of
Immunology and Cell Biology, Mario Negri Institute, I-20157 Milan,
Italy
ABSTRACT
TOP
ABSTRACT
INTRODUCTION
REFERENCES
B is thought to be required for cytokine release
from LPS-responsive cells, a critical step for endotoxic effects. Here
we investigated the role and involvement of interleukin-1 (IL-1) and
tumor necrosis factor (TNF-
) signal transducer molecules in LPS
signaling in human dermal microvessel endothelial cells (HDMEC) and
THP-1 monocytic cells. LPS stimulation of HDMEC and THP-1 cells
initiated an IL-1 receptor-like NF-B signaling cascade. In transient
cotransfection experiments, dominant negative mutants of the IL-1
signaling pathway, including MyD88, IRAK, IRAK2, and TRAF6 inhibited
both IL-1- and LPS-induced NF-B-luciferase activity. LPS-induced
NF-B activation was not inhibited by a dominant negative mutant of
TRAF2 that is involved in TNF signaling. LPS-induced activation of
NF-B-responsive reporter gene was not inhibited by IL-1 receptor
antagonist. TLR2 and TLR4 were expressed on the cell surface of HDMEC
and THP-1 cells. These findings suggest that a signal transduction
molecule in the LPS receptor complex may belong to the IL-1
receptor/toll-like receptor (TLR) super family, and the LPS signaling
cascade uses an analogous molecular framework for signaling as IL-1
in mononuclear phagocytes and endothelial cells.
INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
REFERENCES
B (NF-B) in both monocytic (13, 14) and endothelial cells
(15). Activation of NF-B is required for release of proinflammatory cytokines, including interleukin-1 (IL-1), interleukin-6 (IL-6), and
tumor necrosis factor (TNF) (16, 17). However, the molecular mechanisms
of the signaling cascade induced by LPS to activate NF-B are
unknown. Furthermore, the signaling LPS receptor is still unidentified.
B
activation cascade (18). The toll family of receptors is defined by
homology to the Drosophila toll protein (19, 20). The
mammalian IL-1 receptor is a member of the toll family (18). Five other
mammalian family members (toll-like receptors 1 through 5, TLR1-5)
have been identified, but their function is uncertain. Several TLRs,
similar to IL-1R, have been observed to signal through the NF-B
pathway (19-22). LPS signaling also leads to activation of NF-B,
and recent studies suggested that a toll-like receptor (TLR) might be a
signaling receptor that is activated by LPS (22, 23). In these reports,
expression of TLR2 in LPS-unresponsive human embryonic kidney cells
(293 cells) enabled these cells to respond to LPS stimulation (22, 23).
These investigators observed that LPS binds to a TLR2 extracellular
domain and suggested that TLR2 is a candidate for a long sought LPS
receptor, although the data were generated from a transfected and
normally LPS-unresponsive cell line (22, 23). A recent study in the
LPS-resistant C3H-HeJ mice has implicated another toll homologue (TLR4)
as a signal-transducing component in the LPS receptor complex (24).
B have been recently
characterized. Upon binding of IL-1 to its receptors (IL-1R), IL-1R
associates with the IL-1 receptor accessory protein (IL-1RAcP) (26,
27). The complex then recruits and activates an adapter protein myeloid differentiation protein (MyD88) (28, 29). MyD88 in turn recruits two
distinct putative serine-threonine kinases, namely IL-1
receptor-activated kinase (IRAK) and IRAK2, to the receptor complex
(30). IRAK and IRAK2 interact subsequently with the adapter molecule,
TNF receptor-associated factor 6 (TRAF6) (31, 32), which links them to
the protein kinase NF-B-inducing kinase (NIK) (33). NIK activates
the IB kinase complex (IKK and IKK
) that directly phosphorylates IB (34-36). The phosphorylation of IB initiates ubiquitin-proteasome-mediated degradation and liberates and activates NF-B (16, 17). On the other hand, TNF and its receptor complex activate TRAF2, but not TRAF6 (37, 38). Downstream signaling pathways
of IL-1 and TNF distal to TRAF6 and TRAF2 converge (16, 17).
B
through IL-1 signaling molecules, namely MyD88, IRAK, IRAK2, and TRAF6
in two LPS-responsive cell types. Dominant negative mutants of these
signaling elements were transfected into human monocytes (THP-1 cells)
and human dermal endothelial cells together with a NF-B-responsive
reporter gene, and LPS-induced NF-B luciferase activity was
measured. Our results indicate that LPS transduces signals of NF-B
activation utilizing the IL-1 signaling molecules in both monocytic and
endothelial cells.
EXPERIMENTAL PROCEDURES
-galactosidase (0.5 µg)
and ELAM-NF-B-luciferase (2 µg) and pcDNA3 empty vector or
dominant negative mutants of MyD88, IRAK, TRAF6, TRAF2, and NIK (3 µg
each) were used. After a 24-h transfection, cells were stimulated for
6 h with 100 ng/ml LPS. Cells were then lysed, and luciferase
activity was measured with a Promega kit (Promega, Madison, WI) and a
luminometer. -Galactosidase activity was determined by the
calorimetric method to normalize transfection efficiency as described
earlier (30). Data shown are means of two independent experiments.
B luciferase construct DNA was 1.5 µg, and empty vector and
various dominant negative constructs were 2 µg each. Cells were
transfected for 24 h and stimulated for 6 h with 100 ng/ml
LPS, human TNF- (200 units/ml, Genzyme, Cambridge, MA), recombinant
human IL-1 (400 units/ml, Genzyme), and recombinant IL-1 receptor
antagonist (100 ng/ml, R&D Systems, Minneapolis, MN) in 2 ml of
serum-containing MCDB-131 medium.
RESULTS AND DISCUSSION
B (4-12) in various LPS-responsive cell types. To
date, the identification of a functional, signal-transducing component
of the putative LPS receptor complex and the signaling pathways
involved in LPS-induced activation of NF-B have remained elusive.
Recent findings suggested that LPS might use signaling molecules of the
TLR and IL-1R superfamilies to transduce signals (23, 24).
B signaling cascades for IL-1 and TNF
together with NF-B-luciferase reporter gene. LPS induced the
activation of NF-B in a time- (Fig.
1A) and
dose-dependent (Fig. 1B) manner in THP-1 cells.
Activation of NF-B reached a maximum at a LPS concentration of 100 ng/ml and when cells were stimulated with LPS for 6 h (Fig. 1,
A and B). Similar results were also obtained from
endothelial cells.
View larger version (14K):
[in a new window]
Fig. 1.
Dominant negative versions of MyD88 and TRAF6
but not TRAF2 inhibited LPS-induced NF- B
activity in human THP-1 cells. Human THP-1 cells were transiently
transfected with NF-B-luciferase and -galactosidase reporter
vectors and dominant negative mutants of MyD88, TRAF6, and TRAF2 for
24 h. The total amount of DNA was kept constant with pcDNA3
vector. The cells were then stimulated with LPS (100 ng/ml) for
different periods of time (A) or increasing amounts of LPS
for 6 h (B). Some cells were transfected with different
amounts of MyD88 mutants and stimulated with 100 ng/ml LPS for 6 h
(C). Cells were transfected with TRAF2 and TRAF6 mutants and
then stimulated with 100 ng/ml LPS for 6 h (D).
Luciferase and -galactosidase assays were performed as described
under "Experimental Procedures." The time and dose response
experiments (A and B) are one representative of
two independent experiments with similar qualitative results.
C and D were graphed with means and standard
deviations of three or more experiments.
MyD88), encoding only for the
COOH-terminal toll-IL-1R-like domain, which abrogates IL-1R-induced NF-B activation (30), inhibited both LPS- and IL-1-mediated NF-B
activation (Figs. 1C and 2, A and B)
but not TNF-induced NF-B activation (Fig.
2C). IRAK and IRAK-2 are two
additional proximal mediators of the IL-1R signaling complex (30).
Dominant negative constructs of IRAK (IRAK) and IRAK2 (IRAK2)
inhibited both LPS- (Figs. 1D and 2A) and
IL-1R-mediated NF-B activation (Fig. 2B), but not
TNF-induced NF-B activation (Fig. 2C).
View larger version (18K):
[in a new window]
Fig. 2.
Dominant negative versions of MyD88, IRAK,
IRAK2, TRAF6, and NIK but not TRAF2 inhibited LPS-induced
NF- B activity in HDMEC. Human dermal
endothelial cells grown on 6-well plates were transfected with dominant
negative mutants of MyD88, IRAK, IRAK2, TRAF6, TRAF2, and NIK as well
as reporter genes for 24 h. The amount of total DNA was kept
constant with pcDNA3 vector. The cells were treated with 100 ng/ml
LPS (A), 400 units/ml human IL-1 (B), 200 units/ml human TNF- (C) for 6 h. Some cells were
also treated with 100 ng/ml IL-1 receptor antagonist for 6 h
(A and B). NF-B luciferase activity was
obtained with luciferase assay and normalized with -galactosidase
activity. Data shown are one representative experiment of two
experiments with similar qualitative results.
NF-B activation induced by various cytokine receptors is mediated by
members of the TRAF adapter family. While TRAF2 plays a crucial role in
NF-B activation by TNFR-1 and TNFR-2 (37, 38), TRAF6 has been
implicated in IL-1 signaling (31, 32). Therefore, we next determined
whether dominant negative versions of TRAF6 (TRAF6) or TRAF2
(TRAF2) could act to inhibit LPS-induced NF-B activity. TRAF-6
but not TRAF2 significantly impaired LPS-induced NF-B activation,
suggesting that TRAF6 may act as an additional downstream mediator of
LPS-induced NF-B activation cascade (Figs. 1D and
2A). TRAF2 blocked TNF-induced NF-B activation in
endothelial cells (Fig. 2C), but not LPS-induced NF-B
activation (Figs. 1D and 2A). Because the
pathways for IL-1 and TNF- signaling converge at the level of NIK
for NF-B activation, we next investigated whether dominant negative
NIK mutant (NIK) would block LPS-induced, as well as IL-1- and
TNF-induced, NF-B activation. As expected, NIK blocked
NF-B activation induced by LPS, IL-1, and TNF- (Fig. 2).
IL-1 receptor antagonist had no effect on LPS-induced NF-B
activation (Fig. 2A) but inhibited IL-1-induced NF-B
activation in endothelial cells (Fig. 2B). This observation
suggests that NF-B activation that we measured following 6 h of
LPS stimulation of cells is not due to an autocrine effect such as
LPS-induced IL-1 release from endothelial cells.
These data suggest that LPS stimulation of endothelial cells and THP-1
cells triggers an IL-1R-like signal relay leading to activation of
NF-B (Fig. 5). Further support for this concept is provided by the
observation of a 15-year-old girl with recurrent infections who was
found to be resistant to both LPS and IL-1 stimulation in
vivo and in vitro (39). The authors suggested that
resistance to LPS and IL-1 was due to a defect very early in the common
signaling pathway for LPS and IL-1 (39).
The experiments with IL-1R antagonist also suggest that LPS does not use IL-1 receptor to transduce signals in endothelial cells. Although recent findings imply that TLR2 or other members of the TLR family, which use the IL-1R signaling pathway, might be an important mediator for LPS signaling (23, 24), further studies are needed to identify naturally existing LPS receptors in LPS-responsive cells. Beutler and coworkers (25) recently reported that TLR4 is the protein encoded by the LPS gene, which is mutated in the LPS-non-responsive C3H-HeJ mice. To investigate the expression of the TLR2 and TLR4 message in HDMEC and THP-1 cells, we used RT-PCR. Human THP-1 and HDMEC were found to express significant levels of both TLR2 and TLR4 mRNA (Fig. 3). Expression levels of TLR2 appeared to be stronger in THP-1 whereas the expression level of TLR4 appeared to be stronger in HDMEC. Expression of TLR2 and TLR4 was confirmed with Northern analysis in THP-1 cells. Immunohistochemistry and immunoblotting data demonstrate that TLR2 and TLR4 proteins are expressed on THP-1 cells and HDMEC (Fig. 4). Staining was absent in THP-1 and HDMEC incubated without the first antibody or incubated with rabbit IgG. These results suggest that TLR2 and TLR4 are expressed in endothelial and monocytic cells and may represent a signaling component of a cellular receptor for LPS which signals through an IL-1-like pathway (Fig. 5).
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In summary, we have demonstrated in endothelial and THP-1 cells that
LPS-induced NF-B activation is mediated by IL-1R signaling molecules, namely MyD88, IRAK, IRAK2, and TRAF6, but not the TNF signaling molecule, TRAF2. We have also shown that TLR2 and TLR4 are
expressed on the cell surface of two LPS-responsive cell types, endothelial cells and THP-1 cells. These data strongly suggest that a
crucial signaling component in the LPS receptor complex may belong to
the IL-1 receptor/TLR superfamily, and the LPS signaling cascade uses
an analogous molecular framework for signaling as IL-1. MyD88 appears
to represent the most upstream mediator of the LPS-mediated signaling
cascade, which ultimately activates NF-B, thus driving
transcriptional activation of several cytokines. Thus, MyD88 may
represent a potentially useful therapeutic target to control the
molecular switch from innate to the adaptive immune response.
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FOOTNOTES |
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* This work was supported by National Institutes of Health Grant AI40275 (to M. A.), by funds from MURST and AIRC, and European Community Grants BIO4CT972107 and BMH4CT983277 (to M. M).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
** To whom correspondence should be addressed: Dept. of Pediatrics, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Rm. 4310, Los Angeles, CA 90048. Tel.: 310-855-4471; Fax: 310-652-0681; E-mail: moshe.arditi{at}cshs.org.
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ABBREVIATIONS |
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The abbreviations used are:
LPS, lipopolysaccharide;
HDMEC, human dermal microvessel endothelial cells;
IL-1, interleukin-1;
IL-1R, IL-1 receptor;
IL-1RacP, IL-1R accessory
protein;
IL-6, interleukin-6;
IRAK, IL-1 receptor-associated kinase;
MyD88, myeloid differentiation protein;
NF-B, nuclear factor-B;
NIK, NF-B-inducing kinase;
RT-PCR, reverse transcription-polymerase
chain reaction;
TLR, toll-like receptor;
TNF, tumor necrosis factor;
TRAF, tumor necrosis factor receptor-associated factor;
PAGE, polyacrylamide gel electrophoresis.
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ABSTRACT
INTRODUCTION
REFERENCES
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