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University of Wisconsin Medical School, Madison
Correspondence: Donna M. Paulnock, Ph.D., Department of Medical Microbiology and Immunology, University of Wisconsin Medical School, 1300 University Avenue, Madison, WI 53706-1532. E-mail: paulnock{at}facstaff.wisc.edu
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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release were
monitored to determine requirements for inflammatory cytokine
production. Cycloheximide, monodansylcadaverine, and cytochalasin B all
blocked TNF- release from macrophages stimulated with LTA or poly
I:C, whereas monensin only nominally reduced TNF- production.
Selected inhibitors of downstream signaling events reduced
SR-A-dependent TNF- release by >95% after stimulation with either
ligand, whereas others were ineffective. The PKC inhibitor H7 reduced
LTA-dependent secretion of TNF- by 94% but inhibited poly
I:C-dependent TNF- production only by 50%. Priming of RAW 264.7
cells with interferon-
potentiated the response to poly I:C but did
not alter inhibitor effects. These results demonstrated that for both
ligands tested here, early events of receptor internalization are
requisite for cellular activation. The response pattern suggests that
tyrosine phosphorylation and activation of the MAP kinase pathway are
key components of SR-A-mediated signal transduction cascades.
Key Words: innate immunity • pattern recognition • cellular signaling • activation • IFN-
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Recent studies of SR-A-deficient mice have emphasized the importance of SR-As in host defense. It has been demonstrated that mice lacking SR-A are more susceptible to intraperitoneal infection with a prototypic gram-positive pathogen, Staphylococcus aureus, than SR-A control mice. SR-A-deficient mice display an impaired ability to clear bacteria from the site of infection despite normal killing of S. aureus by neutrophils and die as a result of disseminated infection [5 ]. SR-A-deficient mice also have a markedly reduced 50% lethal dose level for the intracellular bacterium Listeria monocytogenes and are more susceptible to herpes simplex virus 1 infection [6 , 7 ]. Thus, impairment of SR-A-mediated pathogen recognition can have significant immunological consequences.
We recently showed that macrophage interaction with the SR-A ligands
mBSA, the double-stranded (ds) DNA molecule polyinosinic:polycytidilic
acid (poly d[I:C]), the dsRNA molecule poly I:C, or LTA induces
distinct patterns of gene expression in the murine macrophage cell line
RAW 264.7 and that this response is largely endocytosis dependent
[8
]. It has also been demonstrated that the additional
SR-A ligands AcLDL and fucoidan induce protein tyrosine phosphorylation
and protein kinase C (PKC) activity, leading ultimately to
urokinase-type plasminogen activator expression and subsequent
remodeling of the extracellular matrix [9
]. That study
thus provided a first look at potential intracellular-signaling events
activated by SR-A engagement; however, only limited changes in gene
expression and macrophage functional activities were explored in the
work. In extending these results, we built on our previous observations
that microbial ligands of SR-A effectively induce production of a range
of inflammatory mediators, including tumor necrosis factor (TNF)-,
interleukin (IL)-1ß, IL-6, and nitric oxide. Here we assess the
specific intracellular signaling pathways of SR-A–mediated induction
of the key inflammatory cytokine TNF-, using biochemical inhibitors.
Our results show that de novo protein synthesis and endocytosis but not
endosomal acidification are required for SR-A-dependent TNF-
production in response to poly I:C and LTA. We also show that the
downstream pathways utilized by LTA and poly I:C are similar with
respect to a requirement for tyrosine phosphorylation and the activity
of mitogen-activated protein kinase (MAPK)-signaling molecule
MAPK/extracellular signaling-related kinase (MEK) and an apparent lack
of requirement for phosphatidylinositol 3 (PI 3)-kinase activity. LTA
stimulation also appears to require PKC activation. These results
provide the first detailed examination of the signaling pathways
required for proinflammatory protein production by macrophages after
SR-A binding. Our findings suggest that multiple downstream pathways
are stimulated after receptor-ligand internalization.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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(Schering Corp., Bloomfield, NJ;
specific activity, 1.7 x 106 U/mg); poly I:C
double-stranded alternating RNA copolymer (Roche Molecular
Biochemicals, Indianapolis, IN); and LTA purified from S.
aureus and polymyxin B (Sigma Chemical Co., St. Louis, MO).
Ligands were resuspended in phosphate-buffered saline or medium for
cell stimulation; RNase inhibitor (Eppendorf, Madison, WI) was added to
poly I:C to a final concentration of 1 U/mL to prevent ligand
degradation. The binding activity of all scavenger receptor (SR)
ligands routinely was assessed by monitoring their ability to displace
binding of the prototype SR ligand, AcLDL (in the form of Bodipy-AcLDL;
Molecular Probes, Eugene, OR), using flow-cytometric analysis (data not
shown).
Cells and cell culture
The RAW 264.7 macrophage cell line, obtained from the American
Type Culture Collection (ATCC, Rockville, MD), was used in all
experiments as the target cell for SR-mediated stimulation. These cells
express readily detectable levels of SR as determined by reactivity
with receptor-specific antibody (data not shown). Mycoplasma-free cell
cultures were maintained in complete medium, consisting of RPMI 1640
medium (Life Technologies, Grand Island, NY) supplemented with 2 mM
glutamine, 1 mM pyruvate, 50 U/mL of penicillin, and 50 µg/mL of
streptomycin, 2 g/L of sodium bicarbonate (all from Sigma), plus 10%
fetal bovine serum (FBS; Life Technologies). Additional aspects of cell
maintenance were as previously described [8
,
10
].
Assessment of secreted TNF- protein
The presence or absence of secreted TNF- in culture
supernatant fluids obtained from stimulated cells was determined using
a sandwich ELISA. The assay was performed in 96-well Immulon I.U. ELISA
plates (Fisher Scientific, Itasca, IL) using capture and biotinylated
detecting antibodies obtained from PharMingen (San Diego, CA).
Vectastain ABC reagent (Vector Laboratories, Burlingame, CA) was added
to the wells according to manufacturer recommendations;
p-nitrophenyl phosphate was added as the substrate (Sigma).
Recombinant murine TNF- (Genzyme, Cambridge, MA) was used to produce
a standard curve. Colorimetric conversion was quantitated on a
Spectramax 250 plate reader (Molecular Devices, Sunnyvale, CA) at an
optical density at 405 nm, using the SoftMax Pro 1.1 software program
for the Macintosh (Molecular Devices).
Inhibitors
RAW 264.7 cells were plated at 7.5 x
104–1.5 x 105 cells/mL in complete RPMI
in 12- or 24-well tissue culture plates (Corning-Costar, Inc., Corning,
NY) and grown to a density of 1–2 x 106 cells/mL.
The cells were then treated with the following inhibitors (all from
Sigma): cytochalasin B (40 µg/mL), monensin (20 µm), chloroquine
(100 µm), cycloheximide (1 µm) [11
],
monodansylcadaverine (100 µm), tyrphostin AG 126 (100 µm), H7 (20
µm) [12
]; UO126 [13
], and wortmannin
(wort) (500 nm) [14
] (resuspended in dimethyl
sulfoxide). Control cells were treated with medium alone or medium
containing the appropriate chemical vehicle for the inhibitor used.
Poly I:C (10 µg/mL) and LTA (10 µg/mL), in the presence of
polymyxin B (15 µg/mL), were added after a 1-h pretreatment with the
inhibitors, and the cells were stimulated at 37°C in the presence of
inhibitors prior to cytokine analysis by ELISA. Viability was assessed
using trypan blue exclusion, and >85% of cells were shown to be alive
after all inhibitor treatments. In IFN- priming studies, IFN- (20
U/mL) was added 24 h before addition of the inhibitors. Inhibitors
were added for 1 h before addition of SR-A ligands, with cells
then incubated for an additional 8 h, again in the presence of
respective inhibitors. All experiments were repeated three to four
times. Percent inhibition of TNF- in the presence of each inhibitor
(A) was calculated using the formula A =
(B - C)/(B - D), where
B = cytokine release (nanograms per milliliter) after
SR-A ligand stimulation, C = cytokine release with no
stimulation (control cells), and D = cytokine release
after stimulation in the presence of inhibitor [12
].
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, using an inhibitor of ribosomal
protein synthesis, cycloheximide. As shown in Figure 1
, TNF- secretion required new protein synthesis demonstrated by
the reduction of protein production by >95% or 88% after stimulation
with LTA or poly I:C, respectively.
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. As shown in Figure 2
, incubation of RAW 264.7 with either monodansylcadaverine or
cytochalasin B reduced LTA-induced TNF- production by >95%, as
compared with cells mock treated with vehicle alone. TNF- production
induced by poly I:C also was markedly reduced by these compounds, with
81% inhibition after monodansylcadaverine treatment and nearly 98%
inhibition by cyt (Fig. 3
).
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production after SR-A ligand binding. Monensin was
considerably less inhibitory than monodansylcadaverine and cytochalasin
B, blocking 60% of LTA-induced TNF- release and 54% of poly
I:C-induced TNF- release (Fig. 3)
. These studies demonstrate that
SR-A ligand-induced TNF- production requires internalization by
clathrin-coated pit formation and actin polymerization but is not
highly dependent on endosomal acidification.
SR-A ligands LTA and poly I:C activate similar downstream
signaling pathways
We used additional chemical inhibitory compounds to
identify the signaling molecules and pathways that might further
contribute to TNF- production. We focused our attention on the
potential role(s) of tyrosine phosphorylation and activation of several
major-signaling-pathway intermediates, including PI 3-kinase, PKC, and
MAPK. As described previously, we pretreated RAW 264.7 cells for 1 h with the inhibitor of interest followed by the addition of SR-A
ligands, either LTA or poly I:C.
Initial studies used the protein tyrosine kinase inhibitor tyrphostin
AG 126, which was previously shown to block LPS-induced TNF- release
from murine macrophages [15
], to block tyrosine
phosphorylation. Tyrphostin effectively blocked all LTA-dependent
TNF- release and inhibited poly I:C induced TNF- production by
86% (Fig. 4
and Fig. 5
, respectively).
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secretion by >95% after stimulation with either LTA
(Fig. 4)
or poly I:C (Fig. 5) .
SR-A contains two putative PKC sites in its cytoplasmic tail. To assess
whether ligand interaction with SR-A induced PKC activation, we used
the inhibitor H7, which has been shown to block PKC activity in a
variety of receptor signaling systems [18
19
]. Both LTA-
and poly I:C-dependent TNF- release was inhibited by H7. However,
>94% inhibition of the response stimulated by LTA was observed (Fig. 4)
, while poly I:C-induced TNF- release was reduced by 50% (Fig. 5)
.
Our results with cytochalasin B suggest that actin polymerization is an
integral step in SR-A signaling. Because PI 3-kinase has been shown to
have several roles in signaling during actin rearrangement, implicated
in both the polymerization of actin fibers and activation of the small
guanosine triphosphatases (GTPases) Cdc42 and rac downstream of
receptor activation [20
, 21
], we used the
inhibitor wortmannin to assess the requirement for PI 3 kinase activity
in SR-A signaling. Treatment of RAW 264.7 cells with PI-3 kinase
resulted in little or no inhibition of TNF- production by LTA (Fig. 4)
or poly I:C (Fig. 5)
.
These results indicate that the SR-A-ligand-induced TNF- production
requires tyrosine phosphorylation and MEK but does not require PI-3
kinase activity. The extent of PKC involvement in signaling appears to
vary according to the ligand utilized.
Poly I:C activation of IFN--primed cells also requires de
novo protein synthesis receptor-ligand internalization
We previously demonstrated that IFN- treatment of RAW 264.7
macrophages "primes" these cells for an enhanced response to
subsequent SR-A stimulation by the ligand poly I:C [8
].
To determine whether signaling requirements are altered by initial
stimulation with IFN-, RAW 264.7 macrophages were stimulated with
IFN- for 24 h, followed by addition of inhibitors for 1 h
and then SR-A ligands for a final 8 h of incubation. Cell-free
supernatant fluids then were collected for ELISA determination of
TNF- levels.
We first assessed the requirement of de novo protein synthesis using
the inhibitor cycloheximide. Cycloheximide significantly inhibited
SR-A-mediated TNF- production in poly I:C-stimulated IFN--primed
cells (Fig. 6
). We then assessed the effect of the early activation inhibitors,
monodansylcadaverine and cytochalasin B on subsequent triggering of
IFN--primed cells. Both of these inhibitors blocked SR-A-dependent
cytokine production to the same extent in IFN--primed cells and
unprimed cells (Fig. 7
). In contrast, treatment with the endosomal acidification
inhibitor monensin enhanced the TNF- response stimulated by IFN-
plus poly I:C by >300%.
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-primed cells to SR-A
ligand activation and that endosomal acidification may be a requirement
for down-regulating SR-A-dependent macrophage activation.
IFN- priming does not alter the downstream signaling pathways
activated by SR-A ligands
We also assessed the potential roles of tyrosine phosphorylation,
MEK activation, and PKC activation in the response of IFN--primed
cells to SR-A ligand poly I:C. In a manner similar to that shown by
unprimed cells, IFN--primed RAW 264.7 cells required both tyrosine
phosphorylation and MEK activation for the subsequent response to poly
I:C (Fig. 8
). Treatment of IFN--primed cells with H7 revealed a clear role
for PKC activation, with the poly I:C response inhibited >95% by this
drug.
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priming does not alter the subcellular requirements for
effective activation through SR-A ligands. |
DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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component of the
macrophage inflammatory response. The results demonstrated that SR-A
dependent signaling is complex and most likely involves multiple
receptor-ligand-mediated events, all of which must cooperate to induce
gene expression effectively.
A critical initial component of signaling appears to be receptor
internalization. Thus, we demonstrated that endocytic uptake of the
SR-A ligands LTA and poly I:C is essential for macrophage production of
the cytokine TNF-. In the presence of the primary amine,
monodansylcadaverine, which blocks clathrin-coated pit formation,
TNF- production was decreased >95% and >80% in response to LTA
and poly I:C, respectively. These results are similar to those seen for
the insulin-like growth factor I receptor and p55 TNF factor receptor
in which all internalization-dependent signaling was abrogated in the
presence of monodansylcadaverine [22
, 23
].
The precise role of the internalization requirement in effective
cellular signaling remains to be determined. It is possible that during
clathrin coat formation, SR-A binds to an adapter protein critical for
mediating an important first downstream activation event. For example,
ß-arrestin, commonly known as a "G-protein-coupled receptor
regulator" has been shown to assemble with insulin-like growth factor
I receptor during endocytosis and to play a role in subsequent MAPK
signaling [24
]. Additionally, a small GTPase, RhoB,
which is entirely localized to the cytosolic face of endocytic
vesicles, has been demonstrated to bind to the RhoA effector PRK1 and
regulate the kinetics of epidermal growth factor receptor traffic as
well as activating the Ras-MAPK cascade [25
]. It is also
possible that SR-A needs to be internalized to interact with a
cytoplasmically located accessory protein which then initiates
downstream signaling, as has been hypothesized in nerve growth factor
receptor signaling [26
].
Similarly, our results also demonstrated that cytochalasin B inhibits
>95% of TNF- release, indicating that actin cytoskeletal
rearrangement is important in SR-A-dependent signaling. There is good
evidence that the actin cytoskeleton is required for receptor-mediated
endocytosis in mammalian cells [27
]. In addition,
Staphylococcus aureus uptake by osteoblasts, a process that
may in part occur via SR-A, requires both actin polymerization and
clathrin pit formation [28
]. The small GTPases Rac,
RhoA, and Cdc42 have been shown to become activated in an actin
polymerization-dependent manner and in turn activate the Ras-MAPK
pathway [29
]. These results are consistent with our own
observations of a role for cytochalasin B in SR-A signaling.
Finally, we showed that dissipation of the endosomal pH via monensin
does not significantly block SR-A-dependent TNF- production, with
LTA-induced TNF- reduced only 60% and poly I:C only 54% by
monensin pretreatment. An explanation of these results may be provided
by the current model for SR-A internalization. Suzuki and colleagues
have shown that SR-A, once internalized, moves to the endosomes, where
the acidic pH protonates the histidine residues in the -helical
coiled-coil domain, shown to maintain the trimeric structure of the
protein. The resulting generation of ionic repulsion is sufficient to
disrupt the collagen-binding domain and thus release the bound ligand
[30
]. It appears that blocking endosomal acidification
in some cases enhances cytokine release. For example, in IFN--primed
RAW 264.7 cells, poly I:C-induced TNF- was increased over basal
levels by 326%. Thus ligand dissociation may be a requirement for
down-modulation in SR-A signaling. Loss of that capacity by the
endosome then in effect would induce the macrophage to undergo a
chronic state of activation, yielding the hyperreponsive state we
observed. It should be noted, however, that the effects of monensin on
intracellular pH are not specific to the endosome. Monensin also has
been shown to inhibit the Golgi Na+/H+
adenosine triphosphatase, thus limiting the cell’s ability to process
and secrete proteins as well as causing the mobilization of
intracellular calcium stores [31
32
33
]. These alterations
potentially could influence diverse cellular-signaling pathways in
which Golgi function is a critical component of signal transduction.
Additional inhibitors used in these studies have provided a first
glimpse of SR-A-mediated intracellular signal transduction. These
studies have demonstrated a positive role for tyrosine phosphorylation
events and activation of the MAPK cascade downstream of receptor
internalization and the lack of involvement of PI 3-kinase. Protein
tyrosine kinase phosphorylation is a ubiquitous occurrence in cellular
activation pathways. We therefore used the inhibitor tyrphostin AG 126
in a preliminary assessment of the requirement for such events in SR-A
signaling. Our results showing >95% inhibition of TNF- production
induced by SR-A ligands clearly indicate that tyrosine phosphorylation
is a requirement for this signaling pathway, as has also been
demonstrated for LPS activation [12
, 15
].
We also demonstrated a potential role for the MAPK protein MEK in
SR-A-dependent TNF- up-regulation, using the inhibitor UO126. MEK is
downstream of Ras-guanosine triphosphate and Raf/MEK-kinase 1 and 2 and
its activation is required for full activation of the MAPK cascade,
including the extracellular regulated kinase (ERK), c-Jun-kinase, and
p38 kinases, and the nuclear translocation of the transcription factors
targeted in that system, including ets-like protein kinase 1, c-Jun,
and activating transcription factor 2. These results are reminiscent of
previous work in which tyrphostin was shown to block LPS-induced
TNF- production from RAW 264.7 cells via the inhibition of p42 MAPK
protein tyrosine phosphorylation [15
]. However, both the
primary tyrosine substrate target and the specific MEK transcription
factor targets of signaling after SR-A ligation remain to be
elucidated.
In contrast to these results, wortmannin, which inhibits PI 3-kinase
activity, was unable to substantially block either poly I:C- or
LTA-induced TNF-, suggesting that this pathway plays little or no
role in SR-A activity.
The inhibition of PKC in SR-A-dependent signaling gave mixed results,
with 50% inhibition of poly I:C-induced TNF- production, while
LTA-dependent cytokine secretion was reduced 94%. This difference may
provide evidence that more than one receptor is engaged by these
ligands. This certainly could be true with respect to LTA, which
recently has been shown to interact with toll-like receptor 2 as well
as SR-A [34
, 35
]. Variations in the level
of inhibition also could be the result of differences in downstream
signaling events triggered after SR-A receptor engagement by diverse
ligands. Finally, it remains possible that there are differences in
ligand-binding affinities for distinct ligands or even multiple
ligand-binding sites on a single SR-A molecule that may influence
downstream intracellular events. Defining the potential involvement of
these aspects of receptor-ligand interactions, as well as the full role
of PKC in SR-A-mediated activation, remains a major challenge in this
system.
Our results also demonstrated that while IFN- priming of RAW 264.7
macrophages enhanced the overall level of TNF- induced by poly I:C
stimulation, it did not alter the pattern of signal transduction
suggested by the initial inhibitor studies. Thus, monodansylcadaverine,
cytochalasin B, tyrphostin, H7, and UO126 blocked TNF- production to
the same or a greater extent to that in unprimed, poly I:C-stimulated
cells. This maintenance of the observed pattern of inhibition indicates
that, although the macrophages may be at an intermediary-activation
state after priming with IFN-, the pathways utilized by SR-A remain
unchanged. The fourfold potentiation of TNF- production after poly
I:C stimulation of IFN--primed cells suggests that SR-A ligands may
need to cooperate with additional activation signals for full induction
of inflammatory response, a situation which would aid in the control of
spurious inflammation after SR-A ligation in vivo.
Taken in sum, these studies provide a broad-stroke picture of the
signaling pathways involved in SR-A-mediated macrophage activation. The
results suggest that, at least for TNF- production, both
receptor-ligand internalization and MAPK pathway activation are key
elements of signaling in the SR-A receptor system. Additional studies
are underway to delineate the specific role of each signaling process
in achieving effective gene induction.
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ACKNOWLEDGEMENTS |
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Received October 30, 2000; revised April 17, 2001; accepted April 19, 2001.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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