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Cutting Edge |
* Unité de Défense Innée et Inflammation, Institut Pasteur, Institut National de la Santé et de la Recherche Médicale, Unité 485, Paris, France;
Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Cincinnati, Cincinnati, OH 45267; and
Department of Medicine, Division of Infectious Diseases, University of Massachusetts Medical School, Worcester, MA 01655
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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B signaling
pathway and up-regulation of cytokine synthesis such as TNF-
and
IL-10 are critically dependent on the TLR4 functional complex. These
findings support the concept that TLR4 is a pattern recognition
receptor that signals in response to both foreign pathogens and
endogenous host mediators. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B pathway and that specific NF-B inhibitors block
SP-A-dependent increases in TNF- mRNA levels (11).
Based on these data, we hypothesized that SP-A and LPS may share a
common functional receptor. According to the current model, the specific cellular recognition of LPS is initiated by the signal-transducing Toll-like receptor (TLR)4 and the accessory molecules CD14 and MD-2, leading to the rapid activation of intracellular signaling pathways, which coordinate the induction of multiple genes encoding inflammatory mediators (12, 13). TLRs appear to represent a conserved family of innate immune recognition receptors. A variety of bacterial and fungal products have been identified that serve as TLR ligands, but TLRs may also regulate homeostasis via interaction with endogenous protein ligands (14, 15, 16, 17).
In the present study, we demonstrate for the first time that SP-A requires a functional TLR4 complex to induce leukocyte activation.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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LPS (Escherichia coli 055:B5), PMA, 4-phorbol
didecanoate, and Gey’s medium were from Sigma-Aldrich (St. Louis, MO).
RPMI 1640 medium, HBSS, antibiotics, and glutamine were from Life
Technologies (Paisley, U.K.). FCS was from HyClone Laboratories (Logan,
UT). Non-phosphothioate-modified oligodeoxynucleotide (ODN)1668 was
custom synthesized by Genset (Paris, France). The immunostimulatory
oligonucleotide sequence was 5'-TCCATGACGTTCCTGATGCT-3' and the
inactive control was 5'-TCCATGAGCTTCCTGATGCT-3'. Human SP-A was
isolated from the lung washings of a patient with alveolar proteinosis
by a modification of a protocol of Suwabe et al. (18),
which included serial sedimentation of the surfactant pellet in the
presence of 1 mM Ca2+, elution with EDTA, and
adsorption to mannose-Sepharose. For some experiments, SP-A was further
purified by gel filtration under physiologic ionic strength conditions
(150 mM NaCl, 10 mM Tris) by Superose 6 gel filtration chromatography
using a fast protein liquid chromatography column with a bed
volume of 10 x 300 mm (Amersham Pharmacia Biotech,
Piscataway, NJ). The level of LPS associated with the SP-A was 140 pg
LPS per microgram of SP-A. Another SP-A preparation was obtained having
no detectable LPS using the QCL1000 kit (BioWhittaker,
Walkersville, MD).
Cell preparation and culture of BMDM
Five- to 6-wk-old female C3H/HeOuJ or C3H/HeJ mice provided by Iffa Credo (L’Arbresle, France) and Institut Pasteur (Paris, France), respectively, were used to prepare bone marrow-derived macrophages (BMDM), as previously described (19). Briefly, mice were euthanized by CO2 exposure and femurs were aseptically collected and placed in cell culture dishes containing sterile HBSS. Bone marrow was collected with HBSS and RBCs were lysed with Gey’s medium. The cell suspension was then centrifuged and the pellet was resuspended in RPMI 1640 medium supplemented with 10% FCS and 10% CSF-1-conditioned medium. Cells were then cultured for 3 days. Nonadherent cells were removed and centrifuged for 10 min at 400 x g. The pellet was resuspended in 1 ml of RPMI 1640 supplemented with 10% FCS and 1% antibiotics. Cell suspension was flushed through 25-, 27-, and 30-gauge needles successively to separate cell aggregates. Cells were resuspended at 2 x 106 cells/ml in RPMI 1640 supplemented with 10% FCS, 2.5% CSF-1-conditioned medium, and 1% antibiotics. A total of 300 µl of the cell suspension was dispensed into 48-well tissue culture plates (Costar, Corning, NY). After an overnight incubation, wells were washed with prewarmed medium and stimulated as indicated in the figures.
Culture of U937 cells
The promonocytic U937 cells were obtained from the American Type
Culture Collection (Manassas, VA) and grown in RPMI 1640 supplemented
with 10% FCS, 1% antibiotics, 1% glutamine, and 10 mM HEPES. Cells
were dispensed into 48-well plates (Costar) at 1.7 x
106 cells/ml and differentiated into macrophages
in the presence of 15 nM PMA or 15 nM 4-phorbol didecanoate as a
negative control for 48 h at 37°C in a 5%
CO2 humidified air atmosphere. Then, adherent
cells were washed with medium and 300 µl of prewarmed medium was
dispensed into each well. Twenty-four hours later, cells were washed
and stimulated as indicated in Results.
Determination of TNF- and IL-10 concentrations
Murine TNF- and IL-10 concentrations in BMDM
supernatants were determined by an ELISA and a solid-phase immunoenzyme
assay as previously described (19), respectively. Human
TNF- concentrations in the supernatant of U937 cells were determined
by ELISA, according to the manufacturer’s protocol (Pelikine compact;
CLB, Amsterdam, The Netherlands).
CD25 expression analysis
The Chinese hamster ovary (CHO)/CD14/TLR4 reporter line is a
stably transfected human CD14- and TLR4-positive CHO cell line that
expresses inducible membrane CD25 under the transcriptional control of
the human E-selectin promoter (13, 20). The promoter
fragment chosen contains an essential NF-B binding site. Flow
cytometry analysis of NF-B activity used cells that were plated in
12-well dishes and stimulated in Ham’s F12 medium containing 10% FCS,
as indicated in Fig. 2
. Subsequently, the cells were harvested with
trypsin-EDTA and labeled with FITC-CD25 mAb. Fluorescence analysis was
performed using a FACScan flow cytometer (BD Immunocytometry Systems,
Mountain View, CA). Binding of anti-CD25 Ab to its epitope is
expressed as the fold increase in median fluorescence intensity over
basal values measured on nontreated cells.
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Each point corresponds to the mean ± SD of the indicated number of experiments. Statistical significance between the individual groups was analyzed using the unpaired Student t test with a threshold of p < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A growing number of reports have suggested that SP-A may have some
host defense-related properties (3, 4). We first sought to
characterize the effect of purified SP-A on murine BMDM, in terms of
cytokine production. Supernatants from BMDM cultured in the absence or
the presence of increasing concentrations of SP-A (2.5–20 µg/ml)
were harvested after 6 or 24 h and assayed for TNF- and IL-10
concentrations, respectively (Fig. 1).
For comparison, BMDM were also activated by an optimal concentration of
LPS (1 µg/ml). To rule out any possible effect associated with
contamination of SP-A by LPS, all experiments performed during this
investigation used SP-A supplemented with 20 µg/ml polymyxin B, a
well-characterized LPS inhibitor (21) (Fig. 1). Under
these experimental conditions, TNF- and IL-10 levels increased to
levels of up to 
250 and 3500 pg/ml upon exposure of BMDM with a
concentration of SP-A above 10 µg/ml, respectively
(p < 0.001; n = 4). LPS
elicited a stronger immunostimulatory effect that was about twice that
measured upon SP-A cell activation (Fig. 1). Experiments were also
performed to determine the effect of SP-A on the secretion of cytokines
from human cells. The undifferentiated human U937 monocytic cell line
failed to up-regulate TNF- release in response to 10 µg/ml SP-A or
1 µg/ml LPS. However, when U937 cells were cultured with PMA, which
promotes differentiation to a more macrophage-like phenotype
(22), this cell line became responsive to both stimuli.
Thus, TNF- levels were 482 ± 70 and 1259 ± 26 pg/ml upon
SP-A and LPS treatment, respectively (p <
0.001 when compared with resting cells; n = 3).
Denaturation of SP-A by boiling reduces this activity by 95% (data
not shown). The heat-sensitive nature of SP-A as well as the failure of
polymyxin B to inhibit its stimulatory effect indicates that
SP-A-induced cytokine secretion from macrophages is LPS independent.
Because purity of the natural SP-A is critical to the interpretation of
these experiments, we also assessed the immunostimulatory activity of
SP-A that was further purified by Superose 6 gel filtration
chromatography (6 million m.w. cut off), a method that excludes lower
and high molecular components such as surfactant protein-D. Upon
incubation of BMDM with 10 µg/ml of the purified SP-A in the presence
of 20 µg/ml polymyxin B, TNF- levels increased up to 264 ±
49 pg/ml (n = 3). This value is consistent with the
TNF- release (263 ± 51 pg/ml; Fig. 1A) observed in
supernatants of BMDM treated with SP-A purified using the modified
protocol of Suwabe et al. (18) alone.
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B signaling pathway through TLR4
Based on the common ability of SP-A and LPS to induce
NF-B-dependent signals leading to similar immune cell responses, we
hypothesized that SP-A and LPS may share a common stimulatory pathway.
In that context, we evaluated whether SP-A could be an endogenous
ligand of the TLR4 complex. Thus, we determined whether SP-A could
activate TLR4 in a CHO-K1 cell line transfected with expression
plasmids for TLR4 and CD14, and the reporter construct
NF-B-dependent pELAM1-CD25. This cell line was challenged with 10
µg/ml LPS-free SP-A supplemented with polymyxin B or with 1 µg/ml
LPS as a positive control. SP-A induced a significant CD25 expression
(p < 0.01, n = 3) that was
70% of the LPS response (Fig. 2
). In
comparison, 10 µg/ml SP-A did not induce any NF-B-dependent CD25
expression in a control cell line that was not transfected with TLR4
and CD14 expression plasmids. By contrast, this control cell line was
strongly responsive to 50 ng/ml murine IL-1
, under the same
experimental conditions (CD25 expression was increased 6.3 ±
0.5-fold over basal values measured on resting cells; n
= 3; p < 0.01; data not shown).
Cytokine production by SP-A-stimulated macrophages is TLR4 dependent
SP-A-induced cytokine secretion was analyzed using BMDM isolated
from the LPS nonresponsive C3H/HeJ mice, carrying an inactivating
mutation in the tlr4 gene (23). We compared
this effect to that observed using BMDM isolated from C3H/HeOuJ mice, a
genetically related but TLR4-sufficient murine strain. Strikingly,
SP-A-induced IL-10 secretion was markedly reduced in TLR4-deficient
BMDM, in comparison with control BMDM (270 ± 164 vs 2079 ±
131 pg/ml; n = 3; p < 0.001; Fig. 3). A similar pattern was observed when
TNF- secretion was examined (data not shown). The BMDM from C3H/HeJ
did not appear to be globally refractory to inflammatory stimuli,
because cell activation was not reduced when BMDM were challenged with
a specific TLR9 ligand, i.e., ODN1668, a CpG ODN derived from a
mycobacterial sequence (24). As expected, the
corresponding nonactive ODN did not trigger any cytokine secretion
(n = 3, Fig. 3).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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production by
alveolar macrophages. These results, which are contradictory with
previous data, may be explained by the primary activation state of
these leukocytes (7) and/or the method of SP-A
purification. A role of SP-A in the down-regulation of pulmonary
inflammation has also been suggested using mice deficient in this
protein, which have increased inflammatory cytokine in response to an
infectious insult compared with wild-type mice (8, 9).
However, it is of note that this anti-inflammatory effect of SP-A
is not observed in a murine model of sepsis-induced lung injury
(26).
In this work we investigated the effect of human SP-A on the production
of cytokines by two well-defined populations of human and murine
macrophages. We show that SP-A, at a concentration likely to be found
in the alveolar spaces (11), induces the secretion of
immunoregulatory molecules such as TNF- and IL-10. These
observations suggest that, under normal in vivo conditions, the
inhibitory effects of the lipids prevail. However, in some lung
diseases or after certain insults, the balance between the inhibitory
and stimulatory influences may be disrupted and result in inflammatory
injury (27). In that regard, an increased level of SP-A
has been found in pulmonary lavages from patients with pneumonitis,
asbestosis, or exposure to hyperoxic conditions. Interestingly, these
pathological conditions are characterized by elevated levels of
cytokines and the presence of an inflammatory state (28).
One could speculate that these changes are the result of an increased
level of SP-A.
During the course of our study, we compared SP-A- and LPS-induced
immunostimulatory activity and found that both mediators stimulate the
expression of the same cytokines. LPS contamination could not account
for SP-A effects because the neutralizing molecule polymyxin B was
systematically added to all SP-A samples and the protein denaturing
heat treatment suppressed SP-A activity. In addition, LPS-free SP-A was
efficient in activating the NF-B signaling pathway through TLR4.
The finding that SP-A induces cell-specific functions led to the search
for its functional receptor. Kuroki and colleagues (29, 30) recently reported that SP-A binds to both CD14 and TLR2 and
that this interaction likely contributes to the ability of SP-A to
affect LPS- and peptidoglycan-mediated cell responses, respectively.
CD14 lacks an intracellular domain necessary for signal transduction
and is believed to present various pathogen-associated molecular
patterns to signal-transducing molecules of the TLR family
(15). Although SP-A may directly bind to the extracellular
domain of TLR2, it does not induce activation of the major downstream
signaling NF-B pathway (29). Our data indicate that
SP-A-induced activation of the NF-B pathway and up-regulation of
cytokine synthesis are strongly dependent on a TLR4 functional complex.
Although the detailed mechanism by which SP-A interacts with this receptor remains to be determined, the results presented in this work argue that TLR4 is a pattern recognition receptor that signals in response to both foreign pathogens and host endogenous mediators. This finding is consistent with recent studies showing that fibrinogen and heat shock protein 60 are putative ligands of the TLR4 complex (16, 17).
In summary, the data presented in this report demonstrate that cell activation by the lung SP-A is mediated by TLR4 and support the concept that SP-A may be an important mediator of inflammation.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Mustapha Si-Tahar, Unité de Défense Innée et Inflammation, Institut Pasteur, 25 rue du Dr. Roux, 75015 Paris, France. E-mail address: sitahar{at}pasteur.fr
3 Abbreviations used in this paper: SP-A, surfactant protein-A; TLR, Toll-like receptor; BMDM, bone marrow-derived macrophage; ODN, oligodeoxynucleotide; CHO, Chinese hamster ovary.
Received for publication February 1, 2002. Accepted for publication April 25, 2002.
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W. Huang, G. Wang, D. S. Phelps, H. Al-Mondhiry, and J. Floros Human SP-A genetic variants and bleomycin-induced cytokine production by THP-1 cells: effect of ozone-induced SP-A oxidation Am J Physiol Lung Cell Mol Physiol, March 1, 2004; 286(3): L546 - L553. [Abstract] [Full Text] [PDF]
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J.-L. Imler and L. Zheng Biology of Toll receptors: lessons from insects and mammals J. Leukoc. Biol., January 1, 2004; 75(1): 18 - 26. [Abstract] [Full Text] [PDF]
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J. F. Alcorn and J. R. Wright Surfactant protein A inhibits alveolar macrophage cytokine production by CD14-independent pathway Am J Physiol Lung Cell Mol Physiol, January 1, 2004; 286(1): L129 - L136. [Abstract] [Full Text] [PDF]
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L. G. Vazquez de Lara, T. M. Umstead, S. E. Davis, and D. S. Phelps Surfactant protein A increases matrix metalloproteinase-9 production by THP-1 cells Am J Physiol Lung Cell Mol Physiol, October 1, 2003; 285(4): L899 - L906. [Abstract] [Full Text] [PDF]
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 Y.-Z. Wu, S. Medjane, S. Chabot, F. S. Kubrusly, I. Raw, M. Chignard, and L. Touqui Surfactant Protein-A and Phosphatidylglycerol Suppress Type IIA Phospholipase A2 Synthesis via Nuclear Factor-{kappa}B Am. J. Respir. Crit. Care Med., September 15, 2003; 168(6): 692 - 699. [Abstract] [Full Text] [PDF]
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S. Chabot, L. Salez, F. X. McCormack, L. Touqui, and M. Chignard Surfactant Protein A Inhibits Lipopolysaccharide-Induced In Vivo Production of Interleukin-10 by Mononuclear Phagocytes during Lung Inflammation Am. J. Respir. Cell Mol. Biol., March 1, 2003; 28(3): 347 - 353. [Abstract] [Full Text] [PDF]
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I. Caramalho, T. Lopes-Carvalho, D. Ostler, S. Zelenay, M. Haury, and J. Demengeot Regulatory T Cells Selectively Express Toll-like Receptors and Are Activated by Lipopolysaccharide J. Exp. Med., February 17, 2003; 197(4): 403 - 411. [Abstract] [Full Text] [PDF]
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0.05). Results are
mean ± SD of three distinct experiments.
