Département de Pneumologie Pédiatrique, Institut National de la Santé et de la Recherche Médicale U515, Hôpital Trousseau Assistance Publique-Hôpitaux de Paris, Université Paris VI, 75012 Paris, France
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ABSTRACT |
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Tumor necrosis
factor (TNF)- is a key molecule in lung inflammation. We have
established the insulin-like growth factor binding protein 2 (IGFBP-2)
as a marker associated with the growth arrest of lung alveolar
epithelial cells (AEC). Here, we studied the effects of TNF-
on AEC
proliferation and the putative protective role of retinoic acid (RA).
We documented an antiproliferative action of TNF-
that was
reversible only at 24 h and then became irreversible with
induction of apoptosis. TNF-
treatment was associated with a
dramatic induction of IGFBP-2. To discover the mechanism of action of
IGFBP-2, we further tested the mitogenic potential of IGF-I to
counteract TNF-
inhibition. Addition of IGF-I to the TNF-
containing medium did not stimulate proliferation, whereas
des(1-3)IGF-I, an analog of IGF-I that bears low affinity for
IGFBPs, was able to restore cell growth. Interestingly, we observed
that RA abrogated TNF-
-induced growth arrest and that this effect
was associated with a dramatic decrease in IGFBP-2 expression. These
results suggest a protective role of RA from TNF-
antiproliferative
action, through mechanisms involving modulation of IGFBP-2 production.
lung epithelial cells; inflammation; insulin-like growth factor; proliferation; retinoic acid
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INTRODUCTION |
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LUNG INFLAMMATION is a critical response for the protection of the respiratory system from infectious as well as noninfectious insults. Although this response is usually beneficial, it can also be deleterious. In particular, chronic inflammation can be viewed as the result of uncontrolled proinflammatory events and inefficiency of repair mechanisms.
The multifunctional cytokine tumor necrosis factor (TNF)- is one of
the key mediators involved in the inflammatory response and its role in
the course of inflammation has been extensively investigated (12,
22). Indeed, TNF-
displays a wide range of activities,
including immunoregulatory and mitogenic functions, and consequently is
a central component of the initiation and the progression of
inflammatory processes.
Among the various structures that compose the lung, alveoli are
especially sensitive to a number of insults. After injury, a rapid
initiation of the repair processes is critical to maintain alveolar
architecture integrity and gas exchange function. Repair of the
alveolar structure is dependent on the proliferative response of the
alveolar epithelial cells and the mesenchymal cells. Recent studies
have provided some information on the influence of TNF- on
fibroblast proliferation during lung injury and repair (13, 23). In several experimental models, it has been reported that pulmonary inflammation and fibrosis could be prevented by injection of
anti-TNF-
antibodies or TNF-
antagonists (35). Yet
little is known on the influence of TNF-
on the alveolar
reepithelialization process, whether beneficial or deleterious.
Repair of the alveolar epithelium is controlled by the ability of the stem cells, the type 2 cells, to proliferate and undergo transition into type 1 cells (1, 2). Among growth factors regulating lung cell proliferation, the insulin-like growth factors (IGF) are mitogenic peptides with an autocrine/paracrine action on lung epithelial cell proliferation (26, 37). The actions of IGF are regulated by a family of high-affinity IGF binding proteins (IGFBP) (19). IGFBPs display opposite effects on proliferation. They can exert antiproliferative action either through IGF-dependant mechanisms by sequestering the IGF from the IGF receptor or through IGF-independent mechanisms. Previously, we reported the involvement of several components of the IGF system in the control of proliferation of type 2 alveolar epithelial cells. Particularly, blocking of type 2 cell proliferation induced by various situations such as serum deprivation, oxidant exposure, or glucocorticoid treatment was found to be associated with accumulation of IGFBP-2 (5, 28, 29). Interestingly, we recently provided data indicating that retinoic acid (RA) could stimulate type 2 cell proliferation and that this effect was associated with a decrease in IGFBP-2 expression (30). Retinoids, including retinol and RA derivatives, have been shown to be involved in the processes of lung repair after injury (6, 7). Several reports have found vitamin A deficiency to be associated with extensive alterations of the epithelial structure that could be reversed by RA treatment. Massaro and Massaro (24) showed that postnatal treatment with RA increased the number of pulmonary alveoli in rats. Moreover, they provided data indicating that RA could reverse the effects of elastase-induced alveolar damage in rats (25). These results fit in well with the current understanding of the effect of retinoids, including retinol and RA, on lung repair.
To provide information on the influence of TNF- on the repair
capacity of the alveolar epithelium, we chose to analyze the effect of
TNF-
on the proliferative response of alveolar type 2 epithelial
cells. Experiments were performed with a rat type 2 cell line that has
been shown in previous studies to regulate some aspects of
proliferation in a fashion similar to that of primary type 2 epithelial
cells (8, 10). Our findings document an antiproliferative
action of TNF-
, an effect that was associated with an increased
expression of IGFBP-2. To document any protective role of RA to reverse
the TNF-
effect, we also examined the consequence of RA treatment on
TNF-
-induced growth inhibition of type 2 epithelial cells. We
provide data indicating that RA was able to restore the proliferative
capacity of the cells through mechanisms that involve a downregulation
of IGFBP-2.
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MATERIALS AND METHODS |
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Cell Culture
The type 2 cell line used in this study was derived from rat primary neonatal type 2 cells and has been extensively studied (10). Cells were grown in Earle's MEM (GIBCO-BRL, Grand Island, NY) supplemented with 4 mM glutamine, 50 units of penicillin/ml, 50 µg of streptomycin/ml, and 10% fetal bovine serum (Eurobio) in 5% CO2-95% air atmosphere at 37°C.Cells treated with TNF- were exponentially grown at a density of
4 × 104 cells/cm2, washed, and further
cultured in serum-free medium containing various concentrations of
recombinant human TNF-
(R&D System) for the indicated durations.
Stock solutions of TNF-
were prepared at a concentration of 10 µg/ml in PBS containing 0.1% of BSA (Sigma, St. Louis, MO) and
stored at
80°C. RA (Sigma) was prepared at a concentration of 10 mM
in 100% ethanol and stored at
80°C. In all experimental
conditions, cell viability was tested using trypan blue.
Cells treated with IGF-I or des(1-3)IGF-I were exponentially grown
at a density of 4 × 104 cells/cm2,
washed, and further cultured in medium containing either vehicle (10 mM
HCl) or 10 nM recombinant human (rh) IGF-I protein (GroPep Pty) or 10 nM rh des(1-3)IGF-I protein (GroPep Pty), with or without TNF-
(10 ng/ml), in combination or not with RA (1 µM).
For experiments with conditioned medium, cells were washed three times with serum-free medium and incubated for an additional 8 h in serum-free medium.
For each protocol, three independent experiments were performed.
Proliferation Studies
Cell number assay. Cell proliferation was evaluated by measurement of cell number as previously described (10). Briefly, cells were harvested with trypsin-EDTA and counted in triplicate using a hemocytometer.
DNA synthesis assay. For autoradiography of labeled nuclei, cells were incubated for 24 h in medium containing 2 µCi/ml [methyl-3H]thymidine (60-70 Ci/mmol), as previously described (9). The plates were then washed three times with cold PBS, fixed with methanol, air dried, and coated with NTB-2 liquid emulsion (Eastman Kodak, Rochester, NY). Twenty-four hours later, they were developed with Kodak Rapid Fix. After being stained with Giemsa, an average of 300 cells in random fields was examined at a magnification of ×400, and labeled nuclei were counted.
Flow cytometry analysis.
The flow cytometric assay was performed after the DNA was stained by
the propidium iodide method. Briefly, exponentially growing cells were
treated with TNF- and other reagents for the indicated durations.
Floating and attached cells were harvested, washed, and centrifuged
(1,000 g for 10 min). Pellets were resuspended in
physiological serum (0.9% NaCl) to reach a cell concentration of
5 × 105-106 cells in 400 µl. The cell
suspension was fixed in 4 ml 70% ethanol. The fixed cell suspension
was allowed to stand for 16 h at 4°C. Cells were centrifuged and
stained by the addition of propidium iodide-staining solution (50 µg/ml propidium iodide) in the presence of 100 µg/ml RNase A
(Sigma) for 30 min at 37°C in the dark. DNA content was analyzed
through a FACStar plus flow cytometer (Becton Dickinson, Franklin
Lakes, NJ). Apoptotic cells were defined as those exhibiting lower
relative fluorescence than the G0/G1 peak.
Western Immunoblotting
The conditioned medium was then harvested, centrifuged (1,000 g for 10 min) to remove debris and unattached cells, desalted on Sephadex G-25 disposable columns (Amersham Pharmacia Biotech, Buckinghamshire, UK), and lyophilized (18, 30). The pellet was dissolved in a volume of 2× Laemmli buffer accordingly to the number of cells (40 µl for 8 × 105 cells). Equal volumes of samples were loaded for each experimental condition and were electrophoresed through an 11% SDS-polyacrylamide gel. Proteins were transferred onto 0.45-µm nitrocellulose (NC) membranes (Bio-Rad, Richmond, CA). Membranes were blocked 2 h at room temperature in PBS plus 0.2% Tween 20 (PBS-T) containing 10% skim milk. Incubation of the membrane was performed using the rabbit anti-bovine IGFBP-2 at 1:1,000 dilution (UBI, Lake Placid, NY) in 5% milk-PBS for 20 h at 4°C. Membranes were then washed three times in PBS-T and incubated for 1 h at 37°C with horseradish peroxidase-conjugated goat anti-rabbit immunoglobulin G (Amersham Pharmacia Biotech) diluted at 1:6,000 in 5% milk-PBS. ECL was performed according to the manufacturer's instructions (ECL Western blotting, Amersham Pharmacia Biotech). Membranes were then exposed to autoradiography film (Hyperfilm-ECL, Amersham Pharmacia Biotech).For IGF-II immunoblotting, 2 ml of conditioned medium (2 × 106 cells equivalent) were concentrated on Centricon C10 (Millipore, Bedford, MA), lyophilized, and loaded on a 15% gel under nonreducing conditions. rIGF-II (100 ng) and protein extracts (250 µg) from normal serum were used as controls and loaded on the same gel to measure IGF-II protein in conditioned media. After transfer, the blots were probed with an anti-rat IGF-II monoclonal antibody (UBI) at 1:500 dilution. This antibody was specific to rat and hIGF-II and showed less than 10% cross-reactivity with IGF-I.
Western Ligand Blotting
Conditioned media were collected after incubation of cells in basal medium and prepared as indicated above. The ligand blotting experiments were performed as previously described (29). Briefly, the lyophilized samples containing the secreted proteins were dissolved in a volume of 1× Laemmli buffer adjusted to cell number and analyzed on SDS-PAGE (11% polyacrylamide) under nonreducing conditions. The proteins were electrotransferred onto an NC filter, and the membranes were washed for 1 h at 4°C in 5 mM Tris · HCl, pH 7.4, and 150 mM NaCl (TBS) containing 0.2% Tween, then incubated for 48 h at 4°C with a mixture of 125I-IGF-I and 125I-IGF-II (200,000 counts/min each) in TBS and 1 mg/ml gelatin (Serva, Heidelberg, Germany). After being washed, the binding proteins were visualized by autoradiography. Relative molecular weight was estimated by running a prestained molecular-weight standard.IGF-I Assay
Each conditioned medium were desalted on Sephadex G25 disposable columns (Amersham Pharmacia Biotech) and lyophilized. Then the lyophilysates were reconstituted with 2 ml of 0.01 N HCl and ultrafiltrated on Centricon C30 (Millipore). After lyophilization and reconstitution with RIA buffer (0.1 M phosphate buffer, pH 7.4, 1 mg/ml IGFBP-free BSA; Biomerieux, Paris, France), each sample were assayed by RIA using anti-IGF-1 antibodies provided by Drs. Closet, Frankenne, and Hennen (Liege, Belgium) as previously described (17, 18).Statistical Analysis
Results were reported as the means ± SE. Data were analyzed using ANOVA, followed, if possible, by Mann-Whitney U-test for multiple comparisons against control conditions. Significance was assigned for P < 0.05. ![]() |
RESULTS |
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Effects of TNF- on Type 2 Alveolar Epithelial Cell
Proliferation
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We then examined restimulation of epithelial cell proliferation after
TNF- treatment. Cells were first cultured in basal medium with or
without TNF-
(10 ng/ml) for 24 or 48 h and then replaced in
serum-containing medium for an additional 24 to 72 h (Fig.
2). In the experimental conditions of a
24-h TNF-
treatment, cells rapidly resumed proliferation (Fig.
2A). By contrast, after a 48-h TNF-
treatment, no
increase in cell number could be observed when cells were returned to
serum-containing medium (Fig. 2B).
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Based on these data and to assess the putative protective action of RA, we chose to use culture conditions without serum (30, 31).
Modulation by RA of TNF- Effects on Cell Proliferation
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To document the effect of TNF- on apoptosis, we stained
cells with propidium iodide and analyzed them by flow cytometry (Table 1). The percentage of
apoptotic cells gradually increased with the duration of
TNF-
treatment: after 48 h the mean percentage was 53.6 ± 5.7%. When cells were treated with RA, the stimulatory effect on type
2 cell proliferation was associated with a significant decrease in the
percentage of cells undergoing apoptosis (P < 0.05 vs. control conditions). Finally, when type 2 cells were treated
with TNF-
in combination with RA, the increase in apop totic cell
number was completely abolished within 16 h of treatment (P < 0.05 vs. TNF-
conditions).
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Taken together, these results indicated that RA could abrogate the
effects of TNF- on cell growth and on apoptosis. To
determine whether the stimulatory action of RA on cell proliferation
could still be observed after an initial exposure to TNF-
,
proliferative cells were washed and cultured for 48 h in basal
medium with or without TNF-
(10 ng/ml), RA (1 µM) being added to
the cultures for the first 24 h or the last 24 h (Fig.
4). The increase in cell number was
significantly higher in the experimental conditions where RA was added
during the first 24 h of TNF-
treatment.
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Modulation by RA of TNF- Effects on IGFBP-2 Secretion
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Effects of IGF-I and des(1-3)IGF-I on Cell Proliferation
To further document the role of IGFBP-2 in the antiproliferative action of TNF-
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Effects of TNF- on IGF Production
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DISCUSSION |
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The alveolar microenvironment after acute lung injury plays a
critical role in the repair process and, therefore, in the proper healing of the gas exchange structure. Repair is initiated by an
extensive proliferative response that leads to reepithelialization of
the alveolar surface. The mechanisms involved in this response imply
the contribution of a number of mediators, including the major
proinflammatory cytokine TNF-. The role of TNF-
on the repair
potential of the alveolar epithelium has been so far poorly investigated. In the present study we provide data indicating that
TNF-
exerts an antiproliferative action on lung alveolar epithelial
type 2 cells. We also show that TNF-
-induced growth arrest is
associated with an increased expression of IGFBP-2. Moreover, we
demonstrate that the antiproliferative effects of TNF-
are reversed
by RA, which is associated with a downregulation of IGFBP-2.
The effects of TNF- on cell proliferation have been reported to vary
depending on the cell types (11, 13, 14, 34, 39). In the
present work, we showed that TNF-
treatment of lung epithelial cells
accelerated the decrease in the labeling index and growth arrest. This
growth arrest was reversible only for a maximal duration of a 24-h
TNF-
exposure. When cells were exposed to TNF-
for 48 h,
they could not resume proliferation when replaced in serum-containing
medium. This observation was associated with a dramatic increase in
number of apoptotic cells. These results suggest that TNF-
is able
to trigger two steps in the responses to inflammatory injury: first a
reversible growth arrest of lung epithelial type 2 cells followed by an
apoptotic process when lesions are more important. Such biphasic
response has already been observed in rat fetal brown adipocytes
maintained in primary culture where TNF-
treatment resulted in an
inhibition of proliferation and induction of apoptosis
(36). Also, histological findings of extensive damage of
the alveolar epithelium reported in transgenic mice that overexpressed
TNF-
in the alveolar epithelial type 2 cells are consistent with our
present observation of antiproliferative effects of TNF-
on type 2 epithelial cells (27, 41).
There is now evidence for an important role of retinoids in the
development, maturation, and homeostasis of the lung. Based on the
current understanding of RA action, it seems that RA displays anti-inflammatory properties that take place at the various steps of
the inflammatory response (16, 33). In a vitamin A
deficiency rat model, Baybutt et al. (3) showed that
scattered inflammation was observed in the vitamin A-deficient animals.
RA influence also occurs at later stages of the inflammatory response
by promoting re-epithelialization. In previous studies, we provided
data indicating that RA could stimulate alveolar epithelial cell
proliferation in serum-free conditions, i.e., in the absence of growth
factors (30). In the present work, we demonstrate that RA
could also exert mitogenic effects on epithelial cells in inflammatory
conditions. Indeed, we found that the antiproliferative action of
TNF- was no longer observed in the presence of RA. Addition of RA at
different time points revealed that RA action occurred mainly within
the first 24 h of TNF-
treatment, suggesting an early function
in the modulation of cell proliferation.
To provide information on the mechanisms potentially involved in the
TNF--induced growth arrest of lung epithelial cells, we focused on
the IGF system, and mainly on IGFBP-2. The interest for IGFBP-2 is
explained by previous reports indicating that IGFBP-2 is the main IGFBP
produced by these cells. IGFBP-2 production is dramatically increased
in conditions of serum deprivation or glucocorticoid and oxidant
exposure. Data reported herein show for the first time an increase in
IGFBP-2 expression upon TNF-
treatment. From these results, it could
be suggested that the growth inhibitory action of TNF-
may involve
a reduction of IGF-I bioavailability and bioactivity resulting
from the competition for IGF-I between IGFBP-2 and the IGF type I
receptor. Effects of TNF-
on the IGF system have been reported in
situations where TNF-
was associated with growth arrest (4,
32, 38). In particular, Katz et al. (20) showed
that TNF-
together with interferon-
exerted an antiproliferative
action on human salivary gland tumor cells through an increase of the
bound form of IGF-1 with IGFBP-3, which led to reduce the availability
of IGF-1 and, consequently, its mitogenic effect. Our results
using des(1-3)IGF-I showed that, in situations of growth
arrest associated with a dramatic accumulation of
IGFBP-2, IGF-I could not stimulate proliferation, whereas
des(1-3)IGF-I was able to promote cell growth. These data provide
evidence for a role of IGFBP-2 in the process of type 2 cell growth
arrest through mechanisms involving a competition for IGF-I
between IGFBP-2 and IGF-1R.
In addition, our results demonstrate that TNF- effects on IGFBP-2
expression are modulated by RA. Indeed, the decreased production of
IGFBP-2 by RA was associated with a mitogenic effect of both IGF-I and
des(1-3)IGF-I. The observations that RA could modulate IGFBP-2
expression and abrogate TNF-
-induced growth arrest of lung
epithelial cells suggest that RA may have a dominant effect. The
mechanisms involved in this protective action of RA need to be further
studied. Several reports have documented the influence of RA on the IGF
system and have shown that RA may regulate IGFBPs at the
transcriptional and/or posttranscriptional level in a cell-specific manner (15, 21, 40). Kim et al. (21)
investigated the effects of RA on IGFBPs in human hepatoma cells. They
found that RA treatment decreased IGFBP-1 and IGFBP-3 mRNA in PLC/PRF/5
cells and caused a downregulation of phosphorylated IGFBP-1 in
PLC/PRF/5 and Hep G2 cells. Our present observation of a protective
action of RA could also involve changes in TNF-
receptor expression. Indeed, Totpal et al. (42) showed that RA treatment led to
a downregulation of p60 and p80 forms of TNF-
receptors, which subsequently desensitized the cells to TNF-
. Studies are currently being pursued to characterize the mechanisms by which RA could reverse
TNF-
induced growth arrest in alveolar epithelial cells.
To conclude, our results demonstrate that TNF- exerts an
antiproliferative action on lung epithelial cells through mechanisms that involve IGFBP-2. We also show that RA can restore the
proliferative capacity of the cells through pathways that include
downregulation of IGFBP-2. This protective action of RA towards TNF-
may have important consequences in vivo. Indeed, the present data raise the possibility that patients with inflammatory diseases might benefit
from vitamin A supplementation during inflammatory injury. At this
stage, further studies are required to characterize the signaling
pathways and the factors involved, particularly the mechanisms by which
RA plays a protective role against TNF-
-induced lung injury.
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ACKNOWLEDGEMENTS |
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We thank Marie-Claude Miesch for technical assistance.
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FOOTNOTES |
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V. Besnard was supported by a grant from the Fondation pour la Recherche Médicale. This work was supported by Association Claude Bernard, Chancellerie des Universités de Paris (Legs Poix), Ligue Nationale contre le Cancer (Comite de Paris), Association pour la Recherche contre le Cancer, University Paris VI.
Address for reprint requests and other correspondence: A. Clement, Département de Pneumologie Pédiatrique, Hôpital Trousseau, 26, Ave Dr. Netter, 75012 Paris, France (E-mail: annick.clement{at}trs.ap-hop-paris.fr).
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.
10.1152/ajplung.00368.2001
Received 18 September 2001; accepted in final form 23 November 2001.
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