* Department of Medicine, University of Colorado School of Medicine, Denver Health Medical Center, Denver; and
Division of Neurosurgery, The First Affiliated Teaching Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China
Correspondence: M-H. Wang, Department of Medicine, UCHSC, Denver Health Medical Center, Mail 4000, 777 Bannock Street, Denver, CO 80204. E-mail: ming-hai.wang{at}uchsc.edu
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Key Words: MSP • apoptosis • PI-3 kinase • iNOS
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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RON (recepteur d’origine nantais) is a receptor tyrosine kinase
belonging to the MET protooncogene family [10
]. The cDNA
encoding human RON was cloned from skin keratinocytes
[10
]. The murine homologue of RON was isolated from
hematopoietic stem cells and named STK (stem cell-derived tyrosine
kinase) [11
12
]. For simplicity, we will refer to
RON/STK as RON in this paper. Mature RON is a 180-kD heterodimeric
protein composed of a 40-kD 
chain and a 140-kD ß chain with
intrinsic tyrosine kinase activity [10
,
13
]. and ß chains are derived from a single-chain
RON precursor by proteolytic conversion [10
,
13
]. The ligand for RON was identified as a
macrophage-stimulating protein (MSP) [13
,
14
], also known as a hepatocyte growth factor-like
protein [15
]. MSP is a serum protein originally
identified by its stimulatory activities in mouse peritoneal resident
macrophages [16
]. RON expression is restricted in
certain types of tissue macrophages including those derived from
peritoneal cavity, skin, and bone [17
18
19
]. Monocytes,
alveolar macrophages, and spleen macrophages do not express RON
[17
]. Experiments using partial knockout mice have found
that the disruption of the RON gene significantly increases the
inflammatory reactions in vivo after LPS challenge [20
,
21
], suggesting that RON might play a critical role in
controlling inflammatory activities of macrophages during inflammation
and septic shock.
The present studies were to determine the effects of RON on LPS-induced apoptosis of macrophages and the potential cellular mechanisms. At present, information related to the functions of RON in protecting macrophage survival is not available, although activation of RON resulting in cell growth or apoptotic death of two established erythroleukemia cell lines was described [22 ]. Because RON activation inhibits LPS-induced NO production, and NO is the principle molecule responsible for LPS-induced macrophage apoptosis [23 , 24 ], we reasoned that RON activation might provide survival signals for activated macrophages. The data presented in this study show that RON activation protects macrophages from apoptosis induced by LPS and chemical NO donor S-nitrosoglutathione (GSNO).
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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p85) were established as
described [25
]. Cells were cultured in serum-free RPMI
1640 at 37°C in a humidified incubator containing 5% CO2
in air and stimulated with LPS and other reagents as detailed in each
experiment.
Reagents
Pure mature human MSP was provided by Dr. E. J. Leonard
(National Cancer Institute, Frederick, MD). Mouse monoclonal antibodies
(mAb; clone ID2) to the extracellular domain of human RON and rabbit
immunoglobulin G (IgG) antibodies to the C-terminal peptide of RON were
as described [25
]. Rabbit IgG antibodies to mouse p53
were from Santa Cruz Biotechnology (Santa Cruz, CA). Rabbit IgG
antibodies to mouse iNOS were from Transduction Laboratories (San
Diego, CA). Mouse interferon-
(IFN-) was from Roche
(Indianapolis, IN). LPS from Escherichia coli serotype
055:B5 was from Sigma Chemical Co. (St. Louis, MO). Chemical NO donor
GSNO, specific PI-3 kinase inhibitor wortmannin, and cycloheximide
(CHX) were from Calbiochem (San Diego, CA).
Animal treatment
Induction of macrophage apoptosis in vivo was performed as
described previously [26
]. C3H/HeN mice (four animals in
each group) were injected intraperitoneally (i.p.) with recombinant
human MSP (10 µg/mouse) or bovine serum albumin (BSA) in 0.2 ml
phosphate-buffered saline (PBS). After 30 min, mice were then injected
with 75 µg LPS plus 150 µg CHX/mouse in 0.4 ml PBS. Peritoneal
macrophages were collected 10 h after LPS injection. The
percentages of apoptotic macrophages were determined using Hoechst dye
33258 staining methods [27
].
Establishment of Raw264.7 cell lines expressing a constitutively
active RON mutant
Transfection of Raw264.7 cells with pcDNA3.1 vector containing a
mutant RON cDNA with D1232V substitution was performed as described
[25
]. This cDNA encodes a RON mutant that is
constitutively active [28
]. To avoid clonal variation,
RON-expressing cells were positively isolated using mAb ID2 and Dynal
beads M-450 coated with goat anti-mouse IgG (Dynal Co., Oslo, Norway)
Briefly, G418-resistant cells were first mixed with rabbit IgG
anti-CD16 (PharMigen, San Diego, CA) to block the Fc receptor on the
cell surface. Cells were then incubated with mAb ID2 followed by Dynal
beads coated with rabbit anti-mouse IgG. The selected cells were washed
and treated immediately with trypsin-ethylenediaminetetraacetate (EDTA)
solution to detach magnetic beads. The isolated cells were pooled and
cultured in Dulbecco’s modified Eagle’s medium (DMEM) with 8% fetal
bovine serum (FBS) in the presence of 800 µg/ml G418. Expression of
RON was determined in Western blotting.
Cell lyses and Western blotting
These methods were performed as described [12
].
Briefly, macrophages (3–6x106) were lysed in 0.2 ml lysis
buffer [0.1 M Tris, pH 7.6, containing 0.15 M NaCl, 2 mM EDTA, 0.5%
Nonidet P-40 (NP-40), 0.5% Triton X-100, 100 µM sodium vanadate, 10
µg/ml leupeptin, 10 µg/ml aprotinin, and 20 µg/ml soybean trypsin
inhibitor]. Cellular proteins were separated in 8% acrylamide gel
under reduced conditions. Rabbit IgG antibodies to p53 or iNOS were
used as detecting antibodies followed by goat anti-rabbit IgG
conjugated with peroxidase. The reaction was developed with enhanced
chemiluminescent reagents (Amersham, Arlington Heights, IL) and exposed
to film.
Assay for NO-2 production
Macrophages at 2 x 106 cells/ml were incubated
in RPMI 1640 in 200 µl/well in a 96-well tissue-culture plate. Cells
were stimulated with LPS. Culture fluids were collected 24 h after
incubation. Synthesis of NO was determined by measuring
NO-2, a stable reaction production of NO with
molecular oxygen, using Griess reagents as described previously
[23
]. NO2 concentrations were calculated by
comparison with a standard curve prepared with NaNO2.
DNA isolation and fragmentation assay
Macrophages were lysed in 500 µl lysis buffer [10 mM Tris
buffer, pH 8.0, containing 1 mM EDTA, 100 mM NaCl, and 1% sodium
dodecyl sulfate (SDS)] with 100 U/ml proteinase K and were incubated
at 50°C overnight. Lysates were then treated with RNase A for 1 h at room temperature. DNAs were extracted with phenol/chloroform and
precipitated at -20°C. DNA (5 µg/sample) was run in a 1% agarose
gel, visualized by ultraviolet fluorescence after staining the gel with
ethidium bromide, and photographed.
Hoechst dye 33258 fluorochrome nuclear-staining assay for apoptotic
cells
The assay was performed as described [27
].
Briefly, macrophages (2x106) were cultured in a
30-mm-diameter culture dish overnight and then stimulated with 1
µg/ml LPS for 24 h. MSP (5 nM) was added after culture
initiation. After stimulation, cells were fixed with 3%
paraformaldehyde for 5 min and washed with PBS. Apoptotic cells were
stained with Hoechst dye 33258 (1.5 µg/ml) for 10 min followed by
extensive wash with distilled water. Stained nuclei were visualized
using a fluorescent microscope (Nikon). A minimum of 200 cells was
counted in each sample. Apoptotic cells were expressed as a percentage
of the total counted nuclei.
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in the presence or absence of MSP. Macrophage
apoptosis was determined by DNA fragmentation and Hoechst dye 33258
staining assays. The results are shown in Figure 1
. LPS induced DNA fragmentation in peritoneal resident macrophages
when cells were cultured under serum-free conditions (Fig. 1A)
. DNA
fragmentation was also seen when cells were stimulated with LPS plus
IFN-. In contrast, stimulation of macrophages with MSP alone did not
induce DNA ladder formation. However, when MSP was added together with
LPS, LPS-induced DNA ladder formation was reduced, indicating that
ligand-induced RON activation has the ability to inhibit LPS-induced
macrophage apoptosis.
 View larger version (26K): [in a new window] |
Figure 1. Protective effect of MSP on apoptosis of primary macrophages stimulated
with LPS. Mouse peritoneal resident macrophages
(2x106/dish) were stimulated with 1 µg/ml LPS alone or
with 100 U/ml IFN-. MSP (5 nM) was added simultaneously. After
incubation of cells for 24 h, apoptotic cells were determined by
DNA fragmentation assay (A) or by Hoechst dye 33258 nuclei staining as
% of apoptotic cells (mean±SD of triplicate wells; B).
CTL, Cytolytic T lymphocytes. Experiments were repeated three times.
Results shown here are from one representative experiment.
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, the increased numbers of apoptotic cells were
observed. The percentages of LPS- or LPS plus IFN--induced
macrophage apoptosis reached about 27% or 23%. However, when MSP was
included in cell cultures together with LPS or LPS plus IFN-, the
percentages of nuclei stained with H33258 were reduced significantly to
8.5% or 6%, respectively. These data suggest that RON activation
blocks LPS-induced apoptotic activities in primary peritoneal
macrophages.
The protective effect of MSP in vivo against LPS-induced macrophage
apoptosis
To confirm the protective effect of RON in vivo, mice were
injected i.p. with human MSP for 30 min and then injected with LPS and
CHX. Peritoneal macrophages were isolated, and the apoptotic rates were
determined 10 h after LPS treatment. The results were shown in
Figure 2
. In mice treated with LPS and CHX, the percentages of apoptotic
macrophages ranged at about 28%. However, when mice were pretreated
with MSP, the numbers of LPS-induced apoptotic macrophages were reduced
to only 15%, an almost 50% reduction. These data suggest that
activation of RON in vivo exerts a protective effect on peritoneal
macrophages against LPS-induced apoptosis. This protective effect could
have implication in RON-mediated anti-inflammatory activities in vivo
[20
, 21
].
 View larger version (17K): [in a new window] |
Figure 2. Protective effect of MSP in vivo on LPS-induced macrophage apoptosis.
Four mice from each group were used for injection as described in
Materials and Methods. Values are means ± SD from
each group.
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was blocked significantly after RON activation. By quantitative
analysis using the Hoechst dye 33258 nuclear-staining assay, we found
that RON activation by MSP significantly prevents LPS-induced Raw264.7
cell apoptosis. The percentages of LPS-induced apoptotic cells (35.4%)
were reduced to 12.7% when MSP was included.
 View larger version (35K): [in a new window] |
Figure 3. Inhibition by MSP of LPS-induced apoptotic death in RON-expressing
Raw264.7 macrophages. Experimental conditions were the same as those
described in Figure 1
, except RON-expressing Raw264.7 cells were used.
Experiments were repeated twice. Results shown here are from one
representative experiment.
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 View larger version (64K): [in a new window] |
Figure 4. Inhibition of LPS-induced apoptotic death of Raw264.7 cells by the
constitutively active RON mutant. Experimental conditions were the same
as described in Figure 1
. Cells were all stimulated with LPS plus
IFN-. Raw-PC refers to Raw264.7 cells transfected with pcDNA3.0
vector alone. Experiments were repeated three times. Results shown here
are from one representative experiment.
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 View larger version (33K): [in a new window] |
Figure 5. Effect of RON activation on GSNO-induced apoptosis of Raw264.7 cells.
RON-expressing Raw264.7 cells were stimulated with GSNO (100 µM) for
24 h in the presence or absence of 5 nM MSP. LPS was used as the
positive control. Apoptotic cells were determined by DNA fragmentation
assay (A) or by Hoechst dye 33258 nuclei staining (B). The data shown
in B are presented as mean ± SD of triplicate wells
and derived from one of three experiments with similar results.
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 View larger version (19K): [in a new window] |
Figure 6. Correlation of MSP-induced inhibition of iNOS expression and cell
apoptosis in Raw264.7 cells expressing RON. Macrophages
(2x106/ml) were stimulated with 1 µg/ml LPS in the
presence or absence of 5 nM MSP. At time 0, 8, or 24 h, cells were
lysed or stained with Hoechst dye 33258. (A) Cellular proteins (50
µg/sample) were separated in 12% SDS-polyacrylamide gel
electrophoresis (PAGE) under reduced conditions. Rabbit IgG against
iNOS was used in Western blotting. Lanes 1, 3, and 5, stimulated with
LPS alone; lanes 2, 4, and 6, stimulated with LPS and MSP. (B) Cells
were stained with H33258 and counted under microscope. Open bars,
stimulated with LPS alone; shaded bars, stimulated with LPS and MSP.
Results are shown as mean ± SD of triplicate wells.
Experiments were repeated twice with similar results.
|
. The effect of MSP on p53 expression was
determined in Western blotting with specific anti-p53 antibodies. The
results are shown in Figure 7A
. The p53 protein was not expressed in unstimulated macrophages.
Also, MSP alone did not induce p53 expression. As expected, LPS induced
p53 expression. However, in the presence of MSP, LPS-induced p53
expression was inhibited. The levels of p53 in cells treated with LPS
and MSP were only about 27% of those induced by LPS. RON-expressing
Raw264.7 cells were also used to see the inhibitory effect of RON on
p53 expression. As shown in Figure 7B
, MSP significantly inhibited
LPS-induced p53 expression. Moreover, GSNO-induced p53 expression was
also inhibited by MSP in a dose-dependent manner. The inhibition ranges
at 44% or 71% in 2 or 10 MSP-treated cells (Fig. 7C)
. These results
suggest that RON activation blocks LPS or GSNO-induced p53 expression
not only in peritoneal resident macrophages but also in established
RON-expressing Raw264.7 cells.
 View larger version (37K): [in a new window] |
Figure 7. Inhibitory effect of MSP on LPS or GSNO-induced p53 expression. Mouse
peritoneal resident macrophages (A) or RON-expressing Raw264.7 cells
(B) at 2 x 106 cells/ml were stimulated with LPS in
the presence or absence of 2 nM MSP for 8 h at 37°C.
RON-expressing Raw264.7 cells were also stimulated with 100 µM GSNO
in the presence of 2 or 10 nM MSP for 8 h (C). Western blotting
was performed as described in Materials and Methods. Experiments were
repeated three times. Results shown here are from one representative
experiment.
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 View larger version (14K): [in a new window] |
Figure 8. Effect of wortmannin on RON-mediated inhibition of macrophage
apoptosis. RON-expressing Raw264.7 cells were pretreated with 50 or 200
nM wortmannin (WT) for 30 min at room temperature and then stimulated
with 1 µg/ml LPS for 24 h. MSP (5 nM) was added with LPS
simultaneously. Nuclei staining with H33258 was performed as described
in Materials and Methods. The results are expressed as the percentages
of stained nuclei (mean±SD of triplicate wells).
Experiments were repeated three times with similar results.
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p85;
clones Rp85-1 and Rp85-2) were used. After stimulation of these
cells with LPS in the presence or absence of MSP, the percentages of
apoptotic macrophages were determined. The results are shown in
Figure 9
. As usual, MSP inhibited apoptosis of control Raw264.7 cells
(expressing RON only) induced by LPS. However, in cells expressing RON
and p85, the inhibitory effect of MSP on LPS-induced apoptosis was
diminished significantly. The numbers of H33258-stained nuclei were
increased to about 18% (clone Rp85-1) and 21% (clone Rp85-2) in
these two cell lines, suggesting that inhibition of endogenous PI-3
kinase by p85 prevented the RON-mediated inhibition of LPS-induced
macrophage apoptosis.
 View larger version (13K): [in a new window] |
Figure 9. Effect of dominant-negative p85 of PI-3 kinase in RON-mediated
inhibition of macrophage apoptosis. Rp85-1 (top panel) or Rp85-2
(middle panel) cells were stimulated with LPS in the presence or
absence of MSP as described in Figure 7
. Raw264.7 cells expressing RON
only (bottom panel) were used as the positive control.
Wortmannin was used at the concentration of 200 nM. H33258 staining was
conducted as described. The top and middle panels represent Rp85-1
and Rp85-2 cells, respectively. The bottom panel represents
RON-expressing Raw264.7 cells. Experiments were repeated twice. Results
shown here are from one representative experiment and are expressed as
the percentages of stained nuclei (mean±SD of triplicate
wells).
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Macrophage apoptosis occurs under various pathological conditions [32 ]. Many stimuli including LPS, bacterial lipoprotein, and Fas ligand are capable of inducing macrophage apoptosis [9 , 33 , 34 ]. We show here that peritoneal resident macrophages were susceptible to LPS-induced apoptosis, as evident by the formation of DNA fragmentation and the increased percentages of the nuclei stained with the DNA-specific fluorochrome Hoechst dye 33258. These cellular damaging activities of LPS were inhibited following RON activation. Moreover, the protective effect of RON could be reproduced by using Raw264.7 macrophage-like cells molecularly engineered to express human RON. These results indicate that ligand-dependent activation of RON is required to block the apoptotic signals induced by LPS. This notion is supported further by the results derived from experiments using Raw264.7 cells expressing a constitutively active RON mutant. In these cells, LPS-induced DNA fragmentation was reduced significantly, even in the absence of MSP.
One of the effector molecules that mediate LPS-induced macrophage
apoptosis is NO [24
]. In murine macrophages, NO has
emerged as a principle molecule responsible for LPS-induced apoptosis
occurring in macrophages derived from different tissues
[9
, 34
, 36
]. NO-induced
apoptosis also occurs in established human or murine
monocyte/macrophage cell lines including Raw264.7 cells
[28
]. Our data showed that RON activation not only
inhibits LPS but also NO donor GSNO-induced apoptotic death of Raw264.7
cells expressing human RON. These results suggest that the effects of
RON are probably mediated by blocking LPS-induced production of NO and
GSNO-induced p53 expression. We have demonstrated previously that
activation of RON results in inhibition of LPS-induced NO formation but
not cytokine production in primary macrophages and Raw264.7 cells
[23
]. Our results presented in Figure 6
further
confirmed that MSP inhibits LPS-induced iNOS expression in a
time-dependent manner, which is correlated with the appearance of
cellular DNA fragmentation. As we showed previously, activated RON
transduces signals that block the promoter activities of the iNOS gene
and the iNOS mRNA expression induced by LPS and IFN-
[25
]. Moreover, these effects were mediated by blocking
LPS-induced nuclear factor-
B (NF-B) activation
[37
]. Because LPS-induced macrophage apoptosis is
mediated mainly by NO, and RON is an endogenous NO inhibitor, we
reasoned that the inhibitory effect of RON on LPS-induced apoptosis is
mediated by inhibition of NO production. However, because the toxic
effect of NO is only a part of LPS activities, which causes macrophage
apoptosis, more studies are needed to determine if other mechanisms are
also involved. As shown in Figure 5
, RON activation inhibits macrophage
apoptosis induced by chemically generated NO. This result suggests a
different mechanism is involved in RON-mediated inhibition of
NO-induced macrophage apoptosis. Inhibition of p53 expression as shown
in Figure 7
might be one of the mechanisms. Thus, the antiapoptotic
effects of RON are not limited in inhibiting iNOS expression. Other
mechanisms such as blocking p53 expression may also apply.
Cellular mechanisms by which LPS and NO induce macrophage apoptosis have been studied extensively [30 , 38 , 39 ]. Induction of p53 accumulation, regulation of Bcl-2 expression, and activation of members of the caspase family are the most commonly observed changes in LPS or NO-stimulated macrophages, which are in the process of apoptosis [30 , 38 , 39 ]. Although defining the detailed mechanisms of how RON inhibits macrophage apoptosis is a subject for future investigation, our current results do provide some clues, which may explain the actions of RON in protecting macrophages from apoptotic death. We found that LPS-induced p53 accumulation was inhibited following MSP treatment. RON activation also partially blocks GSNO-induced p53 expression. The p53 protein is well-known for its role in the cellular response to DNA damage caused by exogenous stimuli including NO [40 ]. It has been demonstrated that p53 activation results in cell-cycle arrest or apoptosis of the affected cells [41 ]. In NO-stimulated Raw264.7 cells, the correlation between accumulation of p53 and induction of apoptosis has been established [20 ]. Biochemical analysis has shown that LPS-induced p53 accumulation is mainly a result of the NO-mediated inhibition of cellular proteasome activities [42 ]. With regard to the effect of RON on LPS-induced p53 expression, we do not know what kind of mechanisms are involved in the action of RON. However, it will be of interest in the future to determine whether RON activation transduces signals that affect p53 expression at the gene level or controls p53 degradation through posttranslational mechanisms.
One of the interesting findings in this study is that PI-3 kinase is involved in RON-mediated inhibition of macrophage apoptosis. PI-3 kinase is well-known for its role in regulating cell growth, migration, differentiation, and survival [43 ]. In PC-12 cells, inhibition of PI-3 kinase by wortmannin or a dominant-negative p85 of PI-3 kinase blocks the cell-surviving effect of the nerve-growth factor [44 ]. Activation of PI-3 kinase is also required for macrophage survival when cultured in serum-free condition [45 ]. We have shown previously that RON activation stimulates PI-3 kinase and causes association of RON with p85 of PI-3 kinase [46 ]. Functional studies also demonstrated that blocking PI-3 kinase activities results in inhibition of RON-mediated macrophage cell-shape change and migration [46 ]. More importantly, suppressing PI-3 kinase prevents RON-mediated inhibition of NO production induced by LPS and inflammatory cytokines [25 ]. We now show that inhibition of RON-mediated activation of PI-3 kinase by specific inhibitor wortmannin or the dominant-negative p85 of PI-3 kinase restores the apoptotic effect of LPS on macrophages. These accumulated evidences provide a functional connection between PI-3 kinase-mediated inhibition of NO production and macrophage apoptosis. We postulate that in macrophages, LPS-induced NO acts on cellular DNA and causes apoptotic death of macrophages. However, in the presence of MSP, activated PI-3 kinase transduces signals that block LPS-induced NO synthesis and p53 accumulation. By antagonizing these LPS-induced toxic effects, activated RON provides survival signals for macrophages. The protective activities of RON could play an important role in regulating macrophage functions during bacterial infection.
p85 of PI-3 kinase. Received February 22, 2001; revised October 6, 2001; accepted October 9, 2001.
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induces the expression of p21waf-1 and arrests macrophage cell cycle, preventing induction of apoptosis Immunity 11,103-113[Medline] and lipopolysaccharide by the STK/RON receptor tyrosine kinase J. Immunol. 163,6606-6613This article has been cited by other articles:
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