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Infection and Immunity, January 2000, p. 87-92, Vol. 68, No. 1
Department of Pathology, University of Turku,
20520 Turku, Finland,1 and Chrysalis
DNX Transgenics, Princeton, New Jersey 085402
Received 10 June 1999/Returned for modification 11 August
1999/Accepted 20 October 1999
Group II phospholipase A2 (PLA2) is a newly recognized
antibacterial acute-phase protein. Recently we observed that transgenic mice expressing group II PLA2 (PLA2+ mice) were able to
resist experimental Staphylococcus aureus infection by killing the bacteria, as indicated by improved survival and by the small numbers of live bacteria in their tissues (V. J. O. Laine, D. S. Grass, and T. J. Nevalainen, J. Immunol. 162:7402-7408, 1999). To establish the role of group II PLA2
in Escherichia coli infection, the host responses of
PLA2+ mice and their PLA2-deficient C57BL/6J littermates
(PLA2 Phospholipase A2 (PLA2; EC 3.1.1.4)
catalyzes the hydrolysis of the sn-2 fatty acyl bond of phospholipids
and produces free fatty acids and lysophospholipids. Activation of PLA2
has been implicated as an early event in the inflammatory pathway
(30). The PLA2s found in human serum (20) are
group I PLA2 (pancreatic) and group II PLA2, which are both 14-kDa
secretory proteins (4). Group II PLA2 was originally
purified from synovial fluid (9) and blood platelets
(15). This enzyme is present in numerous human tissues and
body fluids (11). The concentration of group II PLA2 in
serum increases during severe acute inflammatory diseases (20) and after surgery (7, 17). The catalytic
activity of PLA2 found in blood plasma is due to the presence of group II PLA2 during various pathological conditions, including sepsis (6), bacterial infections (29), arthritis
(14), acute pancreatitis (21), and multiple organ
failure (25). It has been suggested that group II PLA2 is an
acute-phase protein (26) produced by hepatocytes (3,
22). Increased concentrations of this enzyme in serum are
indicative of a poor prognosis for patients with severe diseases such
as sepsis (8) and multiple organ failure (25).
Inflammatory mediators, such as prostaglandins, have been proposed to
play a crucial role in the development of multiple organ failure. The
rate-limiting step in the generation of these mediators is the release
of arachidonic acid by PLA2 (1). Thus, inhibition of PLA2
has been proposed as a possible means of intervention in preventing
symptoms of severe inflammatory diseases (1). However, the
exact role of group II PLA2 in inflammation remains unknown.
C57BL/6J mice lack endogenous group II PLA2 production because of
a mutation in the gene encoding this enzyme (PLA2 Recently, we found that the PLA2+ mice were resistant to
experimental Staphylococcus aureus infection
(16). The resistance was presumably due to killing of the
bacteria by group II PLA2, as indicated by improved clearance of
S. aureus from the tissues of the PLA2+ mice
compared to that of their PLA2 The present study was aimed at finding out whether the overexpression
and high concentrations of human group II PLA2 in sera of
PLA2+ mice would be harmful or beneficial to the host
during severe E. coli infection. To address this issue, host
defense of both PLA2+ and PLA2 Experimental animals.
The production of transgenic mice
expressing human group II PLA2 is described in detail elsewhere
(5). Of the several transgenic mouse lines characterized,
one with high-level catalytic activity of PLA2 in serum was chosen for
the production of PLA2+ and PLA2 Bacteria and infection protocol.
E. coli bacteria
(ATCC 25922; American Type Culture Collection, Manassas, Va.) were
stored in water with 20% glycerol at
0019-9567/0/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Resistance of Transgenic Mice Expressing Human
Group II Phospholipase A2 to Escherichia coli
Infection
ABSTRACT
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
mice) were studied after intraperitoneal
administration of E. coli. The levels of group II PLA2 in
sera of PLA2+ mice increased after the administration of
E. coli, and the concentration of group II PLA2 correlated
significantly with the catalytic activity of PLA2 in serum.
PLA2+ mice showed lower rates of mortality and less
bacterial growth in peritoneal lavage fluid, blood, and spleen and
liver tissues than PLA2 mice. Unlike the observations
with staphylococcal infection, serum and peritoneal lavage fluid did
not inhibit the growth of E. coli in vitro. The results
indicate that expression of the group II PLA2 transgene
improves the host defense of mice against E. coli infection.
INTRODUCTION
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
mice)
(12). Recently, transgenic C57BL/6J mice expressing the human group II PLA2 gene were generated (5).
Human group II PLA2-transgenic mice (PLA2+ mice)
have alopecia and epidermal and cutaneous adnexal hyperplasia but no
other abnormality in phenotype, whereas PLA2 mice have a
normal phenotype (5). In PLA2+ mice, expression
of group II PLA2 has been observed in hepatocytes, epidermal
keratinocytes, fibroblast-like cells of the dermis, connective tissue
fibroblasts, epithelial and smooth muscle cells of the urinary bladder,
and cells of Bowman's capsule (24).
littermates. Moreover,
group II PLA2 was responsible for killing S. aureus
incubated in serum of PLA2+ mice in vitro (16).
Earlier, purified group II PLA2 was shown to be bactericidal against
gram-positive organisms in vitro (32). However, the
bactericidal potency of group II PLA2 against Escherichia coli and other gram-negative microbes in vitro is minimal
(32) and requires the action of other proteins, e.g.,
bactericidal/permeability-increasing protein (33) and
complement (19).
mice during
experimental E. coli peritonitis was studied. Our results
show that PLA2+ mice have a higher level of resistance to
E. coli infection than PLA2 mice.
MATERIALS AND METHODS
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
mice for the
present experiments (5). The animals were kept under
pathogen-free conditions as described previously (16). Male
mice were used throughout the present experiments. PLA2+
mice were identified by their specific phenotype (5) and by the presence of high concentrations of human group II PLA2 in their
sera as measured by time-resolved fluoroimmunoassay (23). Nontransgenic male C57BL/6J littermates of the same age (8 to 10 weeks)
and approximately the same weight were used as PLA2
control animals.
70°C before the onset of
experiments. The bacteria were cultured on brain heart infusion agar
(BHIA; Life Technologies, Paisley, United Kingdom) for 18 to 24 h.
Three colonies of bacteria were suspended in 10 ml of brain heart
infusion broth (Life Technologies) and was shaken (240 rpm) for 1 h at 37°C. The volume was adjusted to 200 ml with BHIB, and the
suspension was shaken (240 rpm) for 2 h 15 min at 37°C and then
centrifuged for 10 min at 3,000 × g and 4°C. The
pellet was resuspended in 10 ml of sterile saline and centrifuged for
10 min at 3,000 × g and 4°C. The washing steps were
repeated three times. The optical density at 650 nm of the final
bacterial suspension was measured with an Ultrospec III densitometer
(Pharmacia LKB, Uppsala, Sweden) and adjusted with sterile saline to
1.10. The bacterial suspensions were further adjusted to the desired
concentrations by dilution with sterile saline. The bacterial
suspensions, diluted to deliver specific numbers of CFU, were injected
intraperitoneally (i.p.) in 0.33-ml volumes in all experiments. For
example, a 1:20 dilution of bacterial suspension (optical density at
650 nm, 1.10) contained 4.8 × 107 CFU of E. coli bacteria/ml of suspension. A 0.33-ml aliquot of this
suspension contained 1.6 × 107 CFU of E. coli. To confirm the number of bacteria used in the in vivo and in
vitro experiments, a series of 10-fold dilutions of the suspension were
plated on BHIA for the measurement of bacterial growth.
Concentration of human group II PLA2 and catalytic activity of
PLA2 in serum.
Time-related changes in the concentration of group
II PLA2 in sera of PLA2+ mice were determined 3, 6, 12, 24, 48, 168, and 336 h after the administration of 5.0 × 106 CFU of E. coli. Mice were anesthesized
mildly with diethyl ether, and blood was collected from their tails
into sterile tubes (Nunc CryoTube; InterMed, Copenhagen, Denmark)
before the administration of E. coli and at various time
points after infection. The animals were sacrificed by cervical
dislocation, and samples for histological analysis were obtained
immediately after blood sampling. Blood specimens were kept at room
temperature for 2 to 3 h. Serum was separated by centrifugation at
2,400 × g and 4°C for 15 min and stored at 70°C
for the biochemical measurements. The concentration of human group II
PLA2 in serum was measured by time-resolved fluoroimmunoassay as
described previously (23). The immunochemically determined
concentrations were then compared to pretreatment values obtained for
the same animals. The catalytic activity of PLA2 in serum was measured
by using radioactive mixed micelles as a substrate as described
previously (18).
Histological examinations. Samples for histological studies were obtained from the internal organs of the experimental animals, fixed in 10% phosphate-buffered formalin, and embedded in paraffin. Five-micrometer-thick sections were stained with hematoxylin and eosin.
Survival of E. coli-inoculated mice.
Based on
preliminary results of studies using a series of dilutions of E. coli suspension (three to six animals/group), 8.0 × 106 CFU/animal (corresponding to an approximate 30% lethal
dose [LD30] in PLA2 mice), 1.6 × 107 CFU/animal (LD70), and 3.0 × 107 CFU/animal (LD85) were chosen for the
evaluation of the differences in mortality between PLA2+
and PLA2 mice. Mortality and clinical status of the mice
were registered 6, 12, and 24 h after the administration of
E. coli and, thereafter, every 24 h up to 4 days.
Samples for histological analysis were obtained from mice found dead
and from surviving mice sacrificed by cervical dislocation 96 h
after the administration of E. coli. Groups of
PLA2+ and PLA2 mice (n = 10/group) were observed for 3 weeks after the administration of
1.6 × 107 CFU of E. coli/animal to confirm
that there was no mortality after 96 h. To study the effect of
bacterial viability on mouse mortality, E. coli bacteria
were killed by heating suspensions at 100°C for 10 min and then
injected into the peritoneal cavities of PLA2 and
PLA2+ mice at a dose corresponding to 1.6 × 107 CFU (the LD70 for PLA2 mice)
of E. coli/animal.
Bacterial growth in the peritoneal cavity, blood, and internal organs of mice after administration of E. coli. To study bacterial growth in the peritoneal cavity, blood, spleen, and liver, blood samples were obtained from the tail and animals were killed 3, 6, 12, and 24 h after the administration of 5.0 × 106 CFU of E. coli. The peritoneal cavity was lavaged with 2 ml of sterile saline. Approximately 0.1-g samples of the spleen and liver tissues were washed with sterile saline and homogenized separately in 0.4 ml of ice-cold sterile saline (Ultra-Turrax homogenizer; IKA, Staufen, Germany). A series of 10-fold dilutions of blood, tissue homogenates, and peritoneal lavage fluid (PLF) were plated on BHIA for the measurement of bacterial growth.
Effect of serum and PLF on growth of E. coli in
vitro.
To obtain serum for in vitro experiments, the animals were
anesthetized lightly with ether and their tails and abdominal skin were
sterilized with 70% ethanol. A 0.2-ml blood sample was collected from
the tip of the tail into a sterile tube (Nunc CryoTube). The samples
were kept at room temperature for 2 to 3 h, centrifuged for 15 min
at 2,400 × g and 4°C, and stored at 70°C. Serum
and PLF were obtained from mice before and 18 h after the
administration of E. coli. The bactericidal activity of
serum in vitro was measured as described previously (32),
with slight modifications. Briefly, 20 µl of HEPES buffer (10 mmol/liter, pH 7.4) containing 1.0 × 105 CFU of
E. coli/ml, 10 mg of bovine serum albumin/ml, and 2 mmol of
CaCl2/liter was mixed with 20 µl of serum or PLF and
shaken at (240 rpm) for 2 h at 37°C. After the incubation, the
number of live E. coli was measured on BHIA plates as
described above.
Statistical analyses.
One-way analysis of variance (ANOVA)
was used to study the significance of the increase in the concentration
of group II PLA2 in serum after the administration of E. coli. Pearson's linear regression analysis was used to study the
correlation between the catalytic activity of PLA2 and the
concentration of human group II PLA2 in sera of PLA2+ mice.
Kaplan-Meier plots were constructed and the log-rank test was used to
test the differences in mortality between the PLA2+ and
PLA2 mice. Kruskal-Wallis nonparametric analysis and the
Mann-Whitney U test were used to test the significance of the
differences between the groups in the numbers of live bacteria in the
PLF, spleen, liver, and blood. One-way ANOVA was used to study the
significance of the differences between the groups in the numbers of
live bacteria in serum and PLF in vitro. Values are expressed as
means ± standard errors of the means (SEM). All statistical
calculations were performed with Statistica software (StatSoft, Tulsa,
Okla.).
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RESULTS |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Concentration of human group II PLA2 and catalytic activity of PLA2
in serum.
To evaluate the systemic PLA2 responses in
PLA2+ and PLA2 mice, we measured the
concentration of group II PLA2 and the catalytic activity of PLA2 in
serum at various time points after the administration of E. coli. The concentration of human group II PLA2 in the sera of
PLA2+ mice increased eightfold after the administration of
5.0 × 106 CFU of E. coli, with a peak at
12 h postinoculation, and decreased to the pretreatment level in
168 h. Thereafter, the levels of group II PLA2 in serum remained
constant (Fig. 1). The concentration of
group II PLA2 in serum correlated with the catalytic activity of PLA2
in both unchallenged and E. coli-infected PLA2+
mice (Fig. 2). Neither human group II
PLA2 nor PLA2 catalytic activity was found in sera of
PLA2 mice.
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Clinical symptoms and histological changes during E. coli infection.
To study the possible role of the group II
PLA2 transgene in the development of symptoms and signs of
inflammation, the clinical status and histological changes in internal
organs of the experimental animals were observed after the
administration of lethal doses of E. coli. All unchallenged
PLA2+ mice exhibited alopecia and cutaneous adnexal
hyperplasia. The PLA2+ mice and their PLA2
littermates behaved normally before the administration of E. coli. During the first day after the administration of E. coli, both PLA2+ and PLA2 mice developed
symptoms typical of endotoxemia, including diarrhea, anorexia,
shivering, lethargy, and lacrimation. The symptoms were more severe in
the PLA2 mice. The PLA2+ mice grew some hair
2 to 4 days after the administration of bacteria. The numbers of
neutrophil polymorphonuclear leukocytes (PMNs) in the peritoneum and
lung parenchyma increased, and occasional small inflammatory cell
infiltrates appeared in the peritoneal loose connective tissue and fat
of both PLA2+ and PLA2 mice 6 to 48 h
after the administration of bacteria.
Survival of mice after E. coli infection.
To
evaluate the possible role of group II PLA2 in the outcome of
experimental E. coli infection, mortality of
PLA2+ and PLA2 mice was studied after the
administration of E. coli at doses corresponding to the
LD30, LD70, and LD85 for
PLA2 mice. It appeared that PLA2+ mice showed
a lower mortality rate than their PLA2 littermates (Fig.
3). At the LD30, however, the
difference was not significant (Fig. 3A). With higher doses of E. coli, the mortality rate of PLA2 mice was much
higher and the protection against death caused by the E. coli was statistically significant (Fig. 3B and C). Heat-killed
bacteria administered at a dose corresponding to the LD70
for PLA2 mice did not cause clinical symptoms or any
deaths in the PLA2+ or PLA2 mice
(n = 5 for both groups).
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Extent of E. coli infection.
Recently we observed
that the transgenic mice used in the present study showed increased
clearance of bacteria from their organs after experimental
S. aureus infection (16). Thus, we tested
the hypothesis that group II PLA2 has a role in the clearance of
E. coli from the host. The numbers of live E. coli in the PLF, spleen, and liver of PLA2+ and
PLA2 mice were measured 3, 6, 12, and 24 h after the
administration of a sublethal dose (5.0 × 106 CFU) of
E. coli (Fig. 4). The numbers
of live E. coli in the spleen and liver were smaller in
PLA2+ than in PLA2 mice. A dramatic decrease
was observed in the liver 24 h after the administration of
bacteria. Statistically significant differences between the groups'
PLF bacterial counts were not observed. There were no live E. coli in the blood of PLA2+ mice (n = 19) during the experiment, while bacteremia developed in 7 of 20 PLA2 mice within 24 h after the administration of
E. coli (9.5 × 104 ± 5.5 × 104 CFU/ml of blood; P = 0.005).
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Effect of serum, PLF, and complement on growth of E. coli in vitro.
Since the clearance of E. coli was
more efficient in PLA2+ mice than in PLA2
mice, we tested the bactericidal potency of serum and PLF from these
mice against E. coli in vitro. It appeared that there were no significant differences between PLA2+ and
PLA2 mice in terms of growth of E. coli in
sera. Moreover, PLF of neither group of mice inhibited the growth of
E. coli in vitro (Table 1).
Since complement is known to effect the lysis of some strains of
E. coli, and since this could affect the results of group II
PLA2-dependent lysis, we examined the killing of our E. coli
strain in normal and heat-inactivated sera. The growth of E. coli in vitro in normal human serum with intact complement was
similar to that in serum with heat-inactivated complement (5.3 × 105 and 6.8 × 105 CFU/ml, respectively).
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DISCUSSION |
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Abstract
Introduction
Materials and Methods
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To investigate the role of group II PLA2 in E. coli
infection, we compared the host defenses of human group II PLA2
transgenic mice and their group II PLA2-deficient littermates after
i.p. administration of live E. coli. The concentration of
group II PLA2 in sera of PLA2+ mice was somewhat higher
(approximately 2,500 µg/liter) (16) than that found in
humans with severe infectious diseases. These diseases include
bacterial infections (240 µg/liter) (29), sepsis (880 µg/liter) (25), peritonitis (440 µg/liter)
(25), and typhoid fever (1,440 µg/liter)
(13). The PLA2+ mice used in the present study
showed no clinical symptoms of inflammation and behaved normally
despite the exceedingly high PLA2 catalytic activity (up to
100-fold higher than in PLA2 mice) and concentration
of group II PLA2 in their sera.
In the present study, we showed that the concentration of group II PLA2 increases in sera of PLA2+ mice, after the administration of E. coli, with a peak at 12 h. The catalytic activity of PLA2 in the sera of PLA2+ mice correlated significantly with the concentration of group II PLA2 in the same sera. These results suggest that the PLA2 activity of PLA2+ mouse serum is derived solely from human group II PLA2 and not from other (inherited mouse) PLA2s. The group II PLA2 response in sera of PLA2+ mice appears earlier than that observed in human patients after surgery (17). However, the increase in concentration of group II PLA2 in sera of PLA2+ mice after the injection of E. coli follows the same time schedule as that seen in sera of healthy volunteers after the administration of endotoxin (27). The results suggest that bacteria and bacterial products induce a rapid systematic increase in the concentration of group II PLA2 in vivo. A more delayed release of the enzyme, perhaps due to secondary endotoxemia, may be responsible for the increased levels of PLA2 in sera of patients who have undergone surgery.
On the one hand, the symptoms of sepsis after the administration of
E. coli were less severe in PLA2+ than in
PLA2 mice. On the other hand, the concentration of group
II PLA2 in sera of PLA2+ mice increased eightfold.
Therefore, the increased amount of group II PLA2 in serum was not
responsible for the septic symptoms of E. coli infection in
the experimental animals of the present study. On the contrary,
PLA2+ mice showed a lower mortality rate than
PLA2 mice after being given large doses of live E. coli, and the bacteria were more effectively cleared from the
tissues and body fluids of the PLA2+ mice. Thus, expression
of human group II PLA2 appears to protect PLA2+ mice
against E. coli administered in amounts that are lethal to
their PLA2 littermates. These data indicate that group II
PLA2 has an important role in the host defense against E. coli infection.
We observed previously that the PLA2+ mice used in the present study were highly resistant to S. aureus infection (16). Human and rabbit group II PLA2s are capable of killing staphylococci and other gram-positive bacteria in vitro (28, 32). Moreover, the bactericidal activity against S. aureus and the concentration of group II PLA2 in plasma increased in parallel during experimental E. coli infection of baboons (31). It has been hypothesized that group II PLA2 alone is sufficient to kill gram-positive bacteria in vitro (28, 32). In contrast, the bactericidal mechanism of group II PLA2 against E. coli and other gram-negative bacteria requires the presence of the bactericidal/permeability-increasing protein of PMNs (33) and/or components of complement that further potentiate the bactericidal effect (19). The host resistance of the PLA2+ mice against S. aureus was effected by direct bacterial killing by group II PLA2 present in their body fluids (16).
To evaluate mechanisms involved in the protection by group II PLA2
against E. coli infection, we studied bacterial killing in
PLA2+ mice after E. coli infection. The
clearance of bacteria from internal organs was faster in
PLA2+ mice than in PLA2 mice. However,
neither serum nor PLF of PLA2+ mice was bactericidal
against E. coli in vitro. These results suggest that group
II PLA2 alone is not able to kill E. coli in mouse body
fluids but presumably requires the coaction of another agent(s) present
in inflammatory and/or tissue cells of PLA2+ mice to act
against E. coli. Because the E. coli strain used in the present study is resistant to complement, it is also unlikely that the increased clearance of E. coli in the
PLA2+ mice is due to an inflammation-mediated increase in
the activity of complement. It is thus possible that there are group II
PLA2-dependent mechanisms other than direct bacterial killing that
improve host resistance to gram-negative bacterial infection.
E. coli lipopolysaccharide (LPS; endotoxin) causes an
increase in the level of group II PLA2 in sera of human volunteers
(27). In the present experiment, doses corresponding to the
LD70 of heat-killed E. coli did not cause
clinical symptoms or deaths in mice, but live bacteria were needed for
these effects. Therefore, LPS released from the E. coli
strain used in the present study obviously played only a minor role in
the mortality of the animals. In another set of experiments, we
injected large doses of E. coli LPS (5 and 20 mg/kg) into
PLA2+ and PLA2 animals and found that the
expression of human group II PLA2 did not markedly influence the course
of E. coli LPS-induced shock and mortality (unpublished
observations). Group II PLA2 seems to decrease the viability of
E. coli or its ability to spread in the host rather
than attenuate the symptoms caused by E. coli endotoxin.
Group II PLA2 is involved in the production of bioactive molecules,
such as prostaglandins and leukotrienes, which in turn are important
mediators of the inflammatory response (30). Group II PLA2
was found to propagate the inflammatory reaction by activating T
lymphocytes (2), and it has been hypothesized that the
action of PLA2 is important in the adhesion of PMNs to tissues
(10). Thus, the improved host response shown by the
PLA2+ mice may result from an increased inflammatory
reaction or improved action of leukocytes. The effects of group II PLA2
on the systemic inflammatory reaction and activation of leukocytes in
internal organs are under investigation. It seems that the
PLA2+ mice have a better systemic inflammatory cell
response than their group II PLA2 littermates
(unpublished data). On the other hand, the abnormal phenotype (adnexal
and epidermal hyperplasia) of the PLA2+ mice does not
involve an increase of the inflammatory infiltrate in the skin
(5).
Taken together, the results presented here show that the expression of human group II PLA2 in transgenic mice improves their host defense against experimental E. coli infection. The detailed mechanisms involved remain to be established.
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ACKNOWLEDGMENTS |
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This work was supported by the Turku University Foundation, Turku University Hospital, the Finnish Medical Foundation, the Emil and Blida Maunula Foundation, and the Maud Kuistila Foundation.
We thank Anne Jokilammi-Siltanen, Kati Talvinen, and Heikki Peuravuori for skillful technical assistance and Klaus Elenius and Mikael Skurnik for valuable advice.
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FOOTNOTES |
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* Corresponding author. Mailing address: Department of Pathology, University of Turku, Kiinamyllynkatu 10, FIN-20520 Turku, Finland. Phone: (358) 2-261 2670. Fax: (358) 2-333 7459. E-mail: vellai{at}utu.fi.
Editor: P. E. Orndorff
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REFERENCES |
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Abstract
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Materials and Methods
Results
Discussion
References
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