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Placental immunomodulator ferritin a novel immunoregulator suppresses experimental arthritis.

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Vol. 48, No. 3, March 2003, pp 846–853
DOI 10.1002/art.10850
© 2003, American College of Rheumatology
Placental Immunomodulator Ferritin, a Novel
Immunoregulator, Suppresses Experimental Arthritis
Abraham Weinberger,1 Marisa Halpern,1 Muayad A. Zahalka,1 Francisco Quintana,2
Leonid Traub,1 and Chaya Moroz1
Objective. To determine the effect of treatment
with C48, the recombinant cytokine-like domain of the
novel human placental immunomodulator ferritin
(PLIF) immunoregulator, on zymosan-induced arthritis
(ZIA) in mice and on adjuvant-induced arthritis (AIA)
in rats.
Methods. The in vitro effect of PLIF/C48 was
tested in mixed lymphocyte cultures (MLCs) of allogeneic mouse splenocytes. Arthritis was induced by intraarticular injection of zymosan into naive mice and by
subcutaneous injection of Mycobacterium tuberculosis
into rats. C48 was injected intraperitoneally daily from
day 3 to day 9 or from day 7 to day 13 after induction of
synovitis by zymosan, and every other day from day 2 to
day 14 after induction of AIA. Swelling of the joints and
histologic features of the synovium were assessed. Th1
and Th2 cytokines were quantified by enzyme-linked
immunosorbent assay.
Results. Both PLIF and C48 significantly inhibited the in vitro immunoreactivity of mouse splenocytes
in MLCs. Treatment of ZIA mice and AIA rats with C48
effectively reduced joint swelling. C48 treatment reduced synovial lining thickening, numbers of mononuclear cells and histiocytes, as well as cartilage destruction and bone erosions. In vitro, activated splenocytes
from C48-treated ZIA and AIA animals produced significantly higher levels of interleukin-10 (IL-10). In
animals with ZIA, this was accompanied by lower levels
of tumor necrosis factor and IL-2.
Conclusion. Human PLIF and C48 were shown to
exert cross-species immunosuppressive activity in vitro.
The in vivo suppression of articular inflammation in the
experimental models of ZIA and AIA was the result of
treatment with the antiinflammatory human C48. These
results suggest that treatment with C48 may offer an
effective immunotherapeutic means of controlling inflammatory polyarthritis.
Several reports have described the high frequency of remission of rheumatoid arthritis (RA) during
pregnancy (1–7). Similarly, most studies of pregnancy in
patients with multiple sclerosis showed tendencies toward remissions during gestation and relapses during the
postpartum period. Indeed, most pregnant women with
RA have reported improvement of joint pain and/or
swelling. A postpartum flare, however, can occur in the
majority of women up to 8 weeks after delivery (7).
Therefore, the state of pregnancy serves as a powerful
and natural research means of identifying potential
pathophysiologic mechanisms that modify disease activity and of generating innovative strategies for the development of new therapies for use in the nonpregnant
The phenomenon of remission in RA can be
attributed to several factors, one of which, an increase in
estrogen secretion, occurs in pregnancy (8–10). In a
collagen-induced arthritis animal model, administration
of estrogen in the postpartum period prevented the
postpartum flare (9). Another possible explanation for
the decrease in arthritis during pregnancy and the
postpartum flare of RA is the finding that glycosylation
of IgG decreases during pregnancy and increases during
the postpartum period (11). A similar explanation could
apply to the postpartum flares seen in animal models of
human arthritis (11,12).
Abraham Weinberger, MD, Marisa Halpern, MD, Muayad
A. Zahalka, PhD, Leonid Traub, PhD, Chaya Moroz, PhD: Felsenstein
Medical Research Center, Rabin Medical Center, Petah Tikva, Israel,
and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel;
Francisco Quintana, PhD: The Weizmann Institute of Science, Rehovot, Israel.
Address correspondence and reprint requests to Chaya
Moroz, PhD, Laboratory of Molecular Immunology, Felsenstein Medical Research Center, Beilinson Campus, Rabin Medical Center, Petah
Tikva 49100, Israel. E-mail:
Submitted for publication July 12, 2002; accepted in revised
form December 9, 2002.
Recent studies by Sirota et al demonstrated that
a unique isoform of placental isoferritin (PLF), composed of 43-kd protein (p43) and ferritin light chain, acts
as a regulatory cytokine that down-regulates the immune response of the mother to her embryo (13). This
protein is highly expressed in syncytiotrophoblast cells,
in Hofbauer cells, and in decidual macrophages (14).
Furthermore, studies by our group showed that elevation of p43 (PLF) begins as early as day 11 of pregnancy,
continues throughout gestation, and declines at term
(15). Recently, the gene coding for p43 has been cloned
and designated placental immunomodulator ferritin
(PLIF). A recombinant form of its bioactive cytokinelike domain (CLD), called C48, is composed of 48 amino
acids. Both PLIF and C48 were subcloned and expressed
in Escherichia coli (16).
PLIF has been localized in the syncytiotrophoblast cells of human placenta at 8 weeks. PLIF and C48
were shown to down-modulate the human allogeneic
mixed lymphocyte reaction and to inhibit the proliferation of peripheral blood mononuclear cells stimulated
with OKT3 monoclonal antibody (16).
The present study was designed to evaluate the
effect of treatment with C48 in zymosan-induced arthritis (ZIA) in mice and in adjuvant-induced arthritis
(AIA) in rats. Our investigation included histopathologic evaluation of knee joint sections, measurement of
joint swelling, and elucidation of the change in cytokine
production. We found that C48 was effective in suppressing the arthritis process in an animal model of
experimental arthritis. Analysis of cytokine secretion by
spleen cells following polyclonal activation revealed a
shift toward the Th2 pathway following treatment.
Animals. Six-week-old female ICR and C57BL mice
and female Lewis rats were fed a standard laboratory diet and
tap water ad libitum. The study was approved by the Animal
Review Board of the Rabin Medical Center.
Induction of ZIA. ZIA was induced as previously
described (17). Briefly, a homogeneous suspension of 15 mg
zymosan A (Saccharomyces cerevisiae; Sigma, St. Louis, MO)
was dissolved in 1 ml saline and sterilized by autoclaving.
Arthritis was induced in both hind knees by injecting 50 ␮g of
zymosan solution into each joint. Measurement of the joint
thickness was performed using a Mitutoyo caliper (Mitutoyo,
Kanagawa, Japan).
C48 administration after ZIA induction. C48, a recombinant form of the CLD of the human PLIF gene, was
produced in E coli as previously reported (16). This PLIF gene
codes for a protein with partial homology to human ferritin
heavy chain, but contains 48 C-terminal amino acids of a novel
sequence with no homology to any known protein.
In one group of mice, 50 ␮g of C48 in 0.5 ml of
phosphate buffered saline (PBS), pH 7.2, was injected intraperitoneally (IP) daily from day 3 to day 9 following the
intraarticular zymosan injection. Similarly, C48 was injected
into another group of mice from day 7 to day 13 (delayedinjection group). The control group of mice received PBS only.
Induction of AIA. AIA was induced as previously
described (18). Briefly, Lewis rats were vaccinated with 1 mg of
Mycobacterium tuberculosis H37Ra (Difco, Detroit, MI) in
Freund’s complete adjuvant (Difco) subcutaneously at the base
of the tail. Severity of disease (arthritis index) was scored by 2
blinded observers (MAZ and LT) according to National
Institutes of Health protocols for AIA (19), where 0 ⫽ no
arthritis, 1 ⫽ redness of the joint, or 2 ⫽ redness and swelling
of the joint. The ankle and tarsometatarsal joints of each foot
were scored. A maximum score of 16 can be obtained, but a
score ⬎8 indicates severe disease.
C48 administration after AIA induction. Rats were
injected IP with 180 ␮g of C48 in 0.5 ml of PBS every other day
from day 2 to day 14 following AIA induction. A control group
of rats was injected IP with 0.5 ml of PBS.
Mixed lymphocyte cultures (MLCs). Responder
splenocytes were obtained from C57BL mice, and allogeneic
stimulator spleen cells were obtained from ICR mice (Harlan,
Rehovot, Israel). Mouse splenocytes were cultured alone
(LCs) or were mixed with irradiated allogeneic stimulator cells
at a ratio of 1:1 (MLCs). For culture treatments, 1 ␮g/ml of
purified PLIF or C48 was added to cultures immediately after
responder cell plating. These experiments were performed in
96-well flat-bottomed tissue culture plates in a culture medium
containing 10% fetal calf serum. On day 4 of the experiment,
cells were pulsed with 1 ␮Ci/well of 3H-thymidine and harvested 16 hours later. The proliferation index (PI) of lymphocyte cultures was calculated as the counts per minute in the
PLIF- or C48-treated cultures divided by the cpm in the
untreated culture. The PI in MLCs was calculated as the cpm
in stimulated MLCs divided by the cpm in unstimulated LCs
for each specific treatment.
Cytokine assay. Mouse spleen cells were harvested
from ZIA mice treated daily with IP injections of C48 (30 ␮g)
or PBS as indicated. Splenocytes (2 ⫻ 106/ml) were cultured
with concanavalin A (Con A; 1 ␮g/ml). Supernatants were
collected after 24, 48, or 72 hours of stimulation with Con A or
medium alone. Murine cytokines were quantitated in the
culture supernatants with an enzyme-linked immunosorbent
assay (ELISA) as previously described (20). Paired antibodies
from BD PharMingen (San Diego, CA) were used for the
detection of interleukin-4 (IL-4), IL-10, and IL-12. Paired
antibodies from Endogen (Cambridge, MA) were used for the
quantitation of IL-2, tumor necrosis factor ␣ (TNF␣), and
interferon-␥ (IFN␥).
Briefly, ELISA plates (Maxisorp; Nunc, Roskilde,
Denmark) were coated overnight at 4°C with capture antibodies. Nonspecific binding was blocked by incubation with 1%
bovine serum albumin (BSA) for 1 hour at room temperature
(RT), and culture supernatants or recombinant cytokines were
incubated overnight at 4°C. Cytokine binding was detected by
biotinylated detection antibodies and streptavidin conjugated
to alkaline phosphatase (Jackson ImmunoResearch, West
Grove, PA). Cytokine levels in supernatants are expressed as
pg/ml based on calibration curves constructed using recombi-
nant cytokines as standards. The lower limits of detection for
these experiments were 15 pg/ml for IL-2, IL-10, IL-12, and
IFN␥, 5 pg/ml for TNF␣, and 30 pg/ml for IL-4.
Rat spleen cells were harvested on day 16 from AIA
rats treated every other day with IP injections of C48 (180 ␮g)
or PBS on days 2–14. Splenocytes (2 ⫻ 106/ml) were cultured
with and without Con A (2 ␮g/ml), and supernatants were
collected after 24, 48, and 72 hours of stimulation with Con A
or medium alone. Rat IL-10, IFN␥, and TNF in the culture
supernatants were quantified by ELISA using the OptEIA kit
(BD PharMingen) with some modifications. Briefly, ELISA
plates (Maxisorp; Nunc) were coated overnight at 4°C with
anti-rat cytokine monoclonal capture antibodies. Nonspecific
binding was blocked by incubation with 1% BSA for 1 hour at
RT, and culture supernatants or recombinant cytokines were
added for 2 hours at RT. After washing the plates, biotinylated
detection antibodies were added for 1 hour at RT, then
extensively washed and incubated with streptavidin conjugated
to alkaline phosphatase (Jackson ImmunoResearch) for 30
minutes at RT. The plates were washed, alkaline phosphatase
substrate (Sigma) was added, and after 30 minutes of incubation at RT, samples were read at 405 nm. Cytokine levels in
supernatants are expressed as pg/ml based on calibration
curves constructed using recombinant cytokines as standards.
The lower limits of detection for these experiments were 15
pg/ml for TNF, IL-10, and IFN␥.
Histologic processing. Animals were killed on day 14,
and the knees were removed in toto, fixed, decalcified, dehydrated, embedded in paraffin, and cut into 4-␮m sections. All
sections were stained with Harris’ hematoxylin and eosin.
Assessment of joint inflammation. The assessment of
all pathologic features was performed by a blinded observer
(MH) using a grading scale of 0–3 according to the proportion
of areolar tissue that was densely infiltrated with mononuclear
Figure 2. Effect of C48 treatment on hind joint swelling in zymosaninduced arthritis. Mice were injected with intraarticular zymosan and
then treated with C48 on days 3–9 (n ⫽ 10) or days 7–13 (delayed
treatment; n ⫽ 10) or with phosphate buffered saline (PBS; n ⫽ 10) on
days 3–9 following zymosan injection. A, Swelling expressed as the
percentage of change in joint diameter. B, Histologic score. Values are
the mean ⫾ SEM. ⴱ ⫽ P ⬍ 0.05 versus control values, by Student’s
Figure 1. Effect of placental immunomodulator ferritin (PLIF) and
C48 on allogeneic mouse mixed lymphocyte cultures. Shown is the
proliferation index (PI) of stimulated mouse spleen cells either untreated or treated with 1 ␮g/ml PLIF or C48. Values are the mean ⫾
SEM of 3 experiments. ⴱ ⫽ P ⬍ 0.01 versus untreated cells, by
Student’s t-test.
cells. Synovial lining cell hyperplasia was graded similarly on
the same scale. A score of 0–3 was used for grading the number
of histiocytes observed in synovial tissue. Cartilage destruction
was scored on a scale of 0–3, ranging from no damage to fully
destroyed cartilage layers. Bone erosion scores were obtained
in a blinded analysis using semiquantitative grading scales: 0 ⫽
Figure 3. Histologic features of joints from C48-treated or control mice with zymosan-induced
arthritis and from C48-treated or control rats with adjuvant-induced arthritis. A, Joint from a
control mouse injected intraarticularly with zymosan, showing extensive cellular infiltration in the
synovium and erosion of cartilage. B, Corresponding specimen from a mouse injected intraarticularly with zymosan and treated intraperitoneally (IP) with C48, showing mild inflammation with
primarily synovial hypertrophy. C, Joint from a control rat injected subcutaneously with Mycobacterium tuberculosis, showing massive synovitis. D, Joint from a rat injected with M tuberculosis and
treated IP with C48, showing mild inflammation. (Hematoxylin and eosin stained; original
magnification ⫻ 10 in A and B; ⫻ 20 in C and D.)
normal, 1 ⫽ minimal loss of cortical bone at a few sites, 2 ⫽
mild loss of cortical trabecular bone, 3 ⫽ moderate loss of
bone at many sites, 4 ⫽ marked loss of bone at many sites, and
5 ⫽ marked loss of bone at many sites with fragmenting and
full-thickness penetration of cortical bone.
Statistical analysis. Student’s t-test was used to determine significant differences between experimental and control
groups. P values less than 0.05 were considered significant.
Figure 4. Suppression of disease progression in rats with recent-onset
adjuvant-induced arthritis (AIA). Twenty rats were vaccinated with
Mycobacterium tuberculosis and randomly assigned to receive treatment with C48 (n ⫽ 10) or phosphate buffered saline (PBS; n ⫽ 10) at
the indicated times following AIA induction (see Materials and
Methods). Values are the mean ⫾ SEM. ⴱ ⫽ P ⬍ 0.001 versus control
AIA rats, by Student’s t-test.
Effect of PLIF and C48 on the mouse immune
response in vitro. To test whether human PLIF has a
cross-species immunosuppressive activity, PLIF and
C48, cleaved and purified from their glutathione Stransferase fusion protein, were tested for their effect on
allogeneic mouse MLCs in vitro. Both PLIF and C48
significantly reduced the allogeneic stimulation (P ⬍
0.01), as indicated by the decreased PIs of the treated
cultures (6.8 and 9.8, respectively) compared with the PI
of the untreated controls (25.4) (Figure 1). These results
indicate a cross-species immunosuppressive activity of
human PLIF and C48.
Effect of C48 on ZIA. Mice that received C48
from day 3 to day 9 developed significantly milder
disease than did the control mice. Joint swelling in these
animals was significantly reduced (P ⬍ 0.05) compared
Figure 5. Production of cytokines in concanavalin A (Con A)–activated spleen cells from mice
with zymosan-induced arthritis (ZIA) treated with C48 or phosphate buffered saline (PBS). Spleen
cells were harvested from 6 mice on day 14 following zymosan inoculation. Mice were injected
intraperitoneally with either C48 (n ⫽ 3) or PBS (n ⫽ 3) from day 5 to day 13. Cells were cultured
with Con A (1 ␮g/ml) for 24, 48, and 72 hours, and their supernatants were tested for levels of
interleukin-10 (IL-10) (A), IL-2 (B), tumor necrosis factor (TNF) (C), IL-4 (D), interferon-␥
(IFN␥) (E), and IL-12 (F). Values are the mean ⫾ SEM. ⴱ ⫽ P ⬍ 0.05 versus control ZIA mice,
by Student’s t-test.
with that in PBS-treated controls (Figure 2A). Delayed
treatment with C48 (days 7–13) also yielded significantly milder swelling, and this effect persisted longer
(Figure 2A).
Histologically, joints from all of the untreated
mice were severely damaged by rapidly expanding synovial pannus. Mononuclear cell infiltration and thickening
of the synovial membrane were apparent (Figures 2B
and 3A). In contrast, IP injection of C48 on either day 3
or day 7 (delayed treatment) suppressed inflammation
in murine hind joints, as shown by a reduced number
of synovial histiocytes, a low amount of mononuclear
cell infiltration, and less synovial membrane thickening
(Figures 2B and 3B). Cartilage destruction and bone
Figure 6. Production of cytokines by Con A–activated spleen cells
from rats with adjuvant-induced arthritis (AIA) treated with C48 or
PBS. Spleen cells were harvested on day 16 from AIA rats that had
been treated from day 2 to day 14 with PBS (n ⫽ 3) or C48 (n ⫽ 3).
Cells were cultured with Con A (2 ␮g/ml) for 24, 48, and 72 hours, and
their supernatants were tested for levels of IL-10 (A), TNF␣ (B), and
IFN␥ (C). Values are the mean ⫾ SEM of 3 animals. ⴱ ⫽ P ⫽ 0.03; ⴱⴱ
⫽ P ⫽ 0.003 versus control AIA rats, by Student’s t-test. See Figure 5
for other definitions.
erosion were significantly reduced (P ⫽ 0.03 and P ⫽
0.003, respectively) in ZIA mice treated early with C48,
while the reduction in these parameters did not reach
statistical significance in the delayed-treatment group
(Figure 2B).
Effect of C48 on AIA. Based on the results
obtained from the early- and delayed-treatment protocols for ZIA mice, we chose to treat AIA rats from day
2 (early) up to the peak of active disease on day 14
covering both periods. As shown in Figure 4, from day 14
through day 39, the arthritis index in AIA rats receiving
treatment with C48 was significantly lower than that in
control rats (P ⬍ 0.001). Histologic examination of joints
chosen randomly from each group revealed less inflammation and less cartilage destruction and bone damage
in animals injected with C48 compared with control
animals (Figures 3C and D).
Levels of Th1/Th2 cytokines in activated splenocytes from C48-treated ZIA mice and AIA rats. As
shown in Figure 5, the time courses of the accumulation
of the different cytokines produced by splenocytes from
PBS- and C48-treated ZIA mice had similar patterns.
However, significant differences were observed in the
levels of cytokines between the two groups. In 48- and
72-hour cultures, there was a significant increase in the
mean level of IL-10 (250% at the peak; P ⫽ 0.049)
accompanied by a significant decrease in the mean levels
of IL-2 and TNF (50%; P ⫽ 0.012 for each comparison)
in C48-treated ZIA mice compared with PBS-treated
control mice (Figures 5A–C). The differences in the
mean levels of IFN␥ and IL-12 in C48-treated mice
compared with PBS-treated mice did not reach significance (P ⫽ 0.09 and P ⫽ 0.06, respectively), while IL-4
levels were undetectable in C48-treated ZIA mice.
Elevation of IL-10 levels was also observed in
AIA rats treated with C48 (Figure 6A). A significant
increase (100%) in the IL-10 level was measured in 48and 72-hour cultures of Con A–activated splenocytes
from C48-treated AIA rats (P ⫽ 0.03 and P ⫽ 0.003,
respectively) compared with those from PBS-treated
AIA rats. Although IFN␥ levels in C48-treated AIA rats
might appear to be lower, the levels of both TNF␣ and
IFN␥ in C48-treated AIA rats did not differ significantly
from those in control AIA rats (Figures 6B and C). It is
noteworthy that in parallel nonactivated cultures, all
cytokines were undetectable.
The data presented in this report indicate that
human PLIF and its C48 peptide exert cross-species
antiproliferative effects in vitro. They also show, as in
human tissue cultures (16), that C48 represents the
bioactive domain of PLIF. C48 is a highly effective form
of therapy for ZIA in mice and for AIA in rats.
Accordingly, it was demonstrated that during the induction phase of arthritis, as well as during established
disease, treatment of animals with C48 led to a significant reduction in both the clinical and histologic severity
of arthritis. It is noteworthy that this effect was more
pronounced when the treatment was started early during
the induction phase of the disease. This finding is similar
to the effect achieved in RA patients, for whom treatment with disease-modifying medication is recommended early in the disease course.
There is direct evidence that TNF, IL-1, and IL-6
play a role in the pathogenesis of experimental arthritis
(21–23). Similarly, TNF, IL-1, and IL-6, which are
produced by Th1 cells, are clearly involved in the disease
process of RA (24,25), whereas IL-4 and IL-10 (produced by Th2 cells) have inhibitory effects. The balance
between Th1 and Th2 cell activity seems crucial in
controlling the proinflammatory immune response.
Therefore, stimulation of Th2 cell activity might ameliorate the RA disease process, either directly by inhibition
of macrophage activity or indirectly by suppression of
Th1 cell proliferation (26–28).
Our findings in the current study and in human
systems (16) have shown a direct inhibition of T cell
proliferation by PLIF and C48. Furthermore, in the
current study, it was shown that C48 treatment of
arthritis caused a systemic shift of the immune response
of the host to a lower proliferation and inflammatory
response, as indicated by the increased IL-10 level both
in ZIA mice and in AIA rats. In ZIA mice, this was also
accompanied by decreased IL-2 and TNF production
following polyclonal immune activation in vitro. Recently, we obtained evidence that PLIF/C48 induces high
levels of IL-10 production by human monocyte/macrophages in vitro via a calcium/calmodulin p38 mitogenactivated protein kinase pathway, and that it decreases
levels of inflammatory cytokines, such as IL-1, TNF, and
IL-6 (29). Accordingly, the mode of action of C48 in
decreasing synovitis would be appropriate with a Th2
PLIF is the gene that codes for p43 of PLF (16).
Indeed, the role of p43 (PLF) as an immunoregulatory
cytokine has been studied in pregnant women (15,30).
Some investigators believe that cytokines such as IL-2
and TNF, which are harmful to the maintenance of
pregnancy, may be secreted by the activated maternal
immune system. However, the fetus protects itself by
producing and secreting various cytokines, such as IL-4
and IL-10, which are normally produced by a subset of
CD4⫹ T cells (Th2) and antigen-presenting cells (31).
PLIF has been shown to be produced by syncytiotrophoblast cells (14) and is elevated in the circulation during
pregnancy (15). It may therefore act as the inducer of
these Th2 cytokines in the placenta as well as systemically, leading to suppression of activated clones at
different sites of disease. This mechanism may be involved in the remissions observed during pregnancy in
patients with RA (5) and multiple sclerosis (32,33).
The role of PLIF in pregnancy-associated clinical
improvement in RA has not been directly exhibited.
However, some circumstantial observations may shed
light on its significance. The increased serum level of
PLIF (p43) during pregnancy declines at term. This may
be linked to the observed postpartum change in the
profile of cytokines secreted by macrophages (to IL-12
and TNF), which results in RA (34). Further, it was
found that pregnant women with low serum levels of
PLIF (p43) have infants who are small for their gestational age (35).
Recently, it was reported that pregnant RA patients whose arthritis was in remission had significantly
heavier babies than did those with active disease (36).
The lack of remission associated with small babies might
be linked to low levels of PLIF (p43) in these patients.
In summary, this study demonstrates that C48 is
a candidate therapeutic agent for RA. Treatment with
C48, an inducer of an antiinflammatory cytokine cascade, was effective in modifying synovitis in two models
of arthritis. Its antiproliferative effect suggests that C48
has pleiotropic effects that, in the context of autoimmunity, are likely to be beneficial.
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