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-Retinoid X Receptor Agonists Increase CD36-Dependent Phagocytosis of Plasmodium falciparum-Parasitized Erythrocytes and Decrease Malaria-Induced TNF-
Secretion by Monocytes/Macrophages1
*
Department of Medicine, University of Toronto, Toronto, Ontario, Canada; and
Tropical Disease Unit, Toronto General Hospital, Toronto, Ontario, Canada
 |
Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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, and sequestration of
parasitized erythrocytes (PEs) in vital organs. The identification of
CD36 as a major sequestration receptor has led to the assumption that
it contributes to the pathophysiology of severe malaria and has
prompted the development of antiadherence therapies to disrupt the
CD36-PE interaction. This concept has been challenged by unexpected
evidence that individuals deficient in CD36 are more susceptible to
severe and cerebral malaria. In this study, we demonstrate that CD36 is
the major receptor mediating nonopsonic phagocytosis of PEs by
macrophages, a clearance mechanism of potential importance in nonimmune
hosts at the greatest risk of severe malaria. CD36-mediated uptake of
PEs occurs via a novel pathway that does not involve thrombospondin,
the vitronectin receptor, or phosphatidylserine recognition.
Furthermore, we show that proliferator-activated receptor 
-retinoid
X receptor agonists induce an increase in CD36-mediated phagocytosis
and a decrease in parasite-induced TNF- secretion. Specific
up-regulation of monocyte/macrophage CD36 may represent a novel
therapeutic strategy to prevent or treat severe
malaria. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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v
3 (15),
and CD36 (16, 17, 18, 19, 20).
CD36, an 88-kDa integral protein found on endothelial cells,
adipocytes, platelets, monocytes, and macrophages (m
s), has been
shown to be a receptor preferentially recognized by most natural
isolates of P. falciparum (7, 9, 21). The
identification of CD36 as a major sequestration receptor has led to the
assumption that it contributes to the pathophysiology of severe malaria
and has prompted the development of antiadherence therapies to disrupt
the CD36-PE interaction (7, 18, 22, 23). However, its role
in cerebral and severe malaria is unclear because little CD36 is
expressed on cerebral microvasculature endothelial cells (5, 24), and studies have reported that significantly higher binding
of PEs to CD36 occurs in cases of nonsevere malaria (25, 26). Furthermore, individuals deficient in CD36 were found to be
more susceptible to severe and cerebral malaria (27).
However, the mechanism by which CD36 may confer protection from severe
disease is unknown.
In contrast to CD36, other adhesion receptors such as ICAM-1 are
expressed in cerebral endothelial cells and may be up-regulated by
inflammatory cytokines such as TNF- (6, 8, 28).
Elevated levels of proinflammatory cytokines such as TNF- and IL-6
have been associated with severe and fatal malaria (8, 29, 30, 31, 32, 33). Furthermore, a genetic predisposition to overproduce
TNF- in response to infection has been proposed as a mechanism
underlying the development of cerebral malaria (34, 35, 36).
Collectively, these data suggest that the sequestration of PEs observed
in cerebral malaria may result from up-regulated ICAM-1 and other
adhesion molecules on the cerebral microvasculature due to excessive or
unbalanced proinflammatory responses (6, 33, 34, 36).
Phagocytic cells are an essential first line of innate defense against
malaria, facilitating control and resolution of infection by clearing
PEs (37, 38). However, the molecular mechanisms by which
these cells recognize PEs are not well understood. Most studies have
focused on the phagocytosis of Ab-opsonized PEs (39, 40, 41).
However, it is uncertain what role opsonic clearance plays in the
nonimmune individuals most at risk for severe and cerebral malaria.
Phagocytes of the monocyte/M lineage are also the primary source of
parasite-induced proinflammatory cytokine responses that have been
linked to adverse clinical outcomes (6, 29, 30, 31). We have
recently shown that CD36 mediates the uptake of nonopsonized PEs by
human monocytes (42). Furthermore, activation of CD36 on
monocytes, either by cross-linking the receptor or during nonopsonic
phagocytosis, does not induce the release of the proinflammatory
cytokine TNF- (42).
Based on these observations, we hypothesized that monocytes/M CD36
may play a beneficial role during infection by mediating nonopsonic
clearance of PEs and by not contributing to the release of
proinflammatory cytokines associated with poor clinical outcomes.
Furthermore, we hypothesized that clinical malaria might benefit from
specific up-regulation of monocyte/M CD36, particularly in the
nonimmune host, where opsonic phagocytosis would be expected to be
less. To test this hypothesis, we have investigated the effect of
up-regulating CD36 on the phagocytosis of nonopsonized PEs by aging
monocytes in culture and by treating monocytes and Ms with
peroxisome proliferator-activated receptor (PPAR)-retinoid X
receptor (RXR) agonists. The CD36 promoter contains a PPAR-RXR
binding site, and the PPAR-RXR complex can modulate CD36 gene
expression through direct promoter interaction (43). In
addition, PPAR-RXR agonists have anti-inflammatory properties;
down-regulating LPS and PMA induced proinflammatory cytokine secretion
(44, 45). If the anti-inflammatory effects of
PPAR-RXR agonists can be extended to malaria-induced inflammation,
then these compounds may be beneficial in decreasing the excessive or
unbalanced secretion of proinflammatory cytokines implicated in severe
malaria (46). We present evidence that PPAR-RXR agonist
treatment results in an increase in CD36-mediated phagocytosis and a
decrease in parasite-induced TNF- secretion.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Endotoxin-free RPMI 1640 culture medium was obtained from Life
Technologies (Burlington, Canada). FCS was obtained from Wisent
(Mississauga, Canada) and was heat inactivated at 55°C for 30 min
before use. The anti-CD36 mAb FA6-152 was obtained from Immunotech
(Marseille, France), the
anti-v3 mAb 23C6
from Serotec (Raleigh, NC), the anti-TSP mAb C6.7 from Medicorp
(Montreal, Canada), and the anti-ICAM-1 mAb 15.2 from Santa Cruz
Biotechnology (Balthesa, CA). Recombinant human TNF- and monoclonal
anti-human TNF- were obtained from Genzyme (Mississauga,
Canada). Ciglitazone,
15-deoxy-
12,14-PGJ2
(15d-PGJ2), and methoprene acid (MA) were
obtained from Biomol (Plymouth Meeting, PA). PMA, DMSO,
9-cis-retinoic acid (RA), saline, trypsin, and sterile water
were obtained from Sigma-Aldrich (Oakville, Canada). Ficoll-Paque,
Percoll, and dextran T500 were obtained from Pharmacia (Peapack, NJ).
Human IgG Fc fragments were obtained from Calbiochem (San Diego, CA).
Lipids were purchased from Avanti Polar Lipids (Alabaster,
AL).
Liposomes were prepared as described (47). Phosphatidylcholine (PC) liposomes were made at 100 mol % PC. Phosphatidylinositol (PI) and phosphatidylserine (PS) liposomes were made at 70 mol % PC and 30 mol % PS or PI.
Parasite cultures were maintained and synchronized as described (48, 49, 50). Parasites from two patient lines (P1 and P2) and the laboratory clone ItG were used. Parasite cultures were treated with mycoplasma removal agent (ICN Pharmaceuticals, Costa Mesa, CA) and tested negative for mycoplasma by PCR analysis before use. Culture supernatants were collected from parasite lines, aliquoted, and frozen for subsequent use.
Monocyte isolation and culture
Venus blood was collected from healthy volunteers, and monocytes
were isolated as described (42). This procedure yields a
platelet-free population of nonactivated monocytes that are >80% CD14
positive by flow cytometry, minimal baseline TNF- secretion, and
>98% viability by trypan blue exclusion. In some experiments,
purified monocytes were adhered to glass coverslips in 12-well
polystyrene plates (250,000 monocytes/well). Nonadherent cells were
washed away, and the monocytes were cultured in RPMI 1640 with
L-glutamine, HEPES, and 10% heat-inactivated FCS (RPMI 10)
at 37°C and 5% CO2. Monocytes, aged in culture
for 5 days to derive Ms, were assayed for phagocytic ability or CD36
expression.
Detection of CD36 by flow cytometry
Human monocytes, THP-1 (a human monocytic cell line), and WR-1 cells (a transformed brain endothelial cell line; the kind gift of Dr. C. Ockenhouse, Walter Reed Army Institute of Research, Washington, DC) subjected to various treatments were stained with 1:100 dilution of the mAb FA6-152 (anti-CD36) for 30 min on ice followed by a 1:50 dilution of a secondary anti-mouse IgG-FITC conjugated Ab. An unstained control and secondary Ab-only stained controls were also performed. The monocytes were fixed in 1% paraformaldehyde/PBS and analyzed using the Epics ELITE flow cytometer and software (Beckman Coulter, Marseille, France).
Up-regulation of CD36 using PPAR-RXR agonists and phagocytosis
assay
Purified human monocytes or culture-derived Ms, plated on
round glass coverslips in 12-well polystyrene plates (250,000
monocytes/well), were exposed to RPMI 10 containing 5 µM
15d-PGJ2 plus 30 µM MA, 5 µM
15d-PGJ2 plus 1 µM 9-cis-RA,
ciglitazone (3–30 µM), or appropriate concentrations of DMSO as a
control and incubated at 37°C 5% CO2 for
22–24 h. THP-1 cells were treated in suspension.
The phagocytosis assay was performed as previously described
(42). The monocytes were washed and incubated with 20
µg/ml Fc fragments for 30 min at room temperature (to block Fc
receptors), followed by a 30-min incubation with 10 µg/ml of various
mAbs or 0.1 mM of liposomes where appropriate. The monocytes were
washed, and 500 µl of 2% hematocrit and 5–8% parasitemia of
carefully synchronized trophozoite-stage parasites in RPMI 10 were
layered on top. The final PE:monocyte/M ratio was 20:1. The assay
was allowed to continue for 4 h at 37°C with gentle rotation.
After 4 h, the coverslips were subjected to hypotonic lysis in
ice-cold water for 30 s to remove nonphagocytosed PEs and were
fixed and stained with Giemsa. The number of monocytes/Ms with fully
internalized PEs was quantitated microscopically. At least 400
monocytes/Ms were counted per coverslip. Phagocytic index was
defined as the percentage of monocytes/Ms with at least one
internalized PE multiplied by the average number of PEs per
monocyte/M for that coverslip (51).
TNF- assay
Purified human monocytes were seeded in 24-well polystyrene
plates (200,000 cells/well) and allowed to adhere for 1 h.
Unattached cells were washed away, and the remaining cells were treated
with PPAR-RXR agonists or DMSO controls as described above, followed
by the addition of 50 nM PMA, 1:10 dilution of various P.
falciparum culture supernatants (mycoplasma free), or no
additions. Following an 18- to 24-h incubation at 37°C, the
supernatants were collected, cleared by centrifugation, and assayed for
TNF- using a sandwich ELISA (52).
TNF- assays were also performed as described above using THP-1 cells
kept in suspension at a concentration of 500,000 cells/ml.
Statistical analysis
All experiments were performed in duplicate or triplicate and repeated at least three times. There was some variation between experiments due to the use of different monocyte donors and parasite cultures. However, within each experiment, the results were consistent. Data are represented as mean ± SD, unless otherwise noted. Statistical significance was determined using the Student’s t test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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s express more CD36 and have increased
phagocytic capacity for nonopsonized PEs
We have recently reported that CD36 is the major receptor on
freshly isolated human monocytes mediating the uptake of nonopsonized
PEs (42). However, our observations with freshly explanted
monocytes may underestimate the potential for nonopsonic clearance of
PEs in vivo. Tissue-resident Ms in the liver, spleen, and
reticuloendothelial system that mediate the uptake of PEs would be
expected to behave more like culture-derived Ms, which have been
reported to express increased levels of CD36 (53). We
investigated the effect of culture maturation of monocytes on CD36
expression and phagocytic capacity for nonopsonized PEs. CD36 surface
levels increased on monocytes aged in culture for 5 days (Fig. 1
a). In association with
increased CD36 levels, the phagocytosis of nonopsonized PEs increased
4-fold (p < 0.01; Fig. 1b).
Phagocytosis occurred in a complement-free environment with Fc receptor
blockade and no prior opsonization of PEs. The mAb blockade of CD36
(FA6-152; 10 µg/ml) resulted in a 50–70% inhibition of phagocytosis
in both day 0 and day 5 monocytes (p < 0.01;
Fig. 1b). There was no phagocytosis of uninfected
erythrocytes by monocytes or culture-derived Ms.
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phagocytosis of nonopsonized PEs is a CD36-specific process
CD36 participates in cooperation with
v3 and TSP in the
phagocytic removal of apoptotic cells (54, 55). We
investigated whether these or other recognized PE receptors such as
ICAM-1 contributed to nonopsonic phagocytosis of PEs by culture-derived
Ms. Receptor blockade of
v3 or TSP on
culture-derived Ms using mAbs (23C6 and C6.7, respectively)
(54, 55) did not decrease PE phagocytosis (Fig. 2a). Blocking
v3, TSP, and CD36 in
combination resulted in a decrease in PE phagocytosis similar to that
observed with CD36 blockade alone (Fig. 2a). Receptor
blockade of ICAM-1, an important sequestration receptor for PEs
expressed on both endothelial cells and monocytes/Ms, had no
significant inhibitory effect on PE phagocytosis (Fig. 2a).
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s
to PS-containing liposomes before phagocytosis. PS-containing liposomes
had no inhibitory effect on nonopsonic PE phagocytosis (Fig. 2
b), nor did PC- or PI-containing liposomes (Fig. 2b).
The ligand for CD36 on the PE is a trypsin-sensitive protein, P.
falciparum erythrocyte membrane protein 1 (56).
Removal of the CD36 ligand by mild trypsinization of the PEs before
phagocytosis resulted in a decrease in phagocytosis similar to that
observed with CD36 receptor blockade (Fig. 2c).
Up-regulating CD36 in monocytes and Ms results in increased
uptake of nonopsonized PEs
Our observations that culture-derived Ms express more CD36 and
have increased phagocytic capacity for PEs prompted us to test the
hypothesis that pharmacologic up-regulation of CD36 would increase
phagocytic uptake of nonopsonized PEs.
The nuclear receptor PPAR, acting in combination with the RXR, has
been shown to up-regulate CD36 expression in monocytic cells
(43). We treated monocytes with the PPAR agonists
15d-PGJ2 (5 µM) or ciglitazone (3–100 µM), a
member of the thiazolidinedione family of drugs, and the RXR agonists
MA (10 µM) or 9-cis-RA (1 µM) to determine whether
PPAR-RXR activation increased CD36 surface levels and CD36-mediated
phagocytic capacity. Monocytes treated overnight with
15d-PGJ2 and a RXR agonist or ciglitazone alone
expressed 40–60% higher levels of CD36 compared with similarly
treated controls as determined by flow cytometry (Fig. 3a and data not shown).
Similar up-regulation was observed in treated THP-1 cells (data not
shown). This increase in surface level of CD36 was associated with a
2-fold or greater increase in the phagocytic uptake of nonopsonized PEs
over controls (p < 0.01; Fig. 3, b
and c). Treated monocytes that internalized at least one PE
increased 40–60%, and 30% more PEs were internalized per
phagocytic-positive monocyte compared with controls (1.51 ± 0.21
vs 1.16 ± 0.13, PEs per monocyte ± SD; n =
16, p < 0.05). In each case, phagocytosis was
inhibited by mAb blockade of CD36 (p < 0.01;
Fig. 3, b and c). Inhibition levels ranged from
50 to 70% (mean = 61.15%) in control and 65–90%
(mean = 72.9%) in treated monocytes. CD36-independent
phagocytosis did not differ significantly between treated and control
monocytes.
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d).
The ability of PPAR and RXR agonists to increase CD36 expression and
phagocytic capacity was not limited to freshly isolated monocytes.
Culture-derived Ms treated with 15d-PGJ2 plus
9-cis-RA showed increased CD36 surface levels 40% over
control Ms and a corresponding increase in nonopsonic phagocytosis
(70% increase in ingested PEs in treated Ms; p
< 0.01; Fig. 4a). Similar to
untreated Ms, phagocytosis of nonopsonized PEs by PPAR-RXR
agonist-treated Ms was inhibited by mAb blockade of CD36 and by
cleaving the CD36 ligand from the PEs and not by receptor blockade of
v3, TSP, and ICAM-1
or preincubation with PS-, PC-, or PI-containing liposomes (Fig. 4, b–d).
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agonists reduce P. falciparum-induced
TNF- from human monocytes
Elevated levels of proinflammatory cytokines such as TNF- have
been associated with disease severity and a poor prognosis, suggesting
that excessive secretion of TNF- by monocytes/Ms in response to
parasite products may promote severe and cerebral malaria (29, 30, 34). PPAR agonists have been shown to reduce LPS and
PMA-induced proinflammatory cytokine secretion from monocytes
(44, 45). We examined whether PPAR agonists would
inhibit P. falciparum-induced TNF- secretion from human
monocytes and THP-1 cells.
We have previously demonstrated that CD36-mediated phagocytosis of
washed well-synchronized mature stage PEs does not induce TNF-
release from monocytes (42). However, human monocytes and
THP-1 cells exposed to parasite culture supernatants containing
parasite GPI toxins released during schizont rupture (57)
do secrete TNF- (Fig. 5, a
and b). Monocyte TNF- secretion induced by PMA was
significantly inhibited by cotreatment of cells with PPAR-RXR
agonists (p < 0.05). Cotreatment of monocytes
or THP-1 cells with 15d-PGJ2 and
9-cis-RA plus a 1:10 dilution of parasite culture
supernatants resulted in a significant decrease in TNF- production
compared with controls (p < 0.05; Fig. 5, a and b). PPAR-RXR agonist-induced inhibition
of TNF- was not limited to the laboratory clone ItG but also
occurred with wild isolates (P1 and P2).
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production (data not
shown). |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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s. This clearance mechanism is of potential
relevance to those at the greatest risk of severe disease, including
nonimmune patient populations. CD36-PE uptake occurs via a novel
phagocytic pathway that is distinct from the cooperative
v3-TSP-CD36 mechanism
involved in the uptake of apoptotic cells and does not appear to
involve PS recognition. Furthermore, we demonstrate that natural and
synthetic PPAR-RXR agonists increase monocytes/M CD36-mediated
phagocytosis of nonopsonized PEs and decrease monocyte secretion of
TNF- in response to malaria toxins. Because most natural parasite isolates bind CD36, it has been considered a target for antisequestration therapy (18, 22, 23). Despite the role of CD36 in cytoadherence, our data putatively assign a protective role for CD36 and suggest that strategies to block CD36-PE interactions may be deleterious to the host. Several additional lines of evidence support this hypothesis. Although almost all wild isolates of P. falciparum malaria adhere to CD36, only a minority of infected nonimmune patients develop cerebral or severe malaria. CD36 expression in the brain is low to absent (5), and cytoadherence to CD36 is unlikely to account for cerebral sequestration. However, CD36 is well expressed in microvascular endothelial cells from sites such as skin and muscle (5). CD36-mediated cytoadherence may direct parasites to these nonvital sites and away from cerebral microvasculature. Sequestration in peripheral sites such as skin might be expected to facilitate transmission (58) while at the same time not compromise host survival. This hypothesis is supported by the work of Newbold and colleagues, who have reported that significantly higher binding to CD36 occurs in cases of nonsevere disease (25). More recent population data has linked CD36 deficiency with an increased susceptibility to severe and cerebral malaria (27). Taken together, our data and the above observations support an emerging model of the CD36-PE interaction as a complex parasite-host adaptation, resulting in improved survival of the parasite with consequent reduced injury to the host (down-regulated proinflammatory response and parasite replication balanced by host clearance).
Several other receptors including ICAM-1 and CD31 support sequestration
of PEs, are expressed on brain endothelium, and are up-regulated by
proinflammatory cytokines (8, 11, 28, 31, 32, 33, 59).
Secretion of inflammatory cytokines during infection has been
associated with a parasite-derived GPI toxin, which stimulates the
release of TNF-, IL-1, and IL-6 from monocytes and Ms. GPI from
P. falciparum has also been shown to be a potent inducer of
inducible NO synthase and NO output, presumably via the activation of
transcription factors such as NF-
B and c-rel (28, 46). NO up-regulates ICAM-1 and VCAM-1 expression and has been
implicated in the etiology of cerebral malaria (reviewed in Ref.
46). PPAR agonists including
15d-PGJ2 and thiazolidinediones have been
reported to inhibit the induction of inflammatory genes via both
PPAR-dependent and -independent mechanisms, an effect mediated, at
least partially, by inhibition of NF-B (44, 45, 60, 61, 62, 63). PPAR agonists down-regulate TNF- and IL-6 and
inhibit activation of inducible NO synthase in response to LPS and PMA
(44, 45, 63). If the anti-inflammatory effects of
PPAR agonists can be demonstrated for malaria GPI-induced
inflammation, then these compounds may decrease excessive induction of
inflammatory cytokines implicated in the etiology of severe malaria
(46). Here we show that PPAR-RXR agonists inhibit
parasite-induced TNF- secretion by monocytes and THP-1 cells.
PPAR agonists have also been shown to inhibit TNF--induced ICAM-1
expression (64). Collectively, these observations have
clinical implications and suggest that adjunctive therapy with
PPAR-RXR agonists might reduce excessive or unbalanced
proinflammatory responses to infection and might inhibit the
up-regulation of endothelial cell receptors associated with severe
malaria.
Whether the use of PPAR agonists to up-regulate CD36 on monocytic
cells will also up-regulate CD36 in other cells will depend on
tissue-specific expression of PPAR and CD36. CD36 is primarily
expressed by monocytes, Ms, adipocytes, myocytes, and endothelial
cells of the skin and reticuloendothelial system, especially the liver
and spleen (5). Increased sequestration in these sites
would not be expected to directly contribute to excess mortality,
because binding within the reticuloendothelial system should
theoretically enhance clearance, and binding to CD36 in nonvital sites
has been proposed to confer protection against severe and cerebral
disease (25, 27, 42). However, it will be important to
determine whether these agents up-regulate CD36 in microvascular
endothelium of vital organs such as the brain. In preliminary studies,
we have observed that treatment of the immortalized human brain
endothelial cell line WR-1 with PPAR-RXR agonists did not increase
CD36 expression (data not shown). However, it will be important to
directly examine the effect of PPAR activation in endothelial cells
from a variety of sites to ensure that CD36-mediated cytoadherence in
vital organs will not be increased.
Previous studies have reported that M ingestion of opsonized PEs or
large amounts of hemazoin results in impaired phagocytic function and
decreased expression of MHC class II Ag (36, 65, 66) These
data suggest that hemozoin loading of Ms may impair both nonspecific
and specific immune responses. Despite these considerations, the great
majority of P. falciparum-infected individuals do not
progress to severe malaria and control their infections due, at least
in part, to the activity of circulating and tissue-resident
monocytes/Ms. Whether CD36-mediated PE phagocytosis will lead to
similar M impairment is currently under investigation. However, even
if the phagocytic function of the circulating pool of monocytes is
decreased, these cells are replaced during the course of clinical
infection by fresh phagocytes. In fact, the recovery phase of human
malaria is coincident with an increased capacity for its phagocytic
clearance (67).
In summary, we present evidence establishing CD36 as a major receptor
mediating nonopsonic uptake of PEs, which is of potential importance in
nonimmune hosts who are at the greatest risk of severe and cerebral
malaria. We also demonstrate that PPAR-RXR agonists induce an
increase in the CD36-mediated phagocytosis of PEs and a decrease in
parasite-induced TNF- production. Specific up-regulation of
monocyte/M CD36 may represent a novel way to immunomodulate host
defense and a new strategy to prevent or treat severe P.
falciparum malaria. Because several PPAR agonists are approved
for human use, this hypothesis can be directly tested (43, 68).
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Kevin C. Kain, Tropical Disease Unit, EN G-224, Toronto General Hospital, 200 Elizabeth Street, Toronto, Ontario, Canada M5G 2C4. E-mail address: kevin.kain{at}uhn.on.ca
3 Abbreviations used in this paper: PE, parasitized erythrocyte; TSP, thrombospondin; m, macrophage; PPAR, peroxisome proliferator-activated receptor ; RXR, retinoid X receptor; PS, phosphatidylserine; PI, phosphatidylinositol; PC, phosphatidylcholine; RA, retinoic acid; MA, methoprene acid; 15d-PGJ2, 15-deoxy-12,14-PGJ2.
Received for publication January 30, 2001. Accepted for publication March 19, 2001.
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 F. Debierre-Grockiego, L. Schofield, N. Azzouz, J. Schmidt, C. Santos de Macedo, M. A. J. Ferguson, and R. T. Schwarz Fatty Acids from Plasmodium falciparum Down-Regulate the Toxic Activity of Malaria Glycosylphosphatidylinositols. Infect. Immun., October 1, 2006; 74(10): 5487 - 5496. [Abstract] [Full Text] [PDF]
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 Y. Adams, C. Freeman, R. Schwartz-Albiez, V. Ferro, C. R. Parish, and K. T. Andrews Inhibition of Plasmodium falciparum Growth In Vitro and Adhesion to Chondroitin-4-Sulfate by the Heparan Sulfate Mimetic PI-88 and Other Sulfated Oligosaccharides. Antimicrob. Agents Chemother., August 1, 2006; 50(8): 2850 - 2852. [Abstract] [Full Text] [PDF]
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N. K. Viebig, U. Wulbrand, R. Forster, K. T. Andrews, M. Lanzer, and P. A. Knolle Direct Activation of Human Endothelial Cells by Plasmodium falciparum-Infected Erythrocytes Infect. Immun., June 1, 2005; 73(6): 3271 - 3277. [Abstract] [Full Text] [PDF]
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K. Ayi, S. N. Patel, L. Serghides, T. G. Smith, and K. C. Kain Nonopsonic Phagocytosis of Erythrocytes Infected with Ring-Stage Plasmodium falciparum Infect. Immun., April 1, 2005; 73(4): 2559 - 2563. [Abstract] [Full Text] [PDF]
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L. Serghides and K. C. Kain Peroxisome Proliferator-Activated Receptor {gamma} and Retinoid X Receptor Agonists Have Minimal Effects on the Interaction of Endothelial Cells with Plasmodium falciparum- Infected Erythrocytes Infect. Immun., February 1, 2005; 73(2): 1209 - 1213. [Abstract] [Full Text] [PDF]
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 K. Asada, S. Sasaki, T. Suda, K. Chida, and H. Nakamura Antiinflammatory Roles of Peroxisome Proliferator-activated Receptor {gamma} in Human Alveolar Macrophages Am. J. Respir. Crit. Care Med., January 15, 2004; 169(2): 195 - 200. [Abstract] [Full Text] [PDF]
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T. G. Smith, L. Serghides, S. N. Patel, M. Febbraio, R. L. Silverstein, and K. C. Kain CD36-Mediated Nonopsonic Phagocytosis of Erythrocytes Infected with Stage I and IIA Gametocytes of Plasmodium falciparum Infect. Immun., January 1, 2003; 71(1): 393 - 400. [Abstract] [Full Text] [PDF]
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), CD36 was blocked by
preincubation with 10 µg/ml FA6-152 (anti-CD36 mAb). Phagocytic
assays were performed as described in the Materials and
Methods. Phagocytic index is defined as the percentage of
monocytes/M
) or DMSO controls (
) for 24 h and
were then used in PE phagocytosis assays. **, p
< 0.01 (Student’s t test, n =
3/group), control vs treated M
, cells treated with 5 µM
15d-PGJ2 plus 1 µM 9-cis-RA. Experiments
were performed in triplicate, and data shown are representative of at
least three independent experiments. *, p < 0.05
(Student’s t test, n = 6 per
group). b, Adherent human monocytes were treated as
described above and assayed for TNF-