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and 
Have Opposing Effects on Monocyte Chemotaxis in Endometriosis
Center for Reproductive Sciences (D.H., L.L.W., E.A.R., F.B., R.N.T.), University of California, San Francisco, California 94143; and Department of Obstetrics and Gynecology (D.H., D.W.), Tuebingen 72076, Germany
Address all correspondence and requests for reprints to: Robert N. Taylor, M.D., Ph.D., Center for Reproductive Sciences, HSE 1689, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, California 94143-0556.
Abstract
The peroxisome proliferator-activated receptors (PPARs) 
and 
are
nuclear receptors that play important roles in inflammatory diseases
like ulcerative colitis and arthritis. In this study, we examined the
possible role of PPARs in macrophage attraction into the peritoneal
cavity of patients with endometriosis. We identified PPAR- and -
messenger RNA by RT-PCR and protein by immunoblotting of lysates of
peritoneal macrophages and monocytic U937 cells. Using
immunocytochemistry, we localized PPAR- and - within the nuclei
of both cell types. Monocyte chemotactic activity of peritoneal fluid
from patients with endometriosis was quantified in Boyden chambers.
Migration of U937 cells was increased by WY 14643 and reduced by
rosiglitazone. Peritoneal fluid from patients with endometriosis
activated U937 cells transiently transfected with a PPAR-/GAL4
luciferase reporter. By contrast, peritoneal fluid did not cause
significant activation of PPAR-/GAL4 constructs. The U937 cells
transiently transfected with a PPAR response element luciferase
reporter showed disease stage-dependent up-regulation when treated with
peritoneal fluid from patients with endometriosis. Treatment with
peritoneal fluid from healthy controls down-regulated PPAR response
element transactivation. We conclude that peritoneal fluid of
endometriosis patients contains activators of PPAR- that stimulate
macrophage chemotaxis. Inhibitors of PPAR- or activators of PPAR-
could be developed for the treatment of inflammation associated with
endometriosis.
OVER THE PAST two decades, considerable evidence for a cell-mediated immunological etiology of endometriosis has accumulated. Resident leukocytes within endometriotic implants have been identified histologically (1, 2, 3). Furthermore, increased numbers of peritoneal leukocytes are found in women with endometriosis (4, 5, 6). Of these, the most numerous are the macrophages, and these cells manifest an activated phenotype in women with laparoscopic evidence of endometriosis (7, 8, 9). It has been proposed that the cytokines elaborated from activated peritoneal macrophages mediate many of the symptoms associated with the endometriosis syndrome (10).
The attraction of inflammatory cells into the peritoneal cavity has been a major focus of our laboratory over the past decade. Shortly following the cloning and characterization of RANTES, a monocyte and T-cell chemokine (11), we reported its detection in peritoneal fluid from women with advanced stages of endometriosis (6). Indeed, a variety of chemokines have been identified in human peritoneal fluid. Most of these predominantly recruit monocytes [e.g. RANTES (6)], monocyte chemotactic protein-1 (12), and vascular endothelial growth factor (13, 14); however chemoattractants for neutrophils [e.g. interleukin-8 (15)], epithelial neutrophil-activating protein-78 (16)), and eosinophils [eotaxin (17)] also have been detected.
A new class of macrophage-modulating factors includes the peroxisome
proliferator-activated receptors (PPARs). PPARs are ligand-dependent
transcription factors of the nuclear hormone receptor superfamily.
Three subtypes of PPARs have been characterized (, ß, and ),
and these are activated by polyunsaturated fatty acid and eicosanoid
metabolites. However, their specific endogenous ligands are yet to be
identified. Among the naturally occurring eicosanoids,
15-deoxy-
-12,14-prostaglandin
J2 (PGJ2) is the compound
with the highest affinity and efficacy on PPAR-. Several
pharmacological PPAR ligands currently are under commercial production.
The most promising of these are clofibrates and thiazolidinediones,
agonists of the PPAR- and - receptors, respectively. The role of
these receptors in macrophage biology has not been well defined, but
recent insights into the role of PPAR- in the monocyte lineage
indicate that it regulates macrophage activation and inflammatory
response (18).
In the current studies, we investigated whether peritoneal macrophages
express PPARs and, if so, whether PPAR activation could modify
macrophage migration in an established functional assay. Further
experiments were performed to characterize the receptors and their
signaling pathways. The data presented in this report demonstrate the
expression of PPAR- and - in human peritoneal macrophages and,
moreover, indicate that PPAR- and - ligands can modulate the
monocyte chemotaxis induced by pelvic fluid constituents. The results
suggest that certain classes of PPAR ligands may be beneficial in
reducing monocyte trafficking into the peritoneal cavity of women with
endometriosis.
Materials and Methods
Patient recruitment and characterization
Healthy ovulatory women, who had not received hormones or GnRH agonist therapy for at least 6 months before surgery, were recruited after they had provided written informed consent under a study protocol approved by the Committee on Human Research at the University of California, San Francisco. Women with endometriosis (n = 32) were staged intraoperatively according to a modification of the revised American Fertility Society system (19). Control subjects were women who had no evidence of pelvic pathology despite careful evaluation at laparoscopy (n = 12).
Sources of peritoneal macrophages and fluid
Peritoneal fluid was aspirated immediately on entering the peritoneal cavity from patients undergoing laparoscopy. Bloody samples, potentially contaminated with peripheral leukocytes, were excluded from our studies. Cells were collected by centrifugation at 2000 x g, and supernatants were frozen at -70 C. Peritoneal macrophages were isolated by centrifugation using lymphocyte separation medium (Cappel, Aurora, OH). Pelvic fluid and peritoneal macrophages were collected from all subjects in the midfollicular phase of the ovulatory cycle as described previously (20).
RT-PCR for PPAR- and - messenger RNA
Total RNA from peritoneal macrophages and U937 cells was isolated using Trizol (Life Technologies, Inc., Grand Island, NY). One microgram of each RNA was reverse transcribed in a 20-µL reaction containing: 5 mM MgCl2, 1x PCR buffer (Life Technologies, Inc.), 1 U reverse transcriptase, 1 mM each of dATP, dCTP, dGTP, and dTTP, and 2.5 µM random hexamers. The entire 20-µL reaction was then subjected to PCR amplification. PCR reaction conditions were similar to above, with Taq + Taqstart antibody (0.5 U Taq equivalent, according to instructions from CLONTECH Laboratories, Inc., Palo Alto, CA) replacing reverse transcriptase. A final volume of the PCR reaction was 100 µL. The oligonucleotide primer sequences (below) were selected using the MacVector program (Oxford Genetics, Madison, WI).
Sequences of the PPAR--specific primers were: upstream, 5'-ACG GAA
AGC CCA CTC TGC CCC CTC TC-3'; downstream, 5'-CTT GTC CCC GCA GAT TCT
ACA TTC G-3'. Cycle parameters for PCR amplification were: 94 C, 5 min;
30 cycles of 94 C, 30 s; 57 C, 30 s, 72 C, 80 s. A final
extension round (72 C, 7 min) was used to maximize complete product
formation.
Sequences of the PPAR--specific primers were: upstream, 5'-GCA GTG
GGG ATG TCT CAT AAT GC-3'; downstream, 5'-CAG GGG GGT GAT GTG TTT GAA
C-3'. Cycle parameters for PCR amplification were identical to those
used for PPAR- complementary DNA amplification. Ten microliters of
PCR products were mixed with sample buffer and loaded onto 4% NuSieve
agarose gels (FMC, Rockland, ME). After electrophoresis,
gels were stained with ethidium bromide and photographed. Both pairs of
primer sets spanned introns, excluding the detection of genomic DNA
sequences. RT-PCR for glyceraldehyde 3-phosphate dehydrogenase
(GAPDH) sequences were included to verify RNA integrity.
PPAR- and - immunoblotting
Peritoneal macrophages and U937 cells were cultured in 50% DMEM
H-21/50% Ham’s F-12 containing 10% FCS and antibiotics. 50
µg of protein lysates from freshly isolated peritoneal macrophages,
cultured macrophages, U937 cells, and their conditioned media were
subjected to SDS-PAGE, and the proteins were blotted to nitrocellulose
paper as described (21). Western blotting for PPAR- and
- was performed with rabbit IgG polyclonal antibodies raised against
human PPAR- (catalog no. sc-9000; Santa Cruz Biotechnology, Inc., Santa Cruz, CA) and - (catalog no.
sc-7196; Santa Cruz Biotechnology, Inc.). Antibodies were
used at a concentration of 2 µg/mL.
Immunocytochemistry
Freshly isolated peritoneal macrophages and U937 cells were
plated onto Lab-Tek four-chamber slides (Miles Laboratories, Naperville, IL), fixed in 100% methanol, and
stained using the Vectastain Elite ABC kit (Vector Laboratories, Inc., Burlingame, CA). Immunoperoxidase staining was performed
overnight at 4 C, using rabbit polyclonal antihuman PPAR- and -
antibodies (2 µg/mL, catalog no. sc-9000 and sc-7196; Santa Cruz Biotechnology, Inc.), mouse monoclonal IgG antibodies
against human CD68 (2 µg/mL; DAKO Corp., Carpinteria,
CA), and rabbit polyclonal antihuman glial fibrillary acidic protein
antibodies (2 µg/mL; Santa Cruz Biotechnology, Inc.) as
a negative control. Diaminobenzidine (Zymed Laboratories, Inc., South San Francisco, CA) was used as the chromagen.
Monocyte chemotaxis assay
Monocyte chemotaxis was assayed in Boyden chambers containing polyethylene terephthalate track-etched membranes with 0.4-µm pores (Becton Dickinson and Co., Franklin Lakes, NJ). In this assay, we used a human histiocytic cell line (U937) that can be induced to display monocytic differentiation and chemotactic responsiveness after treatment with 1 mM 8-bromo-cAMP (22). The U937 cells were cultured at 37 C with 5% CO2 in 50% DME H-21/50% F-12 medium supplemented with 10% FCS and penicillin G (100 U/mL), streptomycin (70 µM), and gentamicin (30 µM) (UCSF Cell Culture Facility) and incubated with 1 mM 8-bromo-cAMP (Sigma, St. Louis, MO) every 24 h for a total of 48 h. Peritoneal fluids were diluted to 25% in PBS with 0.1% BSA and placed in the bottom wells of the Boyden chambers (600 µL per well). In some experiments the fluids were subjected to heat denaturation or dialysis. P.E.T track-etched membranes were then fixed in place in 24-well plates to separate bottom from top compartments and 500,000 U937 cells in 200 µL of PBS containing 0.1% BSA were added to the upper wells. The loaded chambers were incubated at 37 C in humidified air with 5% CO2 for 120 min. Nonmigrating cells were removed from the top of the membrane by several washes with PBS, and migrating cells were fixed to the underside of the membrane with absolute methanol overnight at 4 C and stained with crystal violet (Sigma). To quantify monocyte chemotaxis, we measured optical absorption of the filters at a wavelength of 570 nm as described previously (20).
To evaluate the effects of PPAR activation on monocyte chemotactic
activity, samples were incubated with rosiglitazone (BRL
49653),
15-deoxy-12,14-PGJ2, WY
14643 (Wyeth-Ayerst Laboratories, Inc., St. Davis, PA) or
9-cis-retinoic acid, and the chemotactic activity was
measured as described above.
Apoptosis enzyme-linked immunosorbent assay (ELISA)
Programmed cell death by apoptosis is characterized by formation of multinucleosomal-sized genomic DNA fragments. DNA fragments are multiples of 180-bp subunits associated with core histones. The levels of DNA released in the cytosol of apoptotic cells were measured using the cell death detection ELISA kit (Roche, Mannheim, Germany). This is a quantitative sandwich ELISA using antibodies against DNA and histones. Extent of DNA fragmentation is expressed as an enrichment factor, calculated by dividing the absorbance of a given sample by the absorbance of the corresponding 10% FCS control.
Plasmids
Constructs for luciferase assays included three copies of the
PPAR response element (PPRE) 5'-GTC GAC AGG GGA CCA GGA CAA AGG TCA CGT
TCG GGA GTC GAC-3' or four copies of the GAL4 element
(UASG) 5'-CGA CGG AGT ACT GTC CTC CGA GCT-3'
cloned into a thymidine kinase (TK)-LUC reporter that contains
the herpes virus thymidine kinase promoter (-105/+51) upstream of
firefly luciferase cDNA (23). GAL4 chimeras were made by
fusing the human PPAR- and - ligand-binding domains to the
C-terminal end of the yeast GAL4 DNA-binding domain (amino acids
1–147) from pSG424 (24). The human PPAR-/GAL4 (amino
acids 167–468 for PPAR-) and human PPAR-/GAL4 (amino acids
176–477 for PPAR-) constructs were generously provided by R. Evans
(Salk Institute, La Jolla, CA; Refs. 25 and
26).
Transient gene transfection and luciferase reporter activity assays
The U937 cells were quiesced for 12 h in medium containing
2.5% dextran charcoal-stripped FCS (DCSS) and then collected by
centrifugation. They were resuspended in PBS (0.5 mL/1.5 x
107 cells) containing 0.1% glucose, 10 µg/mL
Biobrene, and 5 µg reporter plasmid. The cells were transferred to a
cuvette and electroporated using a gene pulser (Bio-Rad Laboratories, Inc., Hercules, CA) as previously described
(27). After electroporation the cells were transferred to
new medium with 2.5% DCSS, plated at 1 mL per dish in 12-well
multiplates and treated in triplicate for 18 h with the PPAR
activators or peritoneal fluid (see below). After overnight incubation,
cells were centrifuged, lysed with 200 µL of lysis buffer
(Promega Corp., Madison, WI), and analyzed using a dual
luciferase protocol (Promega Corp.) that allows
independent measurement of PPRE3-TK-firefly
luciferase, PPAR-/GAL4 or PPAR-/GAL4 firefly luciferase and
TK-renilla luciferase. Firefly luciferase activity was expressed as a
ratio of renilla luciferase activity for all calculations to correct
for transfection efficiency. Luciferase activity in treated cells was
normalized to activity in cells incubated with 2.5% DCSS alone as a
means of comparing the different raw values obtained in each
independent experiment.
Influence of peritoneal fluid on PPRE activation
The U937 cells were treated as described above. After electroporation the cells were transferred to new medium with 2.5% DCSS and plated at 800 µL per dish in 12-well multiplates and treated in triplicate for 18 h. 200 µL of peritoneal fluid were added to 800 µL media and used to treat triplicate wells of transfected U937 cells for 18 h. After overnight incubation, cells were centrifuged and lysed, and luciferase activity was analyzed as described before. As a control, some wells were treated with 1 µM rosiglitazone, 5 µM WY 14643, or 1 µM 9-cis-retinoic acid to verify normal signaling. Dose response experiments performed with each of these substances indicated that the above concentrations were the EC50 for each compound. Data were normalized to 2.5% DCSS controls. Luciferase activity was analyzed as described above.
Statistical analyses
All experiments were repeated a minimum of three times, and results are expressed as the mean ± SD. Data were analyzed by nonparametric methods using the Kruskal-Wallis and Mann-Whitney statistics. Significant differences were accepted when two-tailed analyses yielded P less than 0.05.
Results
Identification of PPAR- and - mRNA transcripts in peritoneal
macrophages and U937 cells
The expression of PPAR- and - mRNA in peritoneal macrophages
and U937 cells was verified by RT-PCR. PPAR- and - mRNA
transcripts were amplified in RNA isolated from cultured peritoneal
macrophages and U937 cells (Fig. 1
, lanes
1–4). Intron-spanning primers used to amplify transcripts of a
constitutive gene, GAPDH, indicated that the RNA preparations were of
good quality and not contaminated by genomic DNA (Fig. 1, lanes 1–4,
bottom). Negative controls for RT and PCR yielded no
nonspecific bands (Fig. 1, lanes 5 and 6).
|
and - immunoblotting
Western immunoblot analysis of cultured peritoneal macrophages and
U937 cells showed that PPAR- and - protein expression is present
in cell lysates of both cell types (Fig. 2, A and B, lanes 1 and 2) but not in
their conditioned media (Fig. 2, A and B, lanes 3 and 4). Freshly
isolated peritoneal macrophages, not subject to in vitro
culture conditions, also expressed detectable PPAR- and -
proteins (data not shown).
|
Peritoneal macrophages and U937 cells were examined subsequently
for PPAR- and - protein expression by immunocytochemistry.
Punctate PPAR- and - staining was noted to be localized in the
nuclei of macrophages (Fig. 3, A and C)
and U937 cells (Fig. 3, B and D). Prominent staining was seen in the
nucleoli of the U937 cells. The arrowheads indicate the thin rim of
cytoplasm in the U937 cells, which showed fainter staining of PPAR
protein (Fig. 3, B and D). CD68 staining of the cytoplasm and golgi
with sparing of the nucleus was observed in the peritoneal macrophages
(Fig. 3E), whereas U937 cells were negative for CD68 (Fig. 3F). Glial
fibrillary acidic protein (GFAP) at the same antibody concentration
served as a negative control for both cell types (Fig. 3, G and H).
|
The biological influence of PPAR activators in peritoneal fluid
specimens was evaluated by measuring their ability to induce monocyte
chemotaxis using the U937 cell bioassay. A peritoneal fluid pool from
patients with moderate or severe endometriosis (n = 16) was tested
and the results normalized to 100%. Relative to this pool, control
peritoneal fluid had 48 ± 10% the chemotactic activity of
endometriosis pelvic fluid, similar to findings we have reported
previously (20). To evaluate the influence of PPAR
activators on the total monocyte chemotactic activity of the peritoneal
fluid, samples were incubated with rosiglitazone (1 µM),
15-deoxy-12,14-PGJ2 (1
µM), WY 14643 (5 µM), or
9-cis-retinoic acid (1 µM).
Rosiglitazone reduced the chemotactic activity of the endometriosis
peritoneal fluid pool by 60 ± 25% and PGJ2
reduced it by 60 ± 31%. Both substances are activators of
PPAR-. WY 14643, an activator of PPAR-, increased the monocyte
chemotactic activity by 38 ± 11%, and 9-cis-retinoic
acid increased it by 27 ± 4% (Fig. 4A). Identical trends were observed when
these PPAR activators were incubated with pelvic fluid from control
subjects. However, the effects were less obvious secondary to lower
monocyte chemotaxis in the control patients’ peritoneal fluid (Fig. 4B).
|
Assessment of apoptosis in PPAR--treated U937 cells
One potential mechanism of chemotaxis inhibition is via monocyte
apoptosis. To assess this hypothesis, we used a DNA fragmentation
ELISA. The U937 cells were cultured for 24 h in 10% FCS. Samples
were incubated with rosiglitazone (1 µM),
15-deoxy-12,14-PJ2 (1
µM), TNF- (6 nM, positive control), or
neat (control). Cells in 10% FCS as well as cells treated with
rosiglitazone did not show any apoptosis, whereas cells treated with
PGJ2 showed a 20-fold enrichment of apoptosis and
cells treated with TNF- a 28-fold enrichment of apoptosis.
Influence of peritoneal fluid from patients with and without endometriosis on PPRE activation in U937 cells
The U937 cells were transiently transfected with PPRE-luciferase
reporter vectors and treated with peritoneal fluid from healthy
controls (n = 12), patients with minimal or mild endometriosis
(n = 16), or patients with moderate or severe endometriosis
(n = 16) and compared with transfected U937 cells incubated with
DCSS alone. All values were expressed as a ratio of cotransfected
renilla luciferase activity to correct for transfection efficiency. The
luciferase activity of cells incubated with 2.5% DCSS were measured
and set to 100%. Peritoneal fluid from healthy controls reduced the
PPRE-luciferase activity to 56 ± 20% (P <
0.05), peritoneal fluid from patients with minimal or mild
endometriosis enhanced the luciferase activity to 110 ± 39%, and
peritoneal fluid from patients with moderate or severe endometriosis
stimulated luciferase activity to 141 ± 32% (P
< 0.05) (Fig. 5).
|
).
|
/GAL4 and PPAR-/GAL4 constructs in U937
cells by peritoneal fluid from patients with and without
endometriosis
The U937 cells were transiently transfected with PPAR-/GAL4 or
PPAR-/GAL4 constructs along with a GAL4 response element luciferase
reporter, treated with peritoneal fluid from healthy controls (n =
5), patients with minimal or mild endometriosis (n = 5), or
patients with moderate or severe endometriosis (n = 5) and
compared with transfected U937 cells incubated with 2.5% DCSS alone.
We observed a significant increase in luciferase activity mediated by
PPAR- in cells treated with peritoneal fluid from advanced stages of
endometriosis, but no significant stimulation mediated via PPAR-. By
contrast, both positive control ligands activated their cognate
receptors: WY14643 stimulated PPAR- signaling 392% and
rosiglitazone stimulated PPAR- signaling 776% (Fig. 7).
|
Previous investigations of monocyte chemotaxis indicate that differentiated U937 cells (22) provide a good model for these experiments. Akoum et al. (12) first showed that 8- bromo-cAMP-treated U937 cells would migrate toward a gradient of endometriosis peritoneal fluid. We have verified that like primary peritoneal macrophages, U937 cells express functional CCR-1 and CCR-5, the two high-affinity RANTES receptors. Blocking these receptors with neutralizing antisera inhibits RANTES- and peritoneal fluid-induced U937 chemotaxis (20).
The current studies further substantiate the utility of the cell model,
demonstrating that like primary peritoneal macrophages, differentiated
U937 cells express functional PPAR- and - receptors. When added
to peritoneal fluid, activators of PPAR- stimulated U937
chemotaxis, whereas PPAR- ligands inhibited monocyte migration.
Using chimeric PPAR- or /GAL4 constructs, we determined that
soluble principles in peritoneal fluid of women with advanced stages of
endometriosis preferentially activate PPAR- and enhance monocyte
migration. The precise identification of this natural PPAR-
activator(s) currently is under investigation. Preliminary
characterization shows that the activity is heat labile and <
10,000 Da, consistent with a cytokine peptide. We postulate that its
actions are mediated via cell membrane arachidonic acid metabolism
resulting in release of fatty acids or eicosanoids that bind and
activate monocyte PPAR-.
Endogenous factors present in human peritoneal fluid can activate PPRE
reporters. The concentration and activity of such factors are elevated
in pelvic fluid from women with moderate to severe endometriosis (Fig. 5
). Strict interpretation of these data must be made with caution. At
least four ligand-receptor interactions could influence the PPRE
cis-element (viz., PPAR-, ß, , and RXR). Our
findings emphasize the complexity of potential signaling molecules in
peritoneal fluid.
Our observation that PPAR- ligands inhibit macrophage activity is
consistent with recent reports in other biomedical settings. PPAR-
ligands can inhibit inflammation in rodent cartilage (28)
and human colon cell (29) models, in part via interference
with inflammatory cytokines.
Recent data indicate that the PPAR- ligand
PGJ2 can induce apoptosis in endothelial
(30) and choriocarcinoma cells (31) and may
directly inhibit macrophage action via induction of apoptosis
(32). In our studies, we observed some apoptotic activity
of PGJ2 on differentiated U937 cells, but
rosiglitazone did not induce apoptosis at the concentration (1
µM) we tested. Thus, programmed cell death does not
account for the reduction in chemotaxis afforded following
rosiglitazone treatment. Further studies suggest that PPAR- ligands
have other potentially beneficial anti-inflammatory effects on targets
including the endothelium (33) and T cells
(34). A ligand of RXR, the obligate heterodimerization
partner of PPARs, augmented activation of the transfected
PPRE-luciferase reporter. It is likely that RXR also contributes to the
anti-inflammatory action of PPAR-.
The elucidation of the mechanisms of PPAR- and - action in human
macrophages will provide new insights toward the development of novel
pharmaceuticals for the treatment of women with endometriosis and other
inflammatory conditions. Our findings indicate that inhibitors of
PPAR- and activators of PPAR- pathways are potential candidates
as new therapeutics for this common and debilitating syndrome.
Acknowledgments
The human PPRE and GAL4 constructs were generously provided by R. Evans (Salk Institute, La Jolla, CA) and rosiglitazone by T. Scanlan and E. Person (University of California, San Francisco, CA). We also thank V. Chao (University of California, San Francisco, CA) for his help with plasmid preparations.
Received November 28, 2000.
Revised February 27, 2001.
Accepted March 23, 2001.
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