| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
and Immunoregulation: PPAR Mediates Inhibition of Helper T Cell Responses1
*
Division of Rheumatic Diseases, Department of Medicine, and
Center for Vascular Biology, Department of Physiology, University of Connecticut Medical School, Farmington, CT 06032
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
has been described in
cells critical to the innate immune system, the monocyte/macrophage. In
addition, evidence for an antiinflammatory role of the PPAR ligand,
15-deoxy-
12,14-PGJ2 (15d-PGJ2)
has been found. In the present studies, we demonstrate, for the first
time, that murine helper T cell clones and freshly isolated splenocytes
express PPAR 1. The PPAR expressed is of functional significance
in that two ligands for PPAR, 15d-PGJ2 and a
thiazolidinedione, ciglitazone, mediate significant inhibition of
proliferative responses of both the T cell clones and the freshly
isolated splenocytes. This inhibition is mediated directly at the level
of the T cell and not at the level of the macrophage/APC. Finally, we
demonstrate that the two ligands for PPAR mediate inhibition of IL-2
secretion by the T cell clones while not inhibiting IL-2-induced
proliferation of such clones. The demonstration of the expression and
function of PPAR in T cells reveals a new level of immunoregulatory
control for PPARs and significantly increases the role and importance
of PPAR in immunoregulation. |
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
, PPAR
(also called ß or NUC-1), and PPAR (3, 4). These three isotypes exhibit distinct patterns of tissue
distribution and differ in their ligand-binding domains. PPAR
expression is relatively high in hepatocytes, heart, enterocytes, and
the kidney, compared with the other PPAR isotypes. Ligands for PPAR
include fibrates, specific fatty acids, and eicosanoids. PPAR is
ubiquitously expressed and binds some of the same ligands as PPAR;
however, its function is unclear.
PPAR was originally characterized as a regulator of adipocyte
differentiation and lipid metabolism (3, 5, 6). It is now
clear that PPAR is also found in other cell types, including
hepatocytes, fibroblasts, myocytes, breast and colon epithelial cells,
the white and red pulp of rat spleen, human bone marrow precursors, and
macrophages/monocytes (7, 8). PPAR expression is
directed by different promoters, leading to at least three PPAR
isoforms (9). Until recently, it had been believed that
the PPAR 1 isoform expression was restricted to liver, adipocytes,
and a few other cell types, and that the PPAR 2 isoform was
predominantly expressed in adipocytes (3). All of the
naturally occurring ligands of PPAR have not yet been clearly
identified, making it still an "orphan" nuclear receptor. It is
known, however, that PPAR is activated by certain polyunsaturated
fatty acids, the thiazolidinedione class of antidiabetic drugs
(10, 11, 12), and a variety of nonsteroidal antiinflammatory
drugs, although the latter have relatively low affinity
(13). The prostanoid PGD2
dehydration product,
15-deoxy-12,14-PGJ2
(15d-PGJ2) is an endogenous ligand for PPAR
(11, 12).
In addition to its function in lipid and glucose metabolism, PPAR
has recently been of interest for its possible role in cell
proliferation and malignancy. Ligands for PPAR have been shown to
mediate both positive and negative effects on the proliferation of
normal and malignant cells (14, 15, 16, 17, 18, 19). Recently, a role for
PPARs has been described in cells critical to the innate immune system,
the monocyte/macrophage (20, 21, 22, 23, 24, 25, 26, 27). In studies further
suggesting a possible role for PPAR in inflammation, Gilroy et al.
have recently presented evidence for an antiinflammatory role of the
PPAR ligand 15d-PGJ2 in a rat model of
carrageenin-induced pleural inflammation (28). However, as
yet, there has been no role demonstrated for PPAR in the adaptive
immune system.
In the present studies we have examined the expression and function of
PPAR in murine T cells. We now document, for the first time, that
PPAR 1 is expressed in T cells. We demonstrate that two ligands for
PPAR, including 15d-PGJ2, mediate a direct
inhibitory role on T cell immune responses. We further demonstrate that
the two ligands for PPAR mediate inhibition of IL-2 secretion by T
cell clones while not inhibiting IL-2-induced proliferation of such
clones. Given the prior demonstration that PPAR-ligation in
differentiated macrophages leads to down-regulation of certain immune
functions of these cells, our present documentation of T cell
inhibition by PPAR greatly expands the role and significance of
PPARs in immunoregulation.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Female SJL/J and C57BL/6 mice, aged 4 to 8 wk old, were obtained from The Jackson Laboratory (Bar Harbor, ME).
Materials
15d-PGJ2 was obtained from Cayman Chemical (Ann Arbor, MI). Ciglitazone was obtained from Biomol (Plymouth Meeting, PA). Bovine myelin basic protein (BMBP) was obtained from Sigma (St. Louis, MO). Anti-murine CD3 Ab was obtained from PharMingen (San Diego, CA). Human recombinant IL-2 was obtained from the National Cancer Institute, (Frederick, MD).
In vitro propagation of T cell clones
The T cell clones are propagated using a 2-wk cycle of alternating stimulation and rest as previously described (29, 30). T cell clones are normally stimulated with irradiated APCs (irradiated, 2600 rad, syngeneic splenocytes) and BMBP, followed by a week of growth in IL-2, and then are passaged for a week without any stimulation and in the absence of IL-2. The medium used is RPMI 1640 with 10% FCS and 5 x 10-5 M 2-ME. In the present studies, the T cell clones were studied using two different modes of activation and at two different time points in their normal cycle of activation and rest. In addition to biweekly stimulation with APCs and BMBP, the clones were alternatively activated using immobilized anti-CD3 Ab in the absence of added APCs. The T cells were harvested, and RNA was obtained from the following groups: 4 days after stimulation with irradiated APCs/BMBP, during which the cells were grown in the presence of IL-2; 4 days after stimulation with immobilized anti-CD3 Ab (no addition of exogenous irradiated APCs for 18 days), grown in the presence of IL-2 after stimulation; 13 days after stimulation with APCs/BMBP and grown for the last 6 days in the absence of IL-2.
RT-PCR
RNA was derived from T cell clones or splenocytes using the method of Chomczynski and Sacchi (31). RNA from 3T3 L1-adipocytes was kindly provided by Dr. Vered Ribon (University of Michigan, Ann Arbor, MI). RT was performed using Moloney murine leukemia virus (MMLV)-RT (Life Technologies, Gaithersburg, MD) and an oligo(dT) primer (Stratagene, La Jolla, CA) as per the directions of the supplier.
PCR for PPAR 1 was performed using an upstream oligonucleotide
primer located in the 5' untranslated region of the murine PPAR 1
cDNA (starts at base No. 306 in GenBank accession number U01841)
(5'-TGAGGAGAAGTCACACTCTG-3') and a downstream oligonucleotide
primer located in the translated region common to both murine PPAR 1
and 2 cDNA (ends at base No. 664 in GenBank accession number
U01841) (5'-TGGGTCAGCTCTTGTGAATG-3'). These primers span a region of
PPAR 1 cDNA that is 359 bp in length. PCR for PPAR 2 was
performed using an upstream oligonucleotide primer located in the 5'
region of murine PPAR 2 that is not shared with PPAR cDNA (starts
at base No. 39 in GenBank accession number U09138)
(5'-TATGGGTGAAACTCTGGGAG-3'). The downstream oligonucleotide primer
was the same as that used for PPAR 1 PCR (ends at base No. 303 in
GenBank accession number U09138). These primers span a region of
PPAR 2 cDNA that is 265 bp in length. PCR was performed using
Taq polymerase (Perkin-Elmer, Norwalk, CT). Amplification
was conducted using 40 cycles at 95°C for 15 s, 54°C for
15 s, and 72°C. for 45 s, followed by an extension at
72°C for 7 min. PCR products were visualized on 1.2% agarose gels.
For sequencing of the PCR product, the product was extracted from low
melt agarose and cloned using TA cloning (Invitrogen, Carlsbad,
CA).
Immunofluorescence
Cells were incubated with 200 µg/ml mouse IgG (Jackson
ImmunoResearch Laboratories, West Grove, PA) for 20 min on ice, washed,
and then permeabilized with Cytofix/Cytoperm solution (PharMingen) as
per the manufacturer’s directions. Cells were incubated with either no
primary Ab or 2 µg/ml rabbit anti-chicken OVA IgG (control
primary Ab; Cappel, Costa Mesa, CA), or 2 µg/ml rabbit
anti-PPAR IgG (Santa Cruz Biotechnology, Santa Cruz, CA; No.
sc-7196) in Perm/Wash (PharMingen) for 1 h at room temperature.
After washing with Perm/Wash, the cells were incubated with
PE-conjugated, affinity-purified F(ab') fragment donkey anti-rabbit
IgG (Jackson ImmunoResearch Laboratories) for 1 h at room
temperature. The cells were then washed with Perm/Wash and examined
using fluorescence microscopy.
Splenic T cell enrichment
Rabbit antiserum to mouse IgG (Cappel) was precoated on tissue culture dishes overnight at 4°C. The dishes were washed extensively before plating of whole splenocytes for 1–2 h at 4°C. The nonadherent population was gently removed. For use in RT-PCR, the SJL/J T cell-enriched splenocytes cells were then used to generate RNA. The SJL/J-enriched populations were 85% T cells as assessed by FACS analysis (data not shown). For the C57BL/6 T cell-enriched splenocyte populations used in proliferation assays, the cells removed from the rabbit anti-mouse IgG plates were next plated on new, uncoated tissue culture dishes and incubated for 1–2 h at 37°C. The nonadherent population was again gently removed and used in proliferation assays. The C57BL/6-enriched populations were 65% T cells as assessed by FACS analysis (data not shown).
T cell proliferation assays
T cells clones were assayed for Ag-specific proliferation as previously described (29, 30). T cell clones were assayed after they had been rested in the absence of IL-2 for 1 wk.
Assay for IL-2 secretion
In the microtiter assays, the T cell clones (1 x 105 cells per well in 0.2 ml) were plated on anti-CD3 Ab-coated wells without the addition of IL-2 or APCs. The medium used is RPMI 1640 with 10% FCS and 5 x 10-5 M 2-ME. The cell supernatants were harvested after 48 h, contaminating cells were removed by centrifugation, and supernatants were frozen at -70°C until used. In the 24-well assays, the T cell clones were plated at 1 x 106/ml in 24-well plates. The culture supernatants were harvested after 24 h, contaminating cells removed by centrifugation, supernatants were frozen at -70°C until used. The supernatants were assayed using a murine-IL-2-specific ELISA (Endogen, Woburn, MA) as per the manufacturer’s directions. Values represent the mean of duplicate determinations.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
mRNA in T cells
Using RT-PCR, we examined the expression of transcripts for
PPAR in murine T cells. We studied two murine, SJL-derived type 1
helper T cell clones, MM4 and B48. These T cell clones are specific for
myelin basic protein and have been extensively characterized (29, 30). These T cells clones are maintained in vitro using
alternating, weekly cycles of stimulation and rest.
PCR for PPAR 1 was performed using an upstream oligonucleotide
primer located in the 5' untranslated region of murine PPAR 1 cDNA
and a downstream oligonucleotide primer located in the translated
region common to both murine PPAR 1 and 2 cDNA (9).
These primers span a region of PPAR 1 cDNA that is 359 bp in length.
RT-PCR using RNA from L1-adipocytes yielded the 359-bp cDNA product
expected using the PPAR 1 amplimers (Fig. 1
A). RNA derived at different
times in the in vitro propagation cycles from both of the T cell
clones, B48 and MM4, also yielded the expected 359-bp cDNA PCR product
(Fig. 1A). RNA derived from the T cell clones 4 days after
BMBP/APC stimulation yielded the PPAR 1 PCR product. We have found
that irradiated splenocytes used as APCs in our studies are 0% viable
by day 3 in culture (data not shown), and, therefore, the PPAR 1 PCR
product seen is not likely to be a contaminant from
macrophage-derived RNA in the APC population. To further
demonstrate the T cell origin of the PPAR 1 PCR product, we
also stimulated our T cell clones with immobilized anti-CD3 Ab in
the absence of APCs. Such T cell cultures have not had APCs added for
18 days and have gone through numerous passages during this time
period. RNA-derived from B48 and MM4 that had been stimulated 4 days
prior by immobilized anti-CD3 Ab yielded the expected 359-bp PCR
product (Fig. 1A), further confirming the T cell origin of
the PPAR 1 PCR product. Finally, RT-PCR using RNA that was derived
from B48 and MM4 when these T cell clones were in a semirested mode
(i.e., 13 days after being stimulated and 5 days out of IL-2-aided
growth) yielded a strong 359-bp PPAR 1 PCR product (Fig. 1A). However, these T cell clones never actually reach a
"nonactive" phenotype during their rest cycle, and, therefore, the
PPAR 1 PCR product detected is not necessarily reflective of
"resting" T cells.
|
1 (GenBank
accession number U01841; data not shown).
To examine the expression of PPAR in naive T cells, RNA was derived
from T cell-enriched splenocytes from naive SJL mice (85% T cells;
data not shown). RT-PCR using RNA derived from splenic T cell-enriched
populations yielded a 359-bp PPAR 1 PCR product that was much weaker
than those products derived from the T cell clone RNA or L1-adipocyte
RNA (Fig. 1
B). Using the same concentrations of input cDNA
that were used in the PPAR 1 PCR reactions depicted in Fig. 1B, PCR with amplimers for G3PDH yielded products that were
essentially of equal density (Fig. 1C). Although it is not
possible to draw quantitative conclusions from these studies, these
results indicate that PPAR is expressed in freshly isolated splenic
T cells.
As it is generally believed that the expression of PPAR 2 is largely
restricted to adipocytes, we next examined the T cell expression of
PPAR 2. RT-PCR was performed using RNA derived from the T cell
clones B48 and MM4, from T cell-enriched splenocytes from SJL mice, and
from L1-adipocytes. PCR for PPAR 2 was performed using an upstream
oligonucleotide primer located in the 5' region of murine PPAR 2
cDNA that is not shared with PPAR 1 cDNA, and the downstream
oligonucleotide primer was the same as that used for PPAR 1 PCR.
These primers span a region of PPAR 2 cDNA that is 265 bp in length.
The 265-bp PCR product was seen in L1-adipocytes but was not seen in T
cell-enriched SJL splenocytes or in the activated T cell clones B48 and
MM4 (Fig. 1D).
Finally, as controls for the RT-PCR reactions, RNA from anti-CD3
Ab-stimulated MM4 and B48, as well as from BMBP/APC-stimulated MM4, was
used to generate cDNA with or without the use of reverse transcriptase.
These products were then used in PCR reactions with the PPAR 1
amplimers. In addition, PCR was conducted in the absence of cDNA to
control for contamination. As seen in Fig. 1E, all of these
controls revealed no amplified product.
Abs to PPAR bind T cell clones
The Th1 T cell clones MM4 and B48 were stimulated in the
absence of APC with immobilized anti-CD3 Ab and maintained in IL-2
for 5 to 14 days before being assayed. The cells were fixed and
permeabilized and incubated with either no primary Ab, rabbit
anti-OVA IgG (control), or rabbit IgG specific for PPAR (human
and murine). All groups were then washed and incubated with the
secondary Ab, PE-conjugated donkey anti-rabbit IgG. Subsequently,
all groups were washed and examined using fluorescence microscopy.
Neither the secondary Ab alone, nor the control rabbit anti-OVA IgG
showed significant binding to either of the T cell clones (Fig. 2, A and B). In
contrast, rabbit anti-PPAR IgG, but not rabbit anti-OVA IgG,
demonstrated significant binding to both B48 and MM4 (Fig. 2, C–E). Given that these T cell clones
morphologically are composed of 
75% nucleus, the anti-PPAR
Ab labeling was difficult to localize but appeared to bind both in
nuclear and cytoplasmic regions (Fig. 2, C–E).
|
1 PCR product noted above for
SJL-derived, T cell-enriched splenocytes, we found that freshly
isolated C57BL/6-derived, T cell-enriched splenocytes showed only very
low level binding with the rabbit anti-PPAR IgG (data not
shown). 15d-PGJ2 inhibits both Ag-induced and anti-CD3 Ab-induced T cell proliferative responses
To assess the function of PPAR in T cells, we first utilized
the PPAR-ligand, 15d-PGJ2. The T cell clones
MM4 and B48 were assayed in 3-day proliferation assays conducted in the
presence of either 2.5 µM or 5 µM 15d-PGJ2 or
vehicle control. Both B48 and MM4 respond to BMBP presented in the
context of SJL APC (29, 30). In addition to such
Ag-specific stimulation, we also tested the T cell proliferative
responses using immobilized anti-CD3 Ab. This mode of T cell
stimulation is independent of macrophages/APC and was conducted without
the addition of exogenous macrophages/APC.
15d-PGJ2, at 5 µM, inhibited the
BMBP/APC-stimulated responses of B48 and MM4 usually by greater than
90%. The same concentration of 15d-PGJ2 also
inhibited the anti-CD3 Ab-stimulated responses of B48 and MM4 by
greater than 90%. In contrast, 5 µM 15d-PGJ2
did not inhibit the response of either B48 or MM4 when IL-2 was used
alone to stimulate proliferation. At 2.5 µM,
15d-PGJ2 inhibited the BMBP/APC-stimulated
responses of B48 and MM4 by 50–70%. At 2.5 µM,
15d-PGJ2 inhibited the anti-CD3 Ab-stimulated
responses of B48 and MM4 by 60–65%. Again, the IL-2-stimulated
responses of both B48 and MM4 were not inhibited at this concentration
of 15d-PGJ2. Results of a typical experiment are
seen in Table I.
|
To further confirm the function of PPAR in T cells we utilized
another PPAR ligand, the thiazolidinedione reagent ciglitazone. The
T cell clones MM4 and B48 were assayed in a 3-day anti-CD3 Ab and
Ag-stimulated proliferation assay. These assays were conducted in the
presence of 40 µM ciglitazone or vehicle control. This concentration
of ciglitazone was chosen based on previous reports in which 40 µM of
ciglitazone or 40 µM of another thiazolidinedione resulted in PPAR
activation in other cell types (17, 22). In these assays,
the BMBP/APC-stimulated responses of B48 and MM4 were decreased by
80–90% in the presence of ciglitazone. The anti-CD3 Ab-induced
proliferative responses of B48 and MM4 were inhibited by
60–85% in the presence of ciglitazone. Typical responses of the T
cell clones in the presence of ciglitazone are seen in Table II. (We also assayed the proliferative
responses of B48 and MM4 2 days after stimulation with immobilized
anti-CD3 Ab. In the 2-day assay, the proliferative responses of B48
and MM4 were inhibited by 70–80% in the presence of ciglitazone (data
not shown).
|
ligands (e.g., Tables
I and II). This dichotomy of inhibition of proliferation resulting from
TCR-mediated stimulation vs IL-2-induced proliferation is of note for
two reasons. First, it demonstrates that the inhibitory effects noted
were not a result of nonspecific toxic effects of
15d-PGJ2 or ciglitazone at the concentrations
studied. Second, it suggests that PPAR-ligation may affect signaling
pathways that are activated after TCR stimulation but not activated
after IL-2-receptor ligation. 15d-PGJ2 and ciglitazone inhibit the anti-CD3 Ab-stimulated response of C57BL/6 splenocytes
To further characterize the expression of PPAR in freshly
isolated naive T cells, we studied the effect of
15d-PGJ2 and ciglitazone on the 2-day
anti-CD3 Ab-stimulated response of freshly isolated C57BL/6-derived
T cell-enriched splenocytes. 15d-PGJ2 (5 µM)
significantly inhibited the anti-CD3 Ab-stimulated splenocyte
response. 15d-PGJ2 (2.5 µM) also inhibited the
splenic anti-CD3 Ab responses, although the level of the inhibition
was less than that seen with 5 µM 15d-PGJ2.
Ciglitazone at 40 µM also significantly inhibited the splenocyte
anti-CD3 Ab-stimulated response, but, as with the T cell clones,
the inhibition was not as great as that mediated by 5 µM
15d-PGJ2. This greater PPAR agonist activity
of 15d-PGJ2 relative to that of ciglitazone or
another thiazolidinedione, is in agreement with the findings in other
cell types (17, 22). In the present experiments, we also
examined the effect of 20 µM ciglitazone. Ciglitazone (20 µM) only
minimally inhibited the 2-day anti-CD3 Ab-stimulated response of
the C57BL/6 T cell-enriched splenocytes. A typical experiment studying
the functional effects of these PPAR ligands on freshly isolated T
cell-enriched splenocytes is shown in Table III.
|
ligands suggest that freshly isolated splenic T cells express PPAR
and that this PPAR is functionally relevant either in freshly
isolated splenic T cells or soon after T cell stimulation. 15d-PGJ2 and ciglitazone inhibit IL-2 secretion by the T cell clones
Given the finding that TCR-mediated proliferation was inhibited by
the PPAR ligands but that IL-2-induced proliferation of the T cell
clones was not, we postulated that the effects of the PPAR ligands
included the inhibition of the secretion of IL-2. To assess this, we
measured the anti-CD3 Ab-stimulated IL-2 production of B48 and MM4
at two T cell concentrations and at two time points (Table IV). Using a murine IL-2-specific ELISA,
we found that 15d-PGJ2 and ciglitazone both
resulted in a dose-related inhibition of anti-CD3 Ab-stimulated
IL-2 production (Table IV). Thus, the PPAR ligands inhibit the IL-2
secretion of the T cell clones while not inhibiting the IL-2-induced
proliferation of the same T cells.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
1. We have shown, using RT-PCR and
immunofluorescence, that SJL-derived type 1 helper T cell clones
express significant levels of PPAR. Using RT-PCR, we also have found
that freshly isolated T cell-enriched splenocytes from SJL mice express
PPAR 1 mRNA. The PPAR expressed both by the T cell clones and by
freshly isolated C57BL/6 T cell-enriched splenocytes was shown to be of
functional significance. This functional significance was demonstrated
through the use of two PPAR-ligands, 15d-PGJ2
and ciglitazone. In the past few years there have been a number of
studies that make use of the specificity of these ligands for PPAR
(e.g. Refs. 20 and 21). Although there
has been some recent suggestion that 15d-PGJ2 may
have some degree of reactivity with PPAR in addition to its major
effects on PPAR, the thiazolidinedione class of reagents, such as
ciglitazone used in our studies, are specific for PPAR
(32). We have found that 15d-PGJ2
and ciglitazone mediated significant inhibition of the Ag-stimulated
responses of the T cell clones and the anti-CD3 Ab-stimulated
proliferative responses of both the T cell clones and the freshly
isolated T cell-enriched splenocytes. This inhibition was directed at
the level of the T cell, given that T cell stimulation with immobilized
anti-CD3 Ab is a macrophage/APC-independent response, and for the T
cell clones, this inhibition was observed in the absence of
monocytes/macrophages. The inhibition of the responses of the T
cell-enriched splenocytes suggests that PPAR is functionally
relevant in freshly isolated T cells or becomes functionally relevant
early in activation.
Finally, we have demonstrated that the two ligands for PPAR mediated
inhibition of IL-2 secretion by the T cell clones while not inhibiting
IL-2-induced proliferation of such clones. This lack of inhibition of
the IL-2-induced proliferation is of note for two reasons. First, it
demonstrates that the inhibitory effects noted were not a result of
toxic effects of 15d-PGJ2 or ciglitazone at the
concentrations studied. Second, it suggests that PPAR-ligation may
effect signaling pathways that are activated after TCR stimulation but
not activated after IL-2-receptor ligation. Preliminary studies in our
laboratory, which may have in vivo relevance, indicate that the
addition of IL-2 at different times relative to PPAR-ligation may
lead to different outcomes. These preliminary studies indicate that, if
the PPAR ligands are removed and exogenous IL-2 is added 2 days
after, rather than simultaneous with, the addition of the higher
concentrations of 15d-PGJ2 (5 µM) or
ciglitazone (40 µM), the T cells go on to die. This T cell death is
not noted either at the lower concentrations of
15d-PGJ2 (2.5 µM) or ciglitazone (20 µM) or
if exogenous IL-2 is added 1 day, rather than 2 days, after the
addition of 15d-PGJ2 or ciglitazone. In light of
the IL-2 secretion data (Table IV), the T cell death noted in these
preliminary studies is likely to be a result both of the lack of
endogenous production of IL-2 and other, as yet to be identified,
PPAR ligand-induced events.
Previous studies dealing with PPAR expression in the immune system
have been limited. Greene et al. (8) screened a human bone
marrow cDNA library and found that peripheral blood lymphocytes
expressed only a truncated PPAR transcript that the authors believed
could not encode all of the PPAR functional domains. In this regard,
it is of note that we have found our T cell clones to express
full-length PPAR transcripts on Northern blots (data not shown).
Braissant et al. studied PPAR expression in rat tissues using in situ
hybridization and immunohistochemistry (7). These authors
describe the expression of PPAR in the white and red pulp of the rat
spleen as well as in the Peyer’s patches of the rat. Evidence for a
more direct role of PPARs in inflammation was first suggested in
PPAR-knockout mice. PPAR-knockout mice are viable but lack
responses to appropriate ligands (no peroxisome proliferation, no gene
activation, no hepatomegaly), exhibit abnormalities in
triglyceride and cholesterol metabolism, and display a
prolonged response to inflammatory stimuli, as measured by ear swelling
in response to leukotriene B4 and arachadonic
acid (33, 34).
Recently, PPAR was identified in monocyte/macrophages. Ricote et al.
have shown that resting bone marrow-derived murine macrophages express
low levels of PPAR, whereas activated peritoneal macrophages express
high levels of PPAR (22). These authors further showed
that 15d-PGJ2 and synthetic PPAR ligands
inhibited the expression of a number of genes that become up-regulated
during macrophage activation (22). Jiang et al. found that
murine macrophage cytokine synthesis induced by PMA or okadaic acid was
inhibited by prostanoids of the PGJ2 family and
by thiazolidinediones (23). Ricote et al. demonstrated
that PPAR is expressed in macrophage foam cells of human
atherosclerotic lesions and that oxidized low density lipoprotein and
M-CSF, which are known to be present in atherosclerotic lesions,
stimulated PPAR expression in primary macrophages and monocytic
lines (21).
Chinetti et al. demonstrated that PPAR expression is induced upon
differentiation of human monocytes into macrophages and that ligand
activation of PPAR resulted in apoptosis induction of differentiated
macrophages (25). These authors also showed that, in
macrophages, PPAR ligation inhibited the transcriptional activity of
the NF-
B p65/RelA subunit. Finally, Gilroy et al., studying COX-2
inhibitors in a rat model of carrageenin-induced pleural inflammation,
presented evidence for an antiinflammatory role of PGD2 and
15d-PGJ2, further suggesting a possible role for
PPAR in inflammation (28).
Our present demonstration of the expression and function of PPAR in
murine helper T cells significantly expands the immunoregulatory role
for PPAR. It is now clear that PPAR-mediated immunosuppression
can be mediated at the level of both the macrophage and T cell. In
vivo, it may be that PPAR-ligation plays an immunoregulatory role
early in the initiation of T cell immune responses as well as in
inhibiting the recruitment of naive T cells into an ongoing immune
response. However, PPAR-ligation may play less of a role in
down-regulating activated T cells involved in an ongoing immune
response when significant levels of IL-2 are already present in the
inflammatory milieu. In the present report, we have not yet defined the
expression or functional role of PPAR 1 in type 2 helper T cells,
CD8-positive T cells, or T cells, and such studies are now
ongoing in our laboratory. The gene or genes regulated by
PPAR-ligation in T cells is as yet unknown. It is likely of
significance that we have demonstrated an inhibition of T
cell-receptor-mediated proliferative responses but not of IL-2-induced
proliferation in T cells. Studies in our laboratory are now being
initiated to define T cell signaling pathways and patterns of cytokine
secretion that are regulated by PPAR. Furthermore, given the varied
patterns of signaling pathways and cytokine secretion found in
different subsets of T cells, we believe it is likely that
PPAR-ligation will have very pleiomorphic effects in different T
cell subsets.
Our demonstration of the T cell immunosuppressive effects of PPAR
ligation suggests that, as additional natural ligands become known,
they will be found to be involved in normal immunoregulatory processes.
The T cell inhibition by PPAR ligation may have other relevance as
well. For example, it may be the case that certain infectious agents
and tumors, by secreting as yet unidentified PPAR ligands, gain
growth advantages through PPAR-mediated immunosuppression. It may
also be the case that autoimmune diseases involve abnormalities in
aspects of normal PPAR-mediated immunosuppression. The
thiazolidinediones presently are in use for the treatment of patients
with type 2 diabetes, and possible T cell effects of such drugs will
now have to be examined in such patients. Similarly, it should prove
interesting to examine the effects of the newly characterized PPAR
partial agonists/antagonists, such as MCC-555 and GW0072, on T cells
(35, 36). It is possible that such reagents could be
useful in enhancing T cell responses. Alternatively,
thiazolidinediones, as well as agents as yet undiscovered that may be
agonists for PPAR 1, may prove useful as immune suppressors in organ
transplants and in the treatment of autoimmune diseases.
In conclusion, the present studies have demonstrated the expression and
function of PPAR in murine T cells, and in doing so have
significantly increased our understanding of the role and
importance of PPAR in immunoregulation. This mode of
immunoregulation could have significant implications not only in
understanding normal immunologic function but also in understanding and
manipulation of the immune response in disease states.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. Robert B. Clark, Department of Medicine, University of Connecticut Medical School, 263 Farmington Avenue, Farmington, CT 06032. E-mail:
3 Abbreviations used in this paper: PPAR, peroxisome proliferator-activated receptor; 15d-PGJ2, 15-deoxy-12,14-PGJ2; PPRE, PPAR response element; RXR, retinoid X receptor; BMBP, bovine myelin basic protein.
Received for publication August 19, 1999. Accepted for publication November 17, 1999.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
2: tissue-specific regulator of an adipocyte enhancer. Genes Dev. 8:1224. 2, a lipid-activated transcription factor. Cell 79:1147.[Medline]
: adipose-predominant expression and induction early in adipocyte differentiation. Endocrinology 135:798.[Abstract]
, -ß, and - in the adult rat. Endocrinology 137:354.[Abstract]
cDNA: expression in hematopoietic cells and chromosomal mapping. Gene Expr. 4:281.[Medline]
(PPAR) gene: alternative promoter use and different splicing yield two mPPAR isoforms. Proc. Natl. Acad. Sci. USA 92:7921.. J. Biol. Chem. 270:12953.12, 14-prostaglandin J2 a ligand for the adipocyte determination factor PPAR. Cell 83:803.[Medline]
and promotes adipocyte differentiation. Cell 83:813.[Medline]
and are activated by indomethacin and other non-steroidal anti-inflammatory drugs. J. Biol. Chem. 272:3406.. Mol. Cell 1:465.[Medline]
induces cell cycle withdrawal: inhibition of E2/DP DNA-binding activity via down-regulation of PP2A. Genes Dev. 11:1987.. Nat. Med. 4:1046.[Medline]
12,14 prostaglandin J2. J. Biol. Chem. 274:17042. enhance colon polyp formation. Nat. Med. 4:1058.[Medline]
promotes the development of colon tumors in C57BL/6j-APCmin/+ mice. Nat. Med. 4:1053.[Medline]
promotes monocyte/macrophage differentiation and uptake of oxidized LDL. Cell 93:241.[Medline]
in human atherosclerosis and regulation in macrophages by colony stimulating factors and oxidized low density lipoprotein. Proc. Natl. Acad. Sci. USA 95:7614. is a negative regulator of macrophage activation. Nature 391:79.[Medline]
agonists inhibit production of monocyte inflammatory cytokines. Nature 391:82.[Medline]
but not by PPAR activators. Nature 393:790.[Medline]
and induces apoptosis of human monocyte-derived macrophages. J. Biol. Chem. 273:25573.. Cell 93:229.[Medline]
in monocytes: less pain, any gain?. Cell 93:153.[Medline]
-deficient mice. J. Biol. Chem. 272:27307.-leukotriene B4 pathway to inflammation control. Nature 384:39.[Medline]
-activating properties. J. Biol. Chem. 273:32679. ligand inhibits adipocyte differentiation. Proc. Natl. Acad. Sci. USA 96:6102.This article has been cited by other articles:
|
|
 |
|
  J. T. Wang, S. Li, J. L. Li, J. W. Zhang, and S. W. Xu Effects of cold stress on the messenger ribonucleic acid levels of peroxisome proliferator-activated receptor-{gamma} in spleen, thymus, and bursa of Fabricius of chickens Poult. Sci., December 1, 2009; 88(12): 2549 - 2554. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Klotz, S. Burgdorf, I. Dani, K. Saijo, J. Flossdorf, S. Hucke, J. Alferink, N. Novak, M. Beyer, G. Mayer, et al. The nuclear receptor PPAR{gamma} selectively inhibits Th17 differentiation in a T cell-intrinsic fashion and suppresses CNS autoimmunity J. Exp. Med., September 28, 2009; 206(10): 2079 - 2089. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Tanaka, T. Hasegawa, Z. Chen, Y. Okita, and K. Okada Renoprotective immunosuppression by pioglitazone with low-dose cyclosporine in rat heart transplantation J. Thorac. Cardiovasc. Surg., September 1, 2009; 138(3): 744 - 751. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. J. Housley, C. A. O'Conor, F. Nichols, L. Puddington, E. G. Lingenheld, L. Zhu, and R. B. Clark PPAR{gamma} regulates retinoic acid-mediated DC induction of Tregs J. Leukoc. Biol., August 1, 2009; 86(2): 293 - 301. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Jaudszus, M. Krokowski, P. Mockel, Y. Darcan, A. Avagyan, P. Matricardi, G. Jahreis, and E. Hamelmann Cis-9,trans-11-Conjugated Linoleic Acid Inhibits Allergic Sensitization and Airway Inflammation via a PPAR{gamma}-Related Mechanism in Mice J. Nutr., July 1, 2008; 138(7): 1336 - 1342. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Collino, N. S.A. Patel, and C. Thiemermann Review: PPARs as new therapeutic targets for the treatment of cerebral ischemia/reperfusion injury Therapeutic Advances in Cardiovascular Disease, June 1, 2008; 2(3): 179 - 197. [Abstract] [PDF]
|
|
|
|
 |
|
 D. Walcher, K. Hess, P. Heinz, K. Petscher, D. Vasic, U. Kintscher, M. Clemenz, M. Hartge, K. Raps, V. Hombach, et al. Telmisartan Inhibits CD4-Positive Lymphocyte Migration Independent of the Angiotensin Type 1 Receptor via Peroxisome Proliferator-Activated Receptor-{gamma} Hypertension, February 1, 2008; 51(2): 259 - 266. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Behshad, K. D. Cooper, and N. J. Korman A Retrospective Case Series Review of the Peroxisome Proliferator-Activated Receptor Ligand Rosiglitazone in the Treatment of Atopic Dermatitis Arch Dermatol, January 1, 2008; 144(1): 84 - 88. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Fionda, F. Nappi, M. Piccoli, L. Frati, A. Santoni, and M. Cippitelli Inhibition of Trail Gene Expression by Cyclopentenonic Prostaglandin 15-Deoxy-{Delta}12,14-Prostaglandin J2 in T Lymphocytes Mol. Pharmacol., November 1, 2007; 72(5): 1246 - 1257. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. A. Wohlfert, F. C. Nichols, E. Nevius, and R. B. Clark Peroxisome Proliferator-Activated Receptor {gamma} (PPAR{gamma}) and Immunoregulation: Enhancement of Regulatory T Cells through PPAR{gamma}-Dependent and -Independent Mechanisms J. Immunol., April 1, 2007; 178(7): 4129 - 4135. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Hontecillas and J. Bassaganya-Riera Peroxisome Proliferator-Activated Receptor {gamma} Is Required for Regulatory CD4+ T Cell-Mediated Protection against Colitis J. Immunol., March 1, 2007; 178(5): 2940 - 2949. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Klotz, I. Dani, F. Edenhofer, L. Nolden, B. Evert, B. Paul, W. Kolanus, T. Klockgether, P. Knolle, and L. Diehl Peroxisome Proliferator-Activated Receptor {gamma} Control of Dendritic Cell Function Contributes to Development of CD4+ T Cell Anergy J. Immunol., February 15, 2007; 178(4): 2122 - 2131. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Sandig, J. E. Pease, and I. Sabroe Contrary prostaglandins: the opposing roles of PGD2 and its metabolites in leukocyte function J. Leukoc. Biol., February 1, 2007; 81(2): 372 - 382. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. J. Kang, Y.-G. Cinn, S. J. Hwang, S. Won Chae, J.-S. Woo, S. H. Lee, and H.-M. Lee Up-regulation of Peroxisome Proliferator-Activated Receptor {gamma} in Perennial Allergic Rhinitis. Arch Otolaryngol Head Neck Surg, November 1, 2006; 132(11): 1196 - 1200. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-H. Jo, C. Yang, Q. Miao, M. Marzec, M. A. Wasik, P. Lu, and Y. L. Wang Peroxisome Proliferator-Activated Receptor {gamma} Promotes Lymphocyte Survival through Its Actions on Cellular Metabolic Activities J. Immunol., September 15, 2006; 177(6): 3737 - 3745. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. M. Simon, M. C. Arikan, S. Srisuma, S. Bhattacharya, L. W. Tsai, E. P. Ingenito, F. Gonzalez, S. D. Shapiro, and T. J. Mariani Epithelial cell PPAR{gamma} contributes to normal lung maturation FASEB J, July 1, 2006; 20(9): 1507 - 1509. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. E. Rockwell, N. T. Snider, J. T. Thompson, J. P. Vanden Heuvel, and N. E. Kaminski Interleukin-2 Suppression by 2-Arachidonyl Glycerol Is Mediated through Peroxisome Proliferator-Activated Receptor {gamma} Independently of Cannabinoid Receptors 1 and 2 Mol. Pharmacol., July 1, 2006; 70(1): 101 - 111. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Kosuge, G. Haraguchi, N. Koga, Y. Maejima, J.-i. Suzuki, and M. Isobe Pioglitazone Prevents Acute and Chronic Cardiac Allograft Rejection Circulation, June 6, 2006; 113(22): 2613 - 2622. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. G. Trivedi, J. Newson, R. Rajakariar, T. S. Jacques, R. Hannon, Y. Kanaoka, N. Eguchi, P. Colville-Nash, and D. W. Gilroy Essential role for hematopoietic prostaglandin D2 synthase in the control of delayed type hypersensitivity PNAS, March 28, 2006; 103(13): 5179 - 5184. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. August, C. Mueller, V. Weaver, T. A. Polanco, E. R. Walsh, and M. T. Cantorna Nutrients, Nuclear Receptors, Inflammation, Immunity Lipids, PPAR, and Allergic Asthma J. Nutr., March 1, 2006; 136(3): 695 - 699. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Klotz, M. Schmidt, T. Giese, M. Sastre, P. Knolle, T. Klockgether, and M. T. Heneka Proinflammatory Stimulation and Pioglitazone Treatment Regulate Peroxisome Proliferator-Activated Receptor {gamma} Levels in Peripheral Blood Mononuclear Cells from Healthy Controls and Multiple Sclerosis Patients J. Immunol., October 15, 2005; 175(8): 4948 - 4955. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z Yuan, Y Liu, Y Liu, J Zhang, C Kishimoto, Y Wang, A Ma, and Z Liu Cardioprotective effects of peroxisome proliferator activated receptor {gamma} activators on acute myocarditis: anti-inflammatory actions associated with nuclear factor {kappa}B blockade Heart, September 1, 2005; 91(9): 1203 - 1208. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. A. Rodie, A. Young, F. Jordan, N. Sattar, I. A. Greer, and D. J. Freeman Human Placental Peroxisome Proliferator-Activated Receptor {delta} and {gamma} Expression in Healthy Pregnancy and in Preeclampsia and Intrauterine Growth Restriction Reproductive Sciences, July 1, 2005; 12(5): 320 - 329. [Abstract] [PDF]
|
|
|
|
|
|
C. Rousseaux, B. Lefebvre, L. Dubuquoy, P. Lefebvre, O. Romano, J. Auwerx, D. Metzger, W. Wahli, B. Desvergne, G. C. Naccari, et al. Intestinal antiinflammatory effect of 5-aminosalicylic acid is dependent on peroxisome proliferator-activated receptor-{gamma} J. Exp. Med., April 18, 2005; 201(8): 1205 - 1215. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. F. M. Wouters Local and Systemic Inflammation in Chronic Obstructive Pulmonary Disease Proceedings of the ATS, April 1, 2005; 2(1): 26 - 33. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Abdelrahman, A. Sivarajah, and C. Thiemermann Beneficial effects of PPAR-{gamma} ligands in ischemia-reperfusion injury, inflammation and shock Cardiovasc Res, March 1, 2005; 65(4): 772 - 781. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. B. Crosby, J. L. Svenson, J. Zhang, C. J. Nicol, F. J. Gonzalez, and G. S. Gilkeson Peroxisome Proliferation-Activated Receptor (PPAR){gamma} Is Not Necessary for Synthetic PPAR{gamma} Agonist Inhibition of Inducible Nitric-Oxide Synthase and Nitric Oxide J. Pharmacol. Exp. Ther., January 1, 2005; 312(1): 69 - 76. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. J. Schlezinger, G. J. Howard, C. H. Hurst, J. K. Emberley, D. J. Waxman, T. Webster, and D. H. Sherr Environmental and Endogenous Peroxisome Proliferator-Activated Receptor {gamma} Agonists Induce Bone Marrow B Cell Growth Arrest and Apoptosis: Interactions between Mono(2-ethylhexyl)phthalate, 9-cis-Retinoic Acid, and 15-Deoxy-{Delta}12,14-prostaglandin J2 J. Immunol., September 1, 2004; 173(5): 3165 - 3177. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. J. Nicol, M. Yoon, J. M. Ward, M. Yamashita, K. Fukamachi, J. M. Peters, and F. J. Gonzalez PPAR{gamma} influences susceptibility to DMBA-induced mammary, ovarian and skin carcinogenesis Carcinogenesis, September 1, 2004; 25(9): 1747 - 1755. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Walcher, M. Aleksic, V. Jerg, V. Hombach, A. Zieske, S. Homma, J. Strong, and N. Marx C-Peptide Induces Chemotaxis of Human CD4-Positive Cells: Involvement of Pertussis Toxin-Sensitive G-Proteins and Phosphoinositide 3-Kinase Diabetes, July 1, 2004; 53(7): 1664 - 1670. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Cunard, Y. Eto, J. T. Muljadi, C. K. Glass, C. J. Kelly, and M. Ricote Repression of IFN-{gamma} Expression by Peroxisome Proliferator-Activated Receptor {gamma} J. Immunol., June 15, 2004; 172(12): 7530 - 7536. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Alvarez-Maqueda, R. E. Bekay, G. Alba, J. Monteseirin, P. Chacon, A. Vega, J. Martin-Nieto, F. J. Bedoya, E. Pintado, and F. Sobrino 15-Deoxy-{Delta}12,14-prostaglandin J2 Induces Heme Oxygenase-1 Gene Expression in a Reactive Oxygen Species-dependent Manner in Human Lymphocytes J. Biol. Chem., May 21, 2004; 279(21): 21929 - 21937. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Marx, H. Duez, J.-C. Fruchart, and B. Staels Peroxisome Proliferator-Activated Receptors and Atherogenesis: Regulators of Gene Expression in Vascular Cells Circ. Res., May 14, 2004; 94(9): 1168 - 1178. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. van Heeckeren, M. Schluchter, L. Xue, J. Alvarez, S. Freedman, J. St. George, and P. B. Davis Nutritional Effects on Host Response to Lung Infections with Mucoid Pseudomonas aeruginosa in Mice Infect. Immun., March 1, 2004; 72(3): 1479 - 1486. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Schmidt, E. Moric, M. Schmidt, M. Sastre, D. L. Feinstein, and M. T. Heneka Anti-inflammatory and antiproliferative actions of PPAR-{gamma} agonists on T lymphocytes derived from MS patients J. Leukoc. Biol., March 1, 2004; 75(3): 478 - 485. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Hammad, H. J. de Heer, T. Soullie, V. Angeli, F. Trottein, H. C. Hoogsteden, and B. N. Lambrecht Activation of Peroxisome Proliferator-Activated Receptor-{gamma} in Dendritic Cells Inhibits the Development of Eosinophilic Airway Inflammation in a Mouse Model of Asthma Am. J. Pathol., January 1, 2004; 164(1): 263 - 271. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Nencioni, K. Lauber, F. Grunebach, L. Van Parijs, C. Denzlinger, S. Wesselborg, and P. Brossart Cyclopentenone Prostaglandins Induce Lymphocyte Apoptosis by Activating the Mitochondrial Apoptosis Pathway Independent of External Death Receptor Signaling J. Immunol., November 15, 2003; 171(10): 5148 - 5156. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Bassaganya-Riera, R. M. Pogranichniy, S. C. Jobgen, P. G. Halbur, K.-J. Yoon, M. O'Shea, I. Mohede, and R. Hontecillas Conjugated Linoleic Acid Ameliorates Viral Infectivity in a Pig Model of Virally Induced Immunosuppression J. Nutr., October 1, 2003; 133(10): 3204 - 3214. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Yuan, Y. Liu, Y. Liu, J. Zhang, C. Kishimoto, Y. Wang, A. Ma, and Z. Liu Peroxisome proliferation-activated receptor-{gamma} ligands ameliorate experimental autoimmune myocarditis Cardiovasc Res, September 1, 2003; 59(3): 685 - 694. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Woerly, K. Honda, M. Loyens, J.-P. Papin, J. Auwerx, B. Staels, M. Capron, and D. Dombrowicz Peroxisome Proliferator-activated Receptors {alpha} and {gamma} Down-regulate Allergic Inflammation and Eosinophil Activation J. Exp. Med., August 4, 2003; 198(3): 411 - 421. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Zeyda, A. B. Szekeres, M. D. Saemann, R. Geyeregger, H. Stockinger, G. J. Zlabinger, W. Waldhausl, and T. M. Stulnig Suppression of T Cell Signaling by Polyunsaturated Fatty Acids: Selectivity in Inhibition of Mitogen-Activated Protein Kinase and Nuclear Factor Activation J. Immunol., June 15, 2003; 170(12): 6033 - 6039. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Angeli, H. Hammad, B. Staels, M. Capron, B. N. Lambrecht, and F. Trottein Peroxisome Proliferator-Activated Receptor {gamma} Inhibits the Migration of Dendritic Cells: Consequences for the Immune Response J. Immunol., May 15, 2003; 170(10): 5295 - 5301. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Tautenhahn, B. Brune, and A. von Knethen Activation-induced PPAR{gamma} expression sensitizes primary human T cells toward apoptosis J. Leukoc. Biol., May 1, 2003; 73(5): 665 - 672. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Liu, H. Li, S. H. Burstein, R. B. Zurier, and J. D. Chen Activation and Binding of Peroxisome Proliferator-Activated Receptor gamma by Synthetic Cannabinoid Ajulemic Acid Mol. Pharmacol., May 1, 2003; 63(5): 983 - 992. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Cunard, D. DiCampli, D. C. Archer, J. L. Stevenson, M. Ricote, C. K. Glass, and C. J. Kelly WY14,643, a PPAR{alpha} Ligand, Has Profound Effects on Immune Responses In Vivo J. Immunol., December 15, 2002; 169(12): 6806 - 6812. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. J. Schlezinger, B. A. Jensen, K. K. Mann, H.-Y. Ryu, and D. H. Sherr Peroxisome Proliferator-Activated Receptor {gamma}-Mediated NF-{kappa}B Activation and Apoptosis in Pre-B Cells J. Immunol., December 15, 2002; 169(12): 6831 - 6841. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. G. Yu, S. Javorschi, A. L. Hevener, Y. T. Kruszynska, R. A. Norman, M. Sinha, and J. M. Olefsky The Effect of Thiazolidinediones on Plasma Adiponectin Levels in Normal, Obese, and Type 2 Diabetic Subjects Diabetes, October 1, 2002; 51(10): 2968 - 2974. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. L. Wang, K. A. Frauwirth, S. M. Rangwala, M. A. Lazar, and C. B. Thompson Thiazolidinedione Activation of Peroxisome Proliferator-activated Receptor gamma Can Enhance Mitochondrial Potential and Promote Cell Survival J. Biol. Chem., August 23, 2002; 277(35): 31781 - 31788. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Bishop-Bailey, T. Hla, and T. D. Warner Intimal Smooth Muscle Cells as a Target for Peroxisome Proliferator-Activated Receptor-{gamma} Ligand Therapy Circ. Res., August 9, 2002; 91(3): 210 - 217. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Zeyda, G. Staffler, V. Horejsi, W. Waldhausl, and T. M. Stulnig LAT Displacement from Lipid Rafts as a Molecular Mechanism for the Inhibition of T Cell Signaling by Polyunsaturated Fatty Acids J. Biol. Chem., August 2, 2002; 277(32): 28418 - 28423. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Nencioni, F. Grunebach, A. Zobywlaski, C. Denzlinger, W. Brugger, and P. Brossart Dendritic Cell Immunogenicity Is Regulated by Peroxisome Proliferator-Activated Receptor {gamma} J. Immunol., August 1, 2002; 169(3): 1228 - 1235. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Hontecillas, M. J. Wannemeulher, D. R. Zimmerman, D. L. Hutto, J. H. Wilson, D. U. Ahn, and J. Bassaganya-Riera Nutritional Regulation of Porcine Bacterial-Induced Colitis by Conjugated Linoleic Acid J. Nutr., July 1, 2002; 132(7): 2019 - 2027. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Ward, I. Dransfield, J. Murray, S. N. Farrow, C. Haslett, and A. G. Rossi Prostaglandin D2 and Its Metabolites Induce Caspase-Dependent Granulocyte Apoptosis That Is Mediated Via Inhibition of I{kappa}B{alpha} Degradation Using a Peroxisome Proliferator-Activated Receptor-{gamma}-Independent Mechanism J. Immunol., June 15, 2002; 168(12): 6232 - 6243. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Cui, K. Miyoshi, E. Claudio, U. K. Siebenlist, F. J. Gonzalez, J. Flaws, K.-U. Wagner, and L. Hennighausen Loss of the Peroxisome Proliferation-activated Receptor gamma (PPARgamma ) Does Not Affect Mammary Development and Propensity for Tumor Formation but Leads to Reduced Fertility J. Biol. Chem., May 10, 2002; 277(20): 17830 - 17835. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. E. Akiyama, S. Sakai, G. Lambert, C. J. Nicol, K. Matsusue, S. Pimprale, Y.-H. Lee, M. Ricote, C. K. Glass, H. B. Brewer Jr., et al. Conditional Disruption of the Peroxisome Proliferator-Activated Receptor {gamma} Gene in Mice Results in Lowered Expression of ABCA1, ABCG1, and apoE in Macrophages and Reduced Cholesterol Efflux Mol. Cell. Biol., April 15, 2002; 22(8): 2607 - 2619. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Marx, B. Kehrle, K. Kohlhammer, M. Grub, W. Koenig, V. Hombach, P. Libby, and J. Plutzky PPAR Activators as Antiinflammatory Mediators in Human T Lymphocytes: Implications for Atherosclerosis and Transplantation-Associated Arteriosclerosis Circ. Res., April 5, 2002; 90(6): 703 - 710. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Monneret, H. Li, J. Vasilescu, J. Rokach, and W. S. Powell 15-Deoxy-{Delta}12,1412,14-prostaglandins D2 and J2 Are Potent Activators of Human Eosinophils J. Immunol., April 1, 2002; 168(7): 3563 - 3569. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Cunard, M. Ricote, D. DiCampli, D. C. Archer, D. A. Kahn, C. K. Glass, and C. J. Kelly Regulation of Cytokine Expression by Ligands of Peroxisome Proliferator Activated Receptors J. Immunol., March 15, 2002; 168(6): 2795 - 2802. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. B. Clark The role of PPARs in inflammation and immunity J. Leukoc. Biol., March 1, 2002; 71(3): 388 - 400. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Diab, C. Deng, J. D. Smith, R. Z. Hussain, B. Phanavanh, A. E. Lovett-Racke, P. D. Drew, and M. K. Racke Peroxisome Proliferator-Activated Receptor-{gamma} Agonist 15-Deoxy-{Delta}12,1412,14-Prostaglandin J2 Ameliorates Experimental Autoimmune Encephalomyelitis J. Immunol., March 1, 2002; 168(5): 2508 - 2515. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Y. Yang, L. H. Wang, K. Mihalic, W. Xiao, T. Chen, P. Li, L. M. Wahl, and W. L. Farrar Interleukin (IL)-4 Indirectly Suppresses IL-2 Production by Human T Lymphocytes via Peroxisome Proliferator-activated Receptor gamma Activated by Macrophage-derived 12/15-Lipoxygenase Ligands J. Biol. Chem., February 1, 2002; 277(6): 3973 - 3978. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Hirai, K. Tanaka, S. Takano, M. Ichimasa, M. Nakamura, and K. Nagata Cutting Edge: Agonistic Effect of Indomethacin on a Prostaglandin D2 Receptor, CRTH2 J. Immunol., February 1, 2002; 168(3): 981 - 985. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. G. Harris, R. S. Smith, and R. P. Phipps 15-Deoxy-{Delta}12,1412,14-PGJ2 Induces IL-8 Production in Human T Cells by a Mitogen-Activated Protein Kinase Pathway J. Immunol., February 1, 2002; 168(3): 1372 - 1379. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. BENAYOUN, S. LETUVE, A. DRUILHE, J. BOCZKOWSKI, M.-C. DOMBRET, P. MECHIGHEL, J. MEGRET, G. LESECHE, M. AUBIER, and M. PRETOLANI Regulation of Peroxisome Proliferator-activated Receptor gamma Expression in Human Asthmatic Airways . Relationship with Proliferation, Apoptosis, and Airway Remodeling Am. J. Respir. Crit. Care Med., October 15, 2001; 164(8): 1487 - 1494. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. TEGEDER, J. PFEILSCHIFTER, and G. GEISSLINGER Cyclooxygenase-independent actions of cyclooxygenase inhibitors FASEB J, October 1, 2001; 15(12): 2057 - 2072. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J S Sidhu and J C Kaski Peroxisome proliferator activated receptor {gamma}: a potential therapeutic target in the management of ischaemic heart disease Heart, September 1, 2001; 86(3): 255 - 258. [Full Text] [PDF]
|
|
|
|
|
|
J. Bassaganya-Riera, R. Hontecillas, D. R. Zimmerman, and M. J. Wannemuehler Dietary Conjugated Linoleic Acid Modulates Phenotype and Effector Functions of Porcine CD8+ Lymphocytes J. Nutr., September 1, 2001; 131(9): 2370 - 2377. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Hornung, L. L. Waite, E. A. Ricke, F. Bentzien, D. Wallwiener, and R. N. Taylor Nuclear Peroxisome Proliferator-Activated Receptors {{alpha}} and {{gamma}} Have Opposing Effects on Monocyte Chemotaxis in Endometriosis J. Clin. Endocrinol. Metab., July 1, 2001; 86(7): 3108 - 3114. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Zhang, J. M. Wang, W. H. Gong, N. Mukaida, and H. A. Young Differential Regulation of Chemokine Gene Expression by 15-Deoxy-{{Delta}}12,1412,14 Prostaglandin J2 J. Immunol., June 15, 2001; 166(12): 7104 - 7111. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. X. Cheng and T. Kupper A New Rexinoid for Cutaneous T-Cell Lymphoma Arch Dermatol, May 1, 2001; 137(5): 649 - 652. [Full Text] [PDF]
|
|
|
|
|
|
J. Padilla, K. Kaur, H. J. Cao, T. J. Smith, and R. P. Phipps Peroxisome Proliferator Activator Receptor-{gamma} Agonists and 15-Deoxy-{Delta}12,1412,14-PGJ2 Induce Apoptosis in Normal and Malignant B-Lineage Cells J. Immunol., December 15, 2000; 165(12): 6941 - 6948. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. N. Ellis, J. Varani, G. J. Fisher, M. E. Zeigler, H. A. Pershadsingh, S. C. Benson, Y. Chi, and T. W. Kurtz Troglitazone Improves Psoriasis and Normalizes Models of Proliferative Skin Disease: Ligands for Peroxisome Proliferator-Activated Receptor-{gamma} Inhibit Keratinocyte Proliferation Arch Dermatol, May 1, 2000; 136(5): 609 - 616. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I-C. Ho, J. P. Arm, C. O. Bingham III, A. Choi, K. F. Austen, and L. H. Glimcher A Novel Group of Phospholipase A2s Preferentially Expressed in Type 2 Helper T Cells J. Biol. Chem., May 18, 2001; 276(21): 18321 - 18326. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. C. Jones, X. Ding, and R. A. Daynes Nuclear Receptor Peroxisome Proliferator-activated Receptor alpha (PPARalpha ) Is Expressed in Resting Murine Lymphocytes. THE PPARalpha IN T AND B LYMPHOCYTES IS BOTH TRANSACTIVATION AND TRANSREPRESSION COMPETENT J. Biol. Chem., February 22, 2002; 277(9): 6838 - 6845. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Marx, B. Kehrle, K. Kohlhammer, M. Grub, W. Koenig, V. Hombach, P. Libby, and J. Plutzky PPAR Activators as Antiinflammatory Mediators in Human T Lymphocytes: Implications for Atherosclerosis and Transplantation-Associated Arteriosclerosis Circ. Res., April 5, 2002; 90(6): 703 - 710. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
X174 RF DNA/Hae 111 fragments
(
X
m.w. markers). E, RNA derived from the stimulated T cell
clones B48 and MM4 was used to generate cDNA either in the presence or
absence of reverse transcriptase. These products or no cDNA were then
used as templates for PCR with PPAR-