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Ligand, Has Profound Effects on Immune Responses In Vivo1
,,,
* Research Service, Veterans Affairs San Diego Healthcare System,
Biomedical Sciences Graduate Program, and Departments of
Cellular and Molecular Medicine and
Medicine, University of California, San Diego, CA 92161
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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and PPAR
are expressed in different lymphocyte subpopulations.
Recently, we have observed that PPAR ligands elicit augmented IL-4
expression in cultures of mitogen-activated splenocytes. The following
studies were undertaken to characterize the in vivo effects of
WY14,643, a PPAR ligand. Our studies demonstrate that oral
administration of WY14,643 markedly reduces splenocyte number in
immunized and nonimmunized C57BL/6 mice. Mice fed WY14,643 display
impaired IgG responses to myelin oligodendrocyte glycoprotein peptide
35–55 (pMOG35–55), following immunization with
pMOG35–55/CFA. Following in vitro restimulation with
pMOG35–55, splenocytes harvested from WY14,643-fed mice
demonstrate impaired production of IFN-, IL-6, and TNF- despite
similar proliferative responses. We also demonstrate higher expression
of PPAR in B than T cells. Finally, to obtain an understanding of
the cause of splenocyte depletion with fibrate therapy, we studied the
effect of WY14,643 on apoptosis of activated splenocytes. WY14,643 in
vitro induces apoptosis in lymphocytes and this effect appears to occur
in a PPAR-independent manner. Thus WY14,643, a fibrate, is a
profound immunosuppressive agent. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, 
(
and NUC1), and , each with distinct
expression patterns (3). PPAR regulates lipid
homeostasis and is a target of fibrates, which are used clinically for
the treatment of hypertriglyceridemia (4, 5). Fatty acids
and eicosanoids are endogenous ligands for PPAR (6).
Ligands for PPAR include the insulin-sensitizing thiazolidinediones
and 15-deoxy-
(12, 14) PGJ2 (7, 8).
PPAR isoforms are differentially expressed in immune subpopulations.
Recently, we and other investigators have identified PPAR in
lymphocytes. PPAR is more highly expressed in B than T cells
and its expression wanes soon after lymphocyte activation (9, 10). In contrast, PPAR is expressed in both T and B
lymphocytes and its expression increases over several days following T
cell activation (10, 11, 12, 13). As in macrophages, PPAR
expression in lymphocytes is up-regulated by administration of IL-4
(10, 14).
PPARs have been shown to possess anti-inflammatory activities
(15, 16, 17). Moreover, administration of PPAR ligands is
reported to attenuate inflammation in murine models of inflammatory
bowel disease (18), nonobese diabetic mice
(19), rodent models of atherosclerosis
(20, 21, 22) and experimental allergic encephalomyelitis (EAE)
(23, 24). Studies performed in lymphocyte subpopulations
have also confirmed the anti-inflammatory actions of the PPAR
ligands (11, 25).
Recently, we have observed that PPAR ligands elicit augmented IL-4
expression in cultures of mitogen-activated splenocytes
(10). However, this response occurs in a
PPAR-independent manner. The goals of the current study were to
determine whether oral administration of WY14,643, a PPAR ligand,
could alter adaptive immune responses in C57BL/6 mice. These studies
show that in vivo treatment with WY14,643 alters the humoral and
cytokine responses to a defined Ag. WY14,643 feeding also causes
profound decrements in splenocyte number in both immunized and
nonimmunized C57BL/6 mice. We have also investigated a potential
mechanism accounting for the observed decline in splenocyte number. The
final objective of these studies has been to determine whether the
WY14,643-induced decline in splenocyte number occurs in a
PPAR-dependent or -independent manner. In summary, the current work
complements previous in vitro studies of PPAR ligands and
demonstrates in vivo that WY14,643 can exert profound immunosuppressive
effects.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6 and BALB/c mice were obtained from The Jackson
Laboratory (Bar Harbor, ME). The mice were used between 6 and 24 wk of
age. Mice were housed and handled in accordance with Veterans Affairs
and National Institutes of Health guidelines under Institute of Animal
Care and Use Committee approved protocols. Mice were
individually housed when receiving drug or vehicle control in their
food. PPAR wild-type and homozygous knockout (KO) mice on a 129/Sv
background were obtained from breeding pairs established by Dr.
F. J. Gonzalez (Laboratory of Metabolism, National Cancer Institute,
National Institutes of Health, Bethesda, MD).
Reagents
IFA and Mycobacterium tuberculosis were obtained from Difco (Detroit, MI). Myelin oligodendrocyte glycoprotein peptide 35–55 (pMOG35–55) was purchased from Research Genetics (Birmingham, AL). CFA was prepared as 4 mg/ml M. tuberculosis and 3 mg/ml pMOG35–55 emulsified 1:1 with IFA. Pertussis toxin (List Biological Laboratories, Campbell, CA) was prepared as a 4-µg/ml suspension in PBS. A 100-mM stock solution of WY14,643 (ChemSyn Laboratories, Lenexa, KS) dissolved in 100% ethanol was used for in vitro studies and a 27.8-mM (9-mg/ml) stock solution was used for in vivo feeding. Con A (Sigma-Aldrich, St. Louis, MO) was used at concentrations of 5 µg/ml. Gerber brand second foods baby food (113 g/jar) was obtained from a local grocery store.
Feeding, immunization, and assessment of EAE
Mice were immunized with 200 µl of pMOG35–55/CFA emulsion s.c. at the base of the tail. For the EAE studies, mice were simultaneously injected with 50 µl of pertussis toxin (200 ng) i.p. The i.p. pertussis injection was repeated 48 h after the initial injection. Following immunization, the mice were individually housed and fed 25 g/day of Gerber baby food that contained either 2 mg of WY14,643 dissolved in 0.221 ml of ethanol, 0.66 mg of WY14,643 dissolved in 0.221 ml of ethanol, or 0.221 ml of ethanol (control). Mice were graded daily for EAE disease activity as previously described (26).
Proliferation assays
The mouse spleens were harvested, prepared into single-cell suspensions with a metal screen, and washed with RBC lysis buffer (20 mM Tris (pH 7.4), 0.83% NH4Cl). A total of 0.2 x 106 cells/well were plated in 96-well plates in RPMI 1640 (Life Technologies, Grand Island, NY) supplemented with 10% heat-inactivated FCS (Gemini Bio-Products, Calabasas, CA), 5.5 x 10-5 M 2-ME (Life Technologies), 130 U/ml penicillin, 130 µg/ml streptomycin, and 2.5 mM L-glutamine (Omega Scientific, Tarzana, CA). For proliferation studies, cells were treated with or without 50 µg/well of pMOG35–55 at day 0, pulsed at 72 h with 1 µCi/well [3H]thymidine (Amersham, Arlington Heights, IL), and harvested 24 h later. For apoptosis studies, splenocytes harvested from C57BL/6 and 129/Sv wild-type and KO mice were plated in 6-well plates (8 x 106 cells/8 ml), stimulated with Con A, and treated with 250 µM WY14,643 or vehicle control. After 24 and 72 h, cells were harvested, washed in PBS, and treated as described in the next section.
FACS analysis
A total of 2 x 106 cells were initially
treated with Fc Block (anti-CD16/CD32; BD PharMingen, San Diego,
CA), stained with anti-CD3
-FITC, anti-CD45R/B220-PE, or
anti-CD45R/B220-FITC (BD PharMingen) and then fixed in 50%
ethanol. Fluorescence was measured with an Elite Flow cytometer (Becton
Coulter, Mountain View, CA and Veterans Affairs San Diego Healthcare
System Research Core FACS Facility, San Diego, CA). Cell cycle
analysis was performed using propidium iodide (PI; BD Phar-Mingen).
Complementary apoptosis studies were performed with the annexin V-FITC
Apoptosis Detection kit (BD PharMingen). Annexin V binds to
phosphatidylserine, which is expressed on the outer plasma membrane of
cells undergoing apoptosis. Annexin V can also bind to necrotic cells,
and PI is used to detect dead cells which have undergone either
necrosis or apoptosis. Therefore, cells staining annexin
V+, PI- were considered to be apoptotic,
whereas annexin V+, PI+ cells were considered
dead (27, 28).
Cytokine ELISAs
Culture supernatant concentrations of IFN-, IL-6, TNF-,
IL-4, and IL-2 were determined by sandwich ELISA with Abs purchased
from BD PharMingen. Cytokine concentrations were determined from
culture supernatants following 96 h of activation with
pMOG35–55 except for IL-2 which was determined from 24-h
cultures. Ab dilutions that maximized signal to noise were determined
for each Ab pair and ELISAs were performed as previously described
(29).
Serum pMOG35–55 specific Ab titer determination
Serum was collected from mice by terminal cardiac puncture. Briefly, 96-well Maxisorp microtiter plates were coated with pMOG35–55 (10 µg/ml in PBS) overnight at 4°C. Plates were blocked for 1 h with PBS containing 4% BSA (Sigma-Aldrich) and 0.05% Tween 20 (Sigma-Aldrich) and then incubated with serum samples for 2.5 h at 37°C. Plates were developed with anti-IgG (Calbiochem, San Diego, CA), anti-IgG1 (Caltag Laboratories, Burlingame, CA), or anti-IgG2a (BD PharMingen) alkaline phosphatase conjugates at 37°C for 2.5 h. Plates were incubated with p-nitrophenylphosphate disodium (1 mg/ml in 1 M carbonate buffer pH = 9.6; Sigma-Aldrich) at room temperature. Samples were evaluated in a microplate reader (Molecular Devices, Sunnyvale, CA) at 405 nm.
TaqMan PCR
Splenocytes isolated from BALB/c mice were stimulated with Con A
and harvested at 24 h and 72 h after stimulation. For T and B
cell separations, splenocytes were stained with anti-CD3-FITC (T
cell marker) and anti-CD45R/B220-PE (B cell marker) and separated
by MOFLO (Cytomation, Fort Collins, CO and Veterans Affairs San Diego
Healthcare System Research Core FACS Facility). RNA was prepared with
the Qiagen RNeasy kit (Qiagen, Valencia, CA) and treated with
Dexoxyribonuclease I (Invitrogen, Carlsbad, CA). cDNA was prepared with
the Superscript II Preamplification system (Invitrogen) according to
the manufacturer’s instructions. TaqMan PCRs were run by the Center
for AIDS Research Genomics Core (University of California, San
Diego, Veterans Medical Research Foundation) using an ABO Prism 7700
Sequence Detector (TaqMan; Applied Biosystems, Foster City, CA).
GAPDH cDNA was used as an internal standard. Primers for
PPAR were: PPAR-1293F, GGA CCT TCG GCA GCT GGT;
mPPAR-1358R, TCG GAC TCG GTC TTC TTG ATG; and
mPPAR-1313T (probe), CGG AGC ATG CGC AGC TCG TAC A.
Statistics
Differences were statistically analyzed using the Student’s t test, one- and two-way ANOVAs with post-hoc Tukey tests for pairwise comparisons. Analysis was accomplished with Statview version 5.0.1 (SAS Institute, Cary, NC).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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WY14,643 causes splenocyte depletion and impaired Ig and cytokine responses to pMOG35–55
Gross inspection of the peritoneal cavity at the time of sacrifice
revealed that the spleens from WY14,643-treated animals were markedly
smaller than spleens from vehicle-fed mice. There was a dose-dependent
diminution in splenocyte number in WY14,643-treated animals compared to
the immunized, vehicle-fed cohort (Fig. 1
). Fig. 2 depicts the mean
[3H]TdR uptake in response to
pMOG35–55 in splenocytes
from the three experimental groups. Splenocytes from animals fed 2
mg/day of WY14,643 had lower [3H]TdR uptake than those
fed 0.66 mg/day or vehicle, but these differences did not attain
statistical significance. Thus, WY14,643 in a dose-dependent manner
elicits a decrease in splenocyte number in immunized mice, but it does
not markedly alter the proliferation of these cells in a recall
response to pMOG35–55.
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, IL-6, and TNF-
produced in response to MOG35–55 (Fig. 3). The concentrations of IL-2 and IL-4
assayed were low in all of the groups and not detectably different.
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).
pMOG35–55-specific IgG1 and total IgG were
suppressed in sera from animals exposed to WY14,643 when compared to
vehicle-treated animals.
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In vivo administration of WY14,643 results in diminished spleen size and marked loss of lymphocytes.
The next set of studies were designed to determine whether the
WY14,643-induced decline in splenocyte number also occurred in
nonimmunized mice. Cohorts of C57BL/6 mice were housed singly and fed
either vehicle, 0.66, or 2 mg/day of WY14,643 for 6 or 10 days. Again,
gross inspection of the peritoneal cavity revealed that the spleens
from WY14,643-treated animals were markedly smaller than spleens from
vehicle-fed mice. Both spleen weights and splenocyte counts in the
WY14,643-treated groups were depressed (Table I). Flow cytometry of splenocytes stained
with anti-CD45R/B220 and anti-CD3 demonstrated that both T
and B cells were markedly diminished following 6 days of in vivo
treatment.
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In the next set of experiments depicted in Fig. 5, six treatment groups were assessed.
Animals were treated with 2 mg/day of
WY14,643 or vehicle control for 8 days. Mice were then euthanized on
days 8, 18, and 29 to assess whether the decrements in splenocyte
number were reversible. On day 8, there was a >60% decline in
splenocyte number in the WY14,643-treated animals when compared to the
vehicle controls. On days 18 and 29, the splenocyte number had
increased. Of note, the ethanol-treated group also had a decline in
lymphocyte number that increased on day 18. This effect of ethanol has
been previously reported (30). FACs analysis confirmed
that there were decreases in both the CD4+ and
CD45R/B220+ populations. Each cell population increased
after treatment was stopped such that the normal percentages were again
present in the spleen. We attempted to determine whether this effect of
WY14,643 required PPAR, by comparing the effects of feeding WY14,643
to PPAR KO mice on the 129/Sv background and their wild-type
littermates. Interestingly, WY14,643 did not elicit splenocyte
depletion in the wild-type control mice. Therefore, we were unable to
determine whether PPAR is required for this effect. This result
implies that the effect of WY14,643 on splenocyte number is dependent,
at least in part, on genetic background.
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is preferentially expressed in splenocyte B cells
Our early studies revealed that PPAR is expressed in
splenocytes early in the course of Con A-induced activation. TaqMan PCR
studies performed on Con A-activated splenocytes confirm these findings
and demonstrate that PPAR is more highly expressed in B than T cells
(Fig. 6).
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Cell cycle studies were performed on activated splenocytes
isolated from C57BL/6 mice exposed in vitro to 250 µM WY14,643 or
vehicle for 72 h. After the cells were harvested they were stained
with anti-CD4-FITC, anti-CD45R/B220-FITC, and PI and analyzed
by flow cytometry. In Fig. 7, A and B, vehicle- and WY14,643-treated
splenocytes (respectively) were stained with PI and cell cycle analysis
was performed. The population of apoptotic cells is represented by the
sub-G1 peak of the cell cycle. In the vehicle-treated
group, 8.7% of the total cells were apoptotic. Treatment with WY14,643
increased the number of apoptotic cells to 32.9%. There were similar
increases in apoptosis in both B and T cells (data not shown).
Complementary studies using annexin V show a 2-fold increment in the
number of apoptotic cells. A total of 12% of the cells in the
vehicle-treated group were annexin+/PI-
compared with 24.4% of annexin+/PI-
cells in the WY14,643-treated group (Fig. 7, C and
D). It is possible that this effect on apoptosis may be a
mechanism leading to splenocyte depletion. However, further studies
will be performed to study this hypothesis.
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-dependent or -independent manner, splenocytes
from PPAR wild-type and KO mice were stimulated with Con A and
treated with 250 µM WY14,643 or vehicle. Fig. 8 depicts the WY14,643-induced increase
in apoptosis in both the wild-type and PPAR KO mice. These data
suggest that WY14,643 causes apoptosis independent of the expression of
PPAR.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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ligands
induce expression of IL-4 (10). The current studies have
focused on the in vivo effects of this agent. Notably, feeding of
WY14,643 causes profound lymphocyte depletion in animals immunized with
pMOG35–55/CFA. Moreover, the immune responses induced to
pMOG35–55/CFA are markedly depressed. Total IgG and
IgG1 are reduced and the production of IFN-, IL-6, and
TNF- are depressed in a dose-dependent manner in WY14,643-fed
animals. This occurs in the absence of an alteration in the recall
proliferative response to Ag. Similar to the effect in immunized
animals, feeding of WY14,643 to naive C57BL/6 mice leads to massive
lymphocyte depletion in the spleen. After 6–10 days of therapy,
dramatic depletion is seen in both the CD4+ T cell
compartment as well as the CD45R/B220+ B cell compartment,
and this is reversible after the agent is stopped. The current TaqMan
PCR studies demonstrate that PPAR is more highly expressed in B than
T cells. Interestingly, in vitro treatment of splenocytes with WY14,643
induces apoptosis of both B and T cell populations. These effects
appear to occur in a PPAR-independent manner.
Fibrates, PPAR ligands, are anti-inflammatory. PPAR is
important in controlling the duration of inflammation induced by
leukotriene B4 and arachidonic acid, and PPAR KO
mice demonstrate a prolonged response to inflammatory stimuli
(17). Studies by Daynes and colleagues (31)
have shown that in vivo administration of PPAR ligands to aged mice
diminishes their augmented NF-
B levels. Fibrates may also
inhibit NF-B DNA binding activity by augmenting the expression of
IB (32). In addition, in vivo administration of
WY14,643 to aged mice corrects the dysregulation of IFN- and splenic
inducible NO synthase, as well as the elevated splenocyte levels of
IL-6 and IL-12 (31, 33).
In the current study, the declines in IL-6, TNF-, and IFN-
depicted in Fig. 3
are likely multifactorial. Promoter studies have
shown that fibrates repress both c-Jun and p65-induced transcription of
the IL-6 promoter (34). Similarly, Combs et al.
(35) have shown in THP-1 monocytes that PPAR agonists
inhibit the -amyloid-stimulated expression of TNF- and IL-6. Our
previous studies have shown in vitro that the decrease in IFN-
induced by WY14,643 is secondary to increases in IL-4
(10). Furthermore, preliminary studies with IFN-
promoter constructs do not show a direct effect of WY14,643 on this
promoter (R. Cunard and M. Ricote, unpublished observations).
In the current studies, we expected to see higher levels of IL-4 in the WY14,643-treated animals. However, the current experiments were performed in C57BL/6 mice which in induced immune responses produce much lower levels of IL-4 than BALB/c mice (10). It is possible that the levels of IL-4 were higher in the treatment groups and that our studies lacked the sensitivity to detect these differences.
Atherosclerosis is currently characterized as an inflammatory disorder
associated with the recruitment of lymphocytes and macrophage/monocytes
(36). For >30 years, fibrates have been effective
therapeutic agents, but it is increasingly evident that effects
distinct from their lipid lowering capacity may contribute to their
efficacy (reviewed in Ref. 37). In hyperlipidemic
patients, fenofibrate treatment was associated with a decline in
TNF- and IFN- levels (38). In a similar manner,
whole-blood aliquots isolated ex vivo from hyperlipidemic patients
produced higher concentrations of TNF- and IL-6 in response to LPS.
Treatment of these patients with bezafibrate reduced the ability of
their activated PBMCs to produce these cytokines (39).
Our findings parallel those of Yang and colleagues (40, 41) who demonstrated splenic and thymic atrophy in C57BL/6 mice fed perfluorooctanoic acid, a peroxisome proliferator agent. Moreover, they recently reported a similar suppression of Ag-specific serum IgG and IgM in mice immunized with horse RBCs (42). Their studies demonstrate a diminished proliferative response to Con A and LPS, which contrasts with our findings of an intact recall proliferative response. This may be due to the nonspecific nature of their stimuli vs the specific recall agent used in our studies.
Enioutina et al. (43) have shown enhancement of mucosal
and systemic humoral responses in aged animals fed WY14,643. They
hypothesize that this PPAR ligand ameliorates dysregulated cytokine
production, which favors the normal production of protective Abs. Their
studies show enhanced humoral immunity with WY14,643 feeding which
contrasts with our findings of reduced Ab production. This discrepancy
could be explained by the differences in the type of immune responses
studied, protective vs disease induction. Also, we used higher
concentrations of WY14,643 in our studies which could have caused a
more pronounced effect on B cells. Further supporting our findings,
perfluorodecanoic acid, another PPAR ligand, significantly decreases
keyhole limpet hemocyanin-specific IgG2a production
(44).
The observation that PPAR is more highly expressed in B than T cells
parallels the findings of Jones et al. (9); however, their
studies support the concept that PPAR expression wanes soon after
lymphocyte activation. To investigate the mechanism contributing to
splenocyte depletion, we treated splenocytes with WY14,643. In vitro
administration of WY14,643 induces apoptosis in both B and T cells.
Investigators have shown that PPAR and PPAR ligands induce
apoptosis in macrophages (45). However, Harris et al.
(13) were only able to demonstrate apoptosis in T cells
treated with PPAR ligands. It is possible that they did not use a
high enough concentration of PPAR ligands in their studies.
Given the evidence of apoptosis in T cells, which presumably don’t
express high levels of PPAR, we chose to examine whether the
apoptotic effect occurred in a PPAR-dependent or -independent
manner. Splenocytes from PPAR KO mice and wild-type littermates were
treated in vitro with WY14,643. Both the wild-type and KO mice
demonstrated a higher percentage of apoptotic cells when treated with
WY14,643. It is clear from our studies that this effect on cell cycle
occurs in a PPAR-independent manner. Although we only see a 2- to
3-fold increase in the number of apoptotic cells with WY14,643
treatment, it is important to consider that our studies only examined
single time points. It is possible that prolonged therapy with this
agent elicits an additive effect which could account for the observed
profound splenocyte depletion. It is also likely that other mechanisms
may also contribute to splenocyte depletion.
These observations are significant as patients on fibrates may not elicit appropriate immunologic responses to life-saving vaccines such as Streptococcus pneumoniae. It is also possible, given their potent effect on humoral immunity, that they may prove efficacious in treating Ab-mediated autoimmune diseases such as systemic lupus erythematosus and autoimmune glomerular basement membrane disease. Our initial interest was to examine the effects of fibrates on EAE. Induction of EAE with pMOG35–55/CFA requires i.p. administration of pertussis toxin. We consistently observed that the combination of pertussis toxin, immunization, and WY14,643 treatment caused mortality 5–10 days following immunization. Therefore, we are currently investigating the effect of fibrates in other models of autoimmune disease that do not require the use of pertussis toxin.
Fibrates are used extensively to treat hypertriglyceridemia. Given the profound effect of WY14,643, a fibrate, on induced immune responses, it will be of utmost importance to further characterize the immunomodulatory effects of these agents.
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Acknowledgments |
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KO mice. |
Footnotes |
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2 D.D. was a first author on this manuscript.
3 Address correspondence and reprint requests to Dr. Robyn Cunard, Research and Medicine Services, Division of Nephrology-Hypertension, University of California, San Diego and Veterans Affairs San Diego Healthcare System 151, 3350 La Jolla Village Drive, San Diego, CA 92161. E-mail address: rcunard{at}ucsd.edu
4 Abbreviations used in this paper: PPAR, peroxisome proliferator-activated receptor; EAE, experimental allergic encephalomyelitis; pMOG35–55, myelin oligodendrocyte glycoprotein peptide 35-55; PI, propidium iodide; KO, knockout.
Received for publication June 24, 2002. Accepted for publication October 7, 2002.
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 M. Liu, C.-C. Chien, M. Burne-Taney, R. R. Molls, L. C. Racusen, R. B. Colvin, and H. Rabb A Pathophysiologic Role for T Lymphocytes in Murine Acute Cisplatin Nephrotoxicity J. Am. Soc. Nephrol., March 1, 2006; 17(3): 765 - 774. [Abstract] [Full Text] [PDF]
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A. E. Lovett-Racke, R. Z. Hussain, S. Northrop, J. Choy, A. Rocchini, L. Matthes, J. A. Chavis, A. Diab, P. D. Drew, and M. K. Racke Peroxisome Proliferator-Activated Receptor {alpha} Agonists as Therapy for Autoimmune Disease J. Immunol., May 1, 2004; 172(9): 5790 - 5798. [Abstract] [Full Text] [PDF]
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 S. Srinivasan, M. E. Hatley, K. B. Reilly, E. C. Danziger, and C. C. Hedrick Modulation of PPAR{alpha} Expression and Inflammatory Interleukin-6 Production by Chronic Glucose Increases Monocyte/Endothelial Adhesion Arterioscler Thromb Vasc Biol, May 1, 2004; 24(5): 851 - 857. [Abstract] [Full Text]
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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]
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D. C. Jones, X. Ding, T. Y. Zhang, and R. A. Daynes Peroxisome Proliferator-Activated Receptor {alpha} Negatively Regulates T-bet Transcription Through Suppression of p38 Mitogen-Activated Protein Kinase Activation J. Immunol., July 1, 2003; 171(1): 196 - 203. [Abstract] [Full Text] [PDF]
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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]
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