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Interactions Between Fatty Acids and Arginine Metabolism: Implications for the Design of Immune-Enhancing Diets
Vishal Bansal, MD,
Kimberly M. Syres, MD,
Valeryia Makarenkova, MD, PhD,
Ryan Brannon, BS,
Benjamin Matta, BS,
Brian G. Harbrecht, MD and
Juan B. Ochoa, MD
From the Department of Surgery, University of Pittsburgh Medical Center,
Pittsburgh, Pennsylvania
Correspondence: Juan B. Ochoa, MD, FACS, F1265 PUH-UPMC, 200 Lothrop St.,
Pittsburgh, PA 15213. Electronic mail may be sent to
ochoajb{at}upmc.edu.
Background: Trauma increases the enzyme arginase, thus depleting
arginine necessary for producing nitric oxide. Arginine and  -3 fatty
acids are components in immune-enhancing diets. These diets decrease
infections in surgical patients, perhaps by preventing arginine deficiency.
This study examines whether -3 fatty acids alter the metabolic fate of
arginine. Thus, we hypothesized there could be differential effects of varying
prostaglandins on regulation of arginase. Methods: Prostaglandins
PGE1, PGE2, and PGE3 were tested using RAW 264.7 cells cultured in the
presence of these prostaglandins for 24 hours. IL-13 (10 ng/mL) was added 24
hours later to induce arginase I. NO production was induced by adding LPS (2
µg/mL) to the cultures after another 24 hours. Results: Arginase
activity (nmol/min/mg) was induced by all prostaglandins but significantly
more by PGE1 (466.05 ± 30.25) and PGE2 (248.45 ± 15.05) than
PGE3 (139.87 ± 19.88; p < .002) when co-cultured with
IL-13. Western blots correlated the increase in arginase I expression. Nitrate
levels (µM) were inversely proportional to activity with PGE3 having the
highest production (3.89 ± 0.19) and PGE2 and PGE1 with the lowest
(2.75 ± 0.49 and 1.54 ± 0.19, respectively). Inhibition of
arginase I using nor-hydroxyarginine increased and equalized nitrate levels.
Conclusions: Different prostaglandins significantly alter the
metabolism of arginine. Prostaglandins from -6 fatty acids increases
arginase I expression. By decreasing arginase I expression, prostaglandins
from -3 fatty acids may increase available arginine. The specific
combinations of dietary fatty acids and arginine should be considered when
tailoring dietary regimens.
Trauma and surgical patients are known to have an impaired immune response,
including suppression the of T-cell proliferation and
function.1–4
In recent years, increasing evidence has shown that the use of
immune-enhancing diets (IEDs) has led to reduced infection rates and
postoperative morbidity in surgical and trauma
patients.5,6
Though the exact mechanism is unclear, IEDs seem to exert their benefits by
restoring depressed T-cell proliferation, which increases the production of
nitric oxide and modulates the production of certain inflammatory
cytokines.7
Varying IED regimens are similar in that they contain high concentrations
of arginine and -3 fatty acids. To date, we have assumed that -3
fatty acids and arginine would exert "beneficial" immune effects
independent of each
other.8,9
In this paper, we forward the hypothesis that -3 fatty acids may play a
synergistic role in overcoming impaired immune function after surgery or
trauma.
We have previously demonstrated that trauma is associated with increased
arginase I expression in myeloid cells, both in humans and in
mice.10 Arginase I
expressed in myeloid cells is able to deplete arginine and by this mechanism
play an immunoregulatory role, depressing T-cell function and the production
of nitric oxide.11
Thus, not surprisingly, elevated expression of arginase I and the consequent
decrease in arginine correlate with T-cell dysfunction and decreased nitric
oxide production in
vivo.12
-3 Fatty acids, namely, eicosapentaenoic and docosahexaenoic acids
(fish oils), metabolically yield series PGE3 prostaglandins, whereas the use
of -6 linoleic acid (corn oil) preferentially leads to the formation of
PGE2 upon induction of cyclo-oxygenase 2 (COX 2) by traumatic stimuli. Borage
oil (also an -6 fatty acid) leads to the production of PGE1. All of
these fatty acids are being used in different diets clinically with the
intention to improve immune
dysfunction.13–15
However, the use of -3 fatty acids and arginine has gained the greatest
attention.
Arginase I expression is up-regulated by prostaglandin E2 and by T helper 2
cytokines such as interleukin
13.16 Thus, it
would be possible that supplementation with -6 fatty acids such as corn
oil after surgery or trauma could profoundly affect the metabolism of arginine
by leading to the up-regulation of arginase I and the depletion of arginine.
Conversely, we hypothesized that -3 fatty acids would protect arginine
by attenuating the up-regulation of arginase. This paper demonstrates the
"proof of concept" that the supplementation of arginine and
-3 fatty acids may exert biologic functions through interactions with
each other. RAW 264.7 cells cultured with PGE1 and PGE2 (-6 fatty
acids) up-regulate arginase I expression significantly and synergize with
IL-13 to even further induce arginase I expression. PGE3 causes only a slight
induction in arginase I, even in the presence of IL-13. Conversely, RAW 264.7
cells cultured with PGE3 exhibit the highest production of nitric oxide in
response to endotoxin when compared with PGE1 or PGE2. Production of nitric
oxide is increased in all cells when the arginase inhibitor arginase inhibitor
N--hydroxy-nor-L-arginine (norNOHA) is added to cultures demonstrating
the regulatory effect of arginase I on nitric oxide production.
The data presented in this paper demonstrate that there may be significant
metabolic interactions when giving 2 nutrients together, in this case
-3 fatty acids and arginine. Such is the case in IEDs. This paper
raises the hypothesis that -3 fatty acids help prevent arginine
deficiency after trauma by modulating arginase I expression.
 |
MATERIALS AND METHODS
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Reagents
PGE1 and PGE2 were purchased from Sigma-Aldrich (St. Louis, MO). PGE3 was
obtained from Cayman Chemical (Ann Arbor, MI). PGE1 and PGE2 were
reconstituted with 200-proof ethanol (ETOH). The solvent for PGE3 was changed
from methylacetate to 200-proof ETOH by evaporating the methyl acetate with
nitrogen gas and reconstituting the solute with 200-proof ETOH. The percent of
ETOH in cell culture media never exceeded 0.036%. IL-13 was purchased from
R&D Systems (Minneapolis, MN). LPS was obtained from Sigma-Aldrich.
N--hydroxy-nor-L-arginine (norNOHA) was purchased
from Bachem (Torrance, CA). KT5720 was purchased from EMD Biosciences, Inc
(San Diego, CA).
Cell Culture and Treatments
RAW 264.7 cells were obtained and were maintained in complete RPMI 1640
(C-RPMI), which contains 1140 mmol/L L-Arg (BioWhitaker
Walkersville, MD) and supplemented with 10% fetal calf serum, 25 mmol/L HEPES,
4 mmol/L L-glutamine, and 100 units/mL penicillin/streptomycin. The
cells were grown to approximately 80% confluence on polystyrene 6-well plates
in C-RPMI unless otherwise specified. All experiments were done in
triplicate.
Arginase Assay
Arginase activity was measured as arginine conversion to ornithine using a
modification of the Konarska and
Tomaszewski17
assay. Cells were harvested using a cell scraper and lysed with lysis buffer
containing 0.5% Triton solution with Trypsis-Chymotrypsin Inhibitor
(Sigma-Aldrich), Leupeptin (Boehringer Ingelheim GmbH, Germany), Aprotonin
(Boehringer), and PMSF (Roche Daignostics Corp, Chicago, IL). After lysis, 25
µL of MnCl2 was added to 25 µL of sample. Incubation at
55°C for 20 minutes was followed by 150 µL of carbonate buffer to each
sample. Using a timer, L-arginine was then added and incubated at
37°C for exactly 10 minutes. The reaction was stopped with 750 mL of
glacial acetic acid, 250 mL of ninhydrin solution was added, and the samples
were boiled for 1 hour. Ornithine production was measured by spectrophotometry
(Molecular Devices, Sunnyvale, CA) using a wavelength of 515 nm. Protein
concentration was measured using the procedure described by
Bradford18 with
reagents from Bio-Rad Laboratories, Hercules, CA. Results of all experiments
are the mean values ± SD of triplicate cultures.
Nitrite Production
To examine the activity of iNOS, the amount of NO was estimated as nitrite
accumulation in the conditioned medium by means of the Griess assay. Culture
supernatant (100 µL) was mixed with 100 µL of 1% sulfanilamide, 0.1%
naphtylenediamine dihydrochloride and 2.5% H3PO4.
Absorbance was measured at 550 nm in an ELISA reader. Nitrite concentration
was quantitated by reference to NaNO2 standards. Results of all
experiments are the mean values ± SD of triplicate cultures.
Arginase I Western Blot
Lysates used for the Western blot were the same as those used for the
arginase assay. The samples were boiled in sodium dodecylsulfate (SDS) buffer
for 7 minutes before they were loaded in s 20% SDS stacking gel. They were
subsequently separated in a 12.5% SDS polyacrylamide resolving gel for 1 hour
at 200 mV using Invitrogen/Novex Tris-glycine SDS running buffer in a XcellII
MiniCell electrophoresis system (Carlsbad, CA). After separation, protein was
transferred to a nitrocellulose membrane (Invitrogen) with Tris-glycine SDS
transfer buffer for 1.5 hours at 250 mAmp. The membranes were blocked in 5%
milk for 1 hour before arginase I primary antibody (mouse IgG1) was added at a
dilution of 1:50,000 and the membranes incubated overnight at 4°C. After
washing with Tween-TBS solution 5 times, secondary antibody (polyclonal
antimouse IgG coupled to horseradish peroxidase) was added at a dilution of
1:5000 (BD PharMingen, San Diego, CA) for 1 hour at room temperature. After
two 10-minute washes and one 2-hour wash with Tween-TBS, the membranes were
developed with the Super-Signal (Pierce, Rockford, IL) chemiluminescence
kit.
Cyclic AMP Assay
A commercial immunoassay was used to measure cAMP accumulation in RAW 264.7
(R & D Systems). Briefly, RAW 264.7 cells were pretreated with 0.5 mmol/L
3-isobutyl-1-methylxanthine (Sigma-Aldrich) to inhibit cAMP destruction by
phosphodiesterases. RAW 264.7 cells were then placed in culture for 15 minutes
in the presence of 10 µmol/L PGE1, PGE2, or PGE3. After that, cells were
harvested, lysed with 0.1 M HCl and cAMP measured after the instructions of
the immunoassay kit.
Statistical Analysis
Results are represented as means ± SD. Data analysis was performed
by one-way ANOVA. Differences were considered statistically significant when
the value was <0.05. All experiments were repeated 3 times.
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RESULTS
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PGE1, 2, and 3 Differentially Up-Regulate Arginase Activity and Synergize With IL-13 to Up-Regulate Arginase I Expression
Induction of arginase activity with Prostaglandin E2 has been previously
been reported by others. The effect of other prostaglandins (ie, PGE1 and
PGE3) has not been studied. To determine if all prostaglandins induced
arginase activity, RAW 264.7 cells were cultured in the presence of increasing
concentrations of PGE1, PGE2 or PGE 3 (0–10 µmol/L) for 24 hours.
Cells were then harvested, and arginase activity was measured. Induction of
arginase activity was observed with all 3 prostaglandins at all
concentrations. However, there was a significant difference between the
activity induced by the different prostaglandins, with PGE1 inducing the
greatest activity (44.7 ± 6.58), whereas PGE3 induced arginase activity
poorly (15.71 ± 1.68; Fig.
1).
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FIG. 1. RAW macrophages exhibit an increase in arginase activity (nmol/min/mg) when
cultured with PGE1 (44.7 ± 6.58) when compared with PGE2 (18.74
± 2.40) and PGE3 (15.71 ± 1.68) (p < .002).
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To determine whether prostaglandins synergized with T helper 2 cytokines
for the induction of arginase I expression and activity, we added IL-13 (10
ng/mL) to RAW cells cultured in the presence of the different prostaglandins.
Arginase activity was induced by IL-13 alone (31.36 ± 6.9 nmol/min/mg;
p < .05 compared with control cells). Arginase activity for PGE1,
PGE2 and PGE3 (all at 10 µmol/L) with IL-13 dramatically increased 466.05
(± 30.25), 248.45 (± 15.05) to 139.87 (± 19.88)
respectively (p < .002) (Fig.
2a). Again, the best induction of arginase activity was
observed with PGE1, whereas the effect of PGE3 was modest compared with the
other prostaglandins. Figure
2b shows the results of the Western blot for arginase I
protein expression. The results from the Western blot correlate with results
from the arginase activity assay.
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FIG. 2. a, Arginase activity was induced by IL-13 alone (31.36± 6.9
nmol/min/mg) (p < .05 compared with control cells). Arginase activity for
PGE1, PGE2, and PGE3 (all at 10 µmol/L) and IL-13 was dramatically
increased 466.05 (± 30.25), 248.45 (± 15.05), and 139.87
(± 19.88), respectively; however, PGE3 remained significantly lower
than both PGE2 and PGE1 (p < .002). b, Western blot of RAW 264.7 cells.
Protein lysates exhibiting highest expression of arginase I protein in cells
cultured in PGE1 with lower expression in cells cultured in PGE2 and the least
expression with PGE3. IL-13 is needed to stimulate arginase expression and
does so synergistically with prostaglandins. Liver protein is a positive
control. c, Cyclic AMP accumulation in RAW 264.7 cells. RAW 264.7 cells were
cultured for 15 minutes in the presence of 10 mmol/L PGE1, PGE2, or PGE3.
Cells were then harvested, and cAMP was measured using an ELISA assay.
Increased accumulation of cAMP was observed with PGE1 and PGE2 when compared
with PGE3.
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Prostaglandins induce the accumulation of cAMP in myeloid cells. In turn,
arginase 1 expression is induced by cAMP. We therefore measured the effect of
PGE1, PGE2, and PGE3 on cAMP accumulation in RAW 264.7 cells. A greater
accumulation of cAMP was observed when RAW 264.7 cells were cultured in the
presence of PGE1 or PGE2 when compared with PGE3
(Fig. 2c). These data
correlate with the higher induction of arginase I protein expression observed
with the different prostaglandins.
PGE1 Promotes the Arginase Pathway; PGE3 and PGE2 Preferentially Promote the iNOS Pathway
To examine the iNOS and arginase pathways, RAW 264.7 cells were incubated
with either PGE1, PGE2, or PGE3 for 24 hours. The cells were then incubated
with IL-13 (10 ng/mL) and LPS (2 µg/mL) to induce the arginase and iNOS
pathways respectively. After 24 hours, the medium was collected for
measurement of nitrite production, and the cells were harvested for
measurement of arginase activity.
Figure 3 shows the results
for nitrite production. The positive control, LPS, produced nitrite at a
concentration of 3.38 (± 0.7) µM. Nitrite produced by cells treated
with PGE1, PGE2, or PGE3 in the presence of LPS was 3.89 (± 0.19), 2.75
(± 0.49), and 1.54 (± 0.19), respectively. PGE1 and PGE2 with
LPS shows a significant decrease in nitrite production when compared with
cells cultured in PGE3 and LPS or LPS alone (p < .001).
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FIG. 3. LPS alone produced 3.38 (± 0.7) µM of nitrite. Nitrite produced
by cells treated with PGE3, PGE2, or PGE1 in the presence of LPS was 3.89
(± 0.19), 2.75 (± 0.49), and 1.54 (± 0.19), respectively.
PGE1 and PGE2 with LPS shows a significant decrease in nitrite production when
compared with cells cultured in PGE3 and LPS or LPS alone (p < .001).
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Several reports have suggested that arginase I successfully competes with
iNOS for available arginine. Therefore, we tested the hypothesis by blocking
arginase I activity, expecting restoration of nitric oxide production found to
be decreased in cells treated with either PGE1 or PGE2
(Fig. 3). RAW 264.7 cells were
cultured for 24 hours in the presence of PGE1, PGE2, or PGE3. norNOHA (100
µmol/L) was then added with LPS (2 µg/mL). After 24 hours, cell culture
supernatant was collected for measurement of nitrite use. The addition of
norNOHA to RAW 264.7 cells increased nitrite production significantly,
independent of the type of prostaglandin added
(Fig. 4). The difference in
nitrite accumulation observed with the different prostaglandins was abrogated
with the use of norNOHA. Therefore, these data demonstrate that there is
significant interaction between arginase I and nitric oxide synthesis.
Inhibition of arginase I results in an increase in arginine availability for
the production of nitric oxide.
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FIG. 4. The addition of nor-NOHA increased nitrite production significantly,
independent of the type of prostaglandin added. The difference in nitrite
accumulation observed in Figure
3 was abrogated with the use NOR-NOHA with nitrite concentrations
for PGE3, PGE2, or PGE1, now 5.40 (± 0.11), 5.84 (± 0.14), and
6.52 (± 0.70), respectively.
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DISCUSSION
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Arginine and -3 fatty acids are common ingredients in IEDs, but the
mechanism of how these ingredients "enhance" the immune system is
unknown. Also unknown is the interaction between arginine and -3 fatty
acids. This study presents a "proof of concept" and is intended to
raise the hypothesis that there are significant potential interactions between
the 2 different dietary components.
Supplemental dietary fatty acids have multiple possible effects on the
immune system, among them, the basic substrate for the production of
prostaglandins. There have been numerous studies showing the benefits of
dietary -3 fatty acids over -6 fatty acids in various
physiologic conditions, including coronary artery disease; chronic
inflammatory conditions such as cancer; and autoimmune disorders, specifically
lupus erythematosus, rheumatoid arthritis, and other inflammatory-mediated
states.19–24
Most of these studies demonstrate that -3 fatty acid diets shift the
balance in the type of prostaglandin produced. Diets rich in fish oils are
associated with a greater production in PGE3 and a decrease in PGE1 and
PGE2.25
Prostaglandins are a product of the metabolism of different fatty acids by
COXs. Two COX isoenzymes are described: COX 1 and 2. COX 2 is grossly
considered an inducible enzyme, and its expression is up-regulated in myeloid
cells upon immune activation. COX metabolizes arachidonic acid into PGE2,
whereas eicosapentaenoic and docosahexaenoic acids (from fish oil) are the
substrate for the production of
PGE3.26,27
Recently, it has been shown that arginase I, expressed in myeloid cells in
the immune system, exerts a regulatory effect on T-cell function because it
causes a depletion in
arginine.11,28
The idea that the immune system is able to deplete specific nutrients, and,
through this mechanism, control its own response has been recently supported
in the literature as it is observed in a growing number diseases such in as
cancer and in chronic
infections.29–32
Arginine is crucial for normal T-cell proliferation and function. A
decrease in arginine, whether caused in vitro by the lack of arginine
in culture media or the addition of the enzyme arginase or in vivo by
trauma or transplantation causes significant alterations in T-cell structure,
including a decrease in CD3 receptors and a decrease in the  -chain
subunit of the T-cell
receptor.33,34
Other authors have previously suggested that arginase I expression in
myeloid cells is induced by prostaglandin
E2.16 Arginase I is
induced in trauma and surgery and appears to significantly contribute to
arginine depletion in this patient
population.10,35
Through arginine depletion, arginase I appears to play a major role in T-cell
dysfunction after trauma or surgery and in preventing the production of nitric
oxide in response to
infection.35 Immune
dysfunction after trauma leads to increased susceptibility to infection and
increased morbidity and mortality.
Our results indicate that PGE1- and PGE2-series prostaglandins
significantly induce arginase activity, whereas PGE3 has only a modest effect.
Not surprisingly, RAW 264.7 cells grown in the presence of PGE3 are capable of
generating nitric oxide in response to endotoxin, probably reflecting better
arginine availability. In contrast, nitric oxide production is blunted by
induction of arginase by both PGE1 and PGE2. To prove the inhibitory effect of
arginase on nitric oxide production, we have used the arginase inhibitor
norNOHA. Indeed, the addition of norNOHA increases nitric oxide
proportionately so that nitric oxide production is similar in the presence of
any of the prostaglandins.
IEDs restore T-cell function after surgery and trauma and result in a
significant decrease in infections, but the mechanism of how IEDs work remains
elusive. The discovery that arginase I expression is increased by trauma and
that arginine depletion occurs in this patient population suggests that
arginine supplementations at supraphysiologic levels restore arginine to
levels necessary for normal immune function. Furthermore, this paper raises
the hypothesis that by shifting the balance in the production of PGE2,
-3 fatty acids may blunt the up-regulation of arginase and,
consequently, arginine deficiency.
This paper lays a foundation to begin both animal and human trials to study
whether supplementation with fish oil will decrease the up-regulation of
arginase I expression observed with trauma and help restore arginine levels.
We look forward to seeing results from these types of studies.
Prostaglandins from -3 fatty acids alter the fate of arginine
compared to prostaglandins from -6 fatty acids. Arginase was induced
more by PGE1 and PGE2 than PGE3 with nitrate levels inversely proportional.
Prostaglandins alter the metabolism of arginine. The combinations of fatty
acids should be considered when tailoring dietary regimens.
Received for publication August 2, 2004.
Accepted for publication August 30, 2004.
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Journal of Parenteral and Enteral Nutrition, Vol. 29, No. 1 suppl,
S75-S80 (2005)
DOI: 10.1177/01486071050290S1S75
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MATERIALS AND METHODS
RESULTS