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Division of Clinical Immunology, Department of Medicine and * Department of Pathology, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3900
2To whom correspondence should be addressed. E-mail: fernandes{at}uthscsa.edu.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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, interleukins-10 and -12 and tumor necrosis
factor-
) levels and lower nuclear factor-
B (NF-B). Reductions
in NF-B were preceded by enhanced superoxide dismutase, catalase and
glutathione peroxidase activities. These findings demonstrate the
profound additive effects of food restriction and (n-3) fatty acids in
prolonging life span in B/W mice. These observations may have
additional implications in the management of obesity, diabetes, cancer
and/or the aging process.
KEY WORDS: • food restriction • (n-3) fatty acids • renal disease • autoimmunity • mice
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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, and subsequent studies have confirmed this
in a variety of models (2
–4)
. Our previous studies showed
that a 40% food-restricted, corn oil–based diet
(CO/FR)3
delays the onset of autoimmune kidney disease (5)
,
decreases renal platelet-derived growth factor A (PDGF-A) and
thrombin receptor expression (6)
, reduces the expression
of serum gp70 and immune complex deposition (7
,8)
, and
decreases glomerular expression of plasminogen activator inhibitor type
1 (9)
.
The autoimmune diseases, rheumatoid arthritis (RA), Sjogren’s Syndrome
(SS) and systemic lupus erythematosis (SLE) are major causes of
disability in the United States. Treatment of these diseases requires
high doses of immunosuppressive agents given over prolonged time
periods. The side effects of these drugs pose a heavy burden to the
patient as well as the economy as a whole, and alternative strategies
are required to reduce the dosage and/or diminish the toxicity of these
potent drugs. Rodent and human studies have demonstrated that dietary
fish oil ameliorates the autoimmune diseases (10
–12)
RA
(13)
, SS (14)
and SLE (15
,16)
as
well as malignancy (17
,18)
and, most notably,
cardiovascular disease (19
–21)
. Nutritional modulation,
particularly energy (calorie) and/or food restriction, offers the
prospect of delaying or suppressing autoimmune disease and malignancy
and has been found to reduce drug toxicity (3
,4
,22)
.
An excellent model with which to study SLE is the (NZB x NZW)F(1)
(B/W) female mouse (23)
, which is frequently used to study
the influence of diet and immunosuppressive drugs on autoimmunity
(24)
. The B/W female, slightly obese mouse develops
nephritis at 
5 mo of age and succumbs to glomerular disease and
renal failure at 6–12 mo of age. In B/W mice, T-lymphocyte
activation and induction of polyclonal B-cell proliferation result
in the production of autoantibodies to histones and double-stranded
DNA. The immune complexes are deposited in the kidney, leading to
mononuclear immune cell recruitment (25)
and release of
the proinflammatory cytokines interferon- (IFN-), tumor necrosis
factor- (TNF-) and PDGF as well as transforming growth factor-ß
(TGF-ß) (26)
. These cytokines can modulate the function
of immune cells (macrophages, B lymphocytes and T lymphocytes) and
resident glomerular cells (26)
.
Substitution of fish oil (FO), enriched in the (n-3) polyunsaturated
fatty acids (PUFA) for corn oil (CO), which is rich in (n-6) PUFA,
delays autoantibody production, resulting in increased life span of B/W
mice (27
–29)
. The increased life span of CO/FR mice is
accompanied by decreased renal expression of the proinflammatory growth
factor TGF-ß and cytokines [interleukin (IL)-1ß, IL-6 and
TNF-], increased expression of antioxidant enzymes
(30)
and decreased expression of c-Myc and c-Ha-Ras
oncogenes (31)
.
Although both FR and FO supplementation profoundly suppress autoimmune
kidney disease in B/W mice (32)
, it is not known whether
the combination of food restriction (FR) with fish oil (FO/FR) is
advantageous over either alone. Therefore, we combined dietary FO with
FR in B/W mice and determined the long-term effects on life span
and body weight in a large number of mice. In addition, renal
pathology, cytokine expression at both the protein and mRNA levels, and
antioxidant enzyme activity were examined at 4 (young) and 8 mo (old)
of age.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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All antibodies were obtained from Pharmingen (San Diego, CA). Dietary
ingredients were from ICN (Costa Mesa, CA). All other chemicals were
reagent grade or better. Fish oil was obtained from the U.S. Department
of Commerce, National Marine Fisheries Service, Charleston, NC and
contained 8.6 g docosahexaenoic acid (DHA) and 13.3 g
eicosapentaenoic acid (EPA)/100 g by gas chromatographic analysis
(33)
.
Mice and diets.
Weanling female B/W mice (4 wk old) were obtained from the Jackson
Laboratory (Bar Harbor, ME) and housed and fed as previously described
(6)
. The AIN76A diet was used with the substitution of
fish oil for corn oil in two of the dietary groups. The four dietary
groups were as follows: 5 g/100 g corn oil, ad libitum consumption
(CO/AL); 5 g/100 g corn oil, 40% food restricted (CO/FR); 5 g/100 g
fish oil + 0.5 g/100 g corn oil, ad libitum consumption (FO/AL); and 5
g/100 g fish oil + 0.5 g/100 g corn oil, 40% food restricted (FO/FR).
Corn oil (0.5 g/100 g) was added to the fish oil diets as a source of
linoleic acid to prevent essential fatty acid deficiency
(9)
. The diet consisted of the following (g/kg): casein,
200; dextrose, 300; cornstarch, 315; oil, 50; cellulose, 35; AIN76A
mineral mixture, 35; AIN-76 vitamin mixture, 15;
DL-methionine, 3; and choline chloride, 2
(34)
. The oils used in the diets were supplemented to
contain 1300 IU -tocopherol and 1 g
t-butylhydroquinone/kg oil to prevent oxidation as
recommended by the NIH. Diets were prepared weekly and stored at 4°C.
Fresh diet was provided daily and any diet remaining from the previous
day was discarded. Food intake per gram of body weight in the CO/FR and
FO/FR groups was similar to that of AL mice (9)
. Mice were
weighed weekly and, beginning at 5 mo of age, proteinuria was
determined weekly using chemstrips (Boehringer Mannheim, Indianapolis,
IN) until mice were killed at 8 mo of age. All procedures performed
were approved by the institutional animal use and care committee. At 4
(young) or 8 mo (old) of age, mice were killed and whole kidneys
removed. One half kidney was placed in OCT 4583 embedding
medium for histology studies (Sakura Finetek, Torrance, CA) and the
other placed in a 1.5-mL cryovial. Both kidneys were snap frozen in
liquid nitrogen and stored at -80°C until further analysis. In each
dietary group, 30 mice were followed until their urinary protein
reached 3+ and they had lost 25% of their body weight; at that time,
they were killed and the life span recorded. Additional similar groups
of mice were utilized for cross-sectional studies at 4 and 8 mo of
age.
Histology.
Tissue for light microscopic examination was fixed in 1.0 g/L buffered
formalin, embedded in paraffin, sectioned at 5 µm and
stained with hematoxylin and eosin (H & E) using standard techniques.
Histological severity of glomerular disease was graded on a
semiquantitative scale from 0 to 4 as described (9
,31)
.
Cytokine Western blotting.
Protein isolation was carried out essentially as previously described
with a few modifications (35)
. Briefly, whole-kidney
tissue (50 mg) was homogenized in lysis buffer containing 50 mmol/L
Tris base, 10 mmol/L EDTA, 150 mmol/L NaCl, 0.01 g/L Tween-20, pH 7.4,
with 1 mg/L leupeptin and pepstatin and 100 µmol/L
phenylmethylsulfonyl fluoride. An equal volume of lysis buffer was
added and the samples incubated for 15 min on ice. The samples were
then centrifuged at 13,000 x g for 3 min and the
supernatant divided into aliquots and stored at -80°C. An aliquot
was retained for protein determination using the BioRad Assay (BioRad,
Hercules, CA). Western blotting was carried out as previously described
(36)
except that 50 µg protein was used
at a 1:2000 dilution. Visualization of the bands was carried out as
described by the manufacturer using SigmaFast diamino benzidine with
metal enhancer tablets (Sigma, St. Louis, MO). Band intensity was
determined using an AlphaImager 2000 (AlphaInotech, San Leandro, CA).
Cytokine mRNA analysis.
Total RNA was isolated from 50 mg of kidney tissue, cDNA synthesized by
reverse transcriptase-polymerase chain reaction (PCR) then
amplified by PCR as previously described (37)
. Briefly,
the PCR reaction was carried out with 27–30 amplification cycles for
IFN-, IL-10 and IL-12 or 17 amplification cycles for
D-glyceraldehyde-3-phosphate dehydrogenase (GAPDH) of
94°C for 30 s, 59°C for 30 s and 72°C for 1 min.
Electrophoretic mobility shift assay (EMSA) for nuclear factor
(NF)-B.
Nuclear extraction and the EMSA were carried out as previously
described (38)
. Briefly, 50 mg of whole kidney tissue was
homogenized, incubated on ice for 15 min and 0.625% nonidet P-40 was
added; the tubes were vortexed for 10 s and centrifuged at 12,000
x g for 30 s. The nuclear pellet was
resuspended in a buffer containing 0.4 mol/L NaCl and incubated for 15
min on ice with vigorous shaking. The nuclear extract was centrifuged
for 5 min at 12,000 x g and protein concentrations
determined using the BioRad Assay. Aliquots were stored at -80°C for
later use.
The double stranded DNA probes for NF-B and alkaline phosphatase
(AP)-1 were from Promega (Madison, WI). The NF-B was labeled with
[32P-]ATP (Amersham, Arlington Heights, IL) using T4
polynucleotide kinase (Promega). Approximately 50,000 cpm of
the labeled NF-B was incubated with 10 µg of kidney
protein for 1 h on ice. The mixture was then loaded onto a 5%
polyacrylamide gel and subjected to electrophoresis at 20 mA. The dried
gel was autoradiographed on Kodak XAR-5 film. The gels were quantitated
by densitometry using NIH Image.
Assay for antioxidant enzyme activity.
Superoxide dismutase (SOD) activity was measured by the method of Flohe
and Otting (39)
Catalase (CAT) activity was assayed
according to the method of Aebi (40)
. Glutathione
peroxidase (GSH-Px) activity was determined by the method of Tappel
(41)
. Glutathione-S-transferase (GST) activity
was measured by the method of Habig et al. (42)
. Protein
was measured using the bicinchoninic acid protein assay reagent
(Pierce, Rockford, IL); bovine serum albumin was the reference
standard.
Statistics.
All data were analyzed by factorial ANOVA using NCSS software v. 5.01 (NCSS, Kaysville, UT) or one-way ANOVA with Bonferroni’s or Newman-Kuels post-hoc test using GraphPad Prism version 3.00 for Windows (GraphPad Software, San Diego, CA). P < 0.05 was considered significant. Survival analysis was conducted using SPSS routines (SPSS, Chicago, IL).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Similar to our previously published observations, both FO/AL
(29)
and CO/FR (5)
increased the median and
maximum life spans of B/W mice compared with CO/AL (242 and 332 d,
respectively, P < 0.0001) (Fig. 1
). When FO and FR were combined (FO/FR), median and maximum life spans
were extended to 645 and 862 d (2.7- and 2.6-fold), much more than
either FO/AL (345 and 466 d, 1.4-fold) or CO/FR (491 and 755 d, 2.0- and 2.3-fold). CO/FR mice had lower body weights relative to
the CO/AL and FO/AL groups (Fig. 2
). Body weights of the AL groups peaked at 8 mo with FO mice reaching
the highest weight. The weight gain of FR mice was less pronounced, but
FO/FR mice again gained somewhat more weight than CO/FR-fed mice. In
both AL and FR mice, body weights declined sharply in the weeks before
death due to the severity of the renal disease.
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As described previously (31)
, substitution of FO for CO
modulated the histological lesions in older AL mice. In CO/AL mice,
both tubular dilation and tubular atrophy, as well as
glomerulosclerosis, were more pronounced than in FO/AL mice
(Table 1
, Fig. 3A
and
C). Both CO/FR and FO/FR mice had normal tubules and glomeruli in most of
the kidneys (Table 1
, Fig. 3
B and D). When FO
supplementation was combined with FR, there was a trend (P
= 0.21) for a lower score in both young and old mice
compared with FR alone (Table 1)
.
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SOD and CAT activity declined by 28% with age in kidney homogenates of
CO/AL mice (Table 2
) (P < 0.02). Both FO/AL and FO/FR, and to a lesser
extent CO/FR, normalized the age-dependent reduction. CO/FR, FO/AL
and FO/FR maintained SOD activity in young mice at levels 18, 22 and
48%, respectively, greater than those of CO/AL mice. There was a 25%
decline in CAT activity with age in the CO/AL group (Table 2)
. CO/FR
marginally blunted the age effect, whereas both FO/AL and FO/FR
increased CAT activity to levels 25 and 51% higher than that of the
young CO/AL control group. FO/AL and FO/FR increased CAT activity by 45
and 50%, respectively, in the young mice, whereas CO/FR was only
marginally effective. GSH-Px activity was not affected by age but
was increased 30% by FR or FO feeding in both young and old mice. GST
was not affected by age, FR or FO.
|
Cytokines exist in hyper- and hypoglycosylated forms, which influence
their biological activity (43)
. Figure 4
shows a representative Western blot for each cytokine. Individually,
IFN-, IL-12, IL-10 and TNF- exhibited a slower migrating
hyperglycosylated band in all diet and age groups, whereas the
appearance of a faster migrating hypoglycosylated band was present
primarily in the CO/AL and FO/AL old groups. In general, FO feeding did
not significantly influence cytokine protein expression in young mice.
Because the major change due to age and diet existed in the
hypoglycosylated band, we have shown data for only the hypoglycosylated
forms for each cytokine (Table 3
). The hypoglycosylated forms of all four cytokines (INF-, IL-12,
IL-10 and TNF-) increased with age and with progression of the
disease in the AL-fed mice, although the increase in IL-12 was not
significant (P = 0.0613). This increase was prevented
by FR (CO/FR, FO/FR).
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is a representative ethidium bromide–stained gel for IFN-, IL-12,
IL-10 and TNF-; Table 4
shows the densitometric analysis expressed as the cytokine to GAPDH
ratio. Similar to the protein levels, diet did not affect cytokine mRNA
expression in young mice. In the CO/AL old mice, however, mRNA
expression for all of the cytokines was increased (P < 0.0001) from 25% to threefold relative to the CO/AL young group. Both
CO/FR and FO/FR diets maintained mRNA expression in the old groups at a
level similar to those in the young groups (P < 0.0001
vs. AL mice), whereas FO feeding decreased only IL-10 and TNF-
expression significantly (P < 0.05) and to a lesser
extent than FR.
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B.
We next examined the influence of diet and age on NF-B nuclear
localization because it plays an important positive role in cytokine
gene expression and function during inflammation (44)
.
Diet did not influence NF-B in the young groups (Table 5
). A representative gel is shown in Figure 6A
. In the old mice, both CO/FR and FO/FR maintained NF-B at levels
comparable to the young groups, whereas FO/AL was only partially
effective. Figure 6
B confirms that the binding was specific
because a 50-fold excess of unlabeled NF-B oligonucleotide
competitively eliminated the NF-B band and a 50-fold excess of an
irrelevant oligonucleotide had no effect.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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,29)
. We now
extend these observations and show for the first time that the
combination of dietary FO and FR (FO/FR) is far more effective than
either treatment individually. The effects observed here could be
attributed only partially to decreased body weight or obesity.
Food-restricted (CO/FR and FO/FR) mice, with 40% lower body
weights, did live significantly longer than mice that ate ad libitum
(CO/AL and FO/AL). However, in spite of slightly greater body weights,
FO/FR mice lived significantly longer than CO/FR mice. Similarly, the
FO/AL group lived longer than the CO/AL mice even though their body
weights were higher. Thus, the source of dietary fat was a key
determinant in suppressing autoimmune renal disease and extending life
span significantly. The extension of life span by FR was associated
with immune suppression because the disease-dependent increases in
IFN-, TNF-, IL-12 and IL-10 were prevented at both the protein
and mRNA levels. Furthermore, age-dependent increases in renal
NF-B nuclear localization were equally blunted by (n-3) lipid
feeding and reduced food intake. Interestingly, these results were
accompanied by increased antioxidant enzyme (SOD, CAT) activity in the
kidneys of relatively disease-free young mice.
Several lines of evidence demonstrate the pivotal role of IFN- in
promoting lupus nephritis. First, IFN- receptor knockout B/W mice
have reduced renal disease (45)
. Second, administration of
soluble IFN- receptor blunts autoimmune nephritis in B/W mice
(46)
. Third, similar results have also been observed in
other lupus-prone mice with respect to the proinflammatory actions
of IFN- (47)
. Consistent with these observations, we
now find that renal IFN- expression is also lower in CO/FR and FO/FR
mice relative to the age-matched CO/AL and FO/AL groups. Similarly,
the reduced levels of IL-10 in CO/FR and FO/FR mice are in agreement
with previous findings that administration of anti-IL-10 antibody
delays the onset of renal disease in B/W mice (48)
. It is
important to note that both IFN- and IL-10 expression are regulated
in the same way, i.e., both increase with disease and decrease in
response to CO/FR and FO/FR. It is generally thought that these two
cytokines are antagonists and if one increases the other decreases.
However, in lupus nephritis as well as other autoimmune disorders, it
is now becoming evident that both Th-1 and Th-2 cytokines may be
involved synergistically (26)
.
Furthermore, cytokine protein levels were also dramatically increased
during the disease process and decreased by FR. Interestingly, the
glycosylation state of the cytokines was also significantly reduced in
the aging, diseased mice. Cytokines exist physiologically as
glycosylated proteins, which present themselves as doublet or multiple
bands by Western blot analysis (43)
. In the diseased
kidney, the cytokines we examined existed primarily in a
hypoglycosylated form, and both CO/FR and FO/FR significantly blunted
this effect. This finding alone is important because, in general, the
hypoglycosylated forms of cytokines are more biologically active and
typically found at sites or in tissues with severe inflammation
(43)
. The regulation of glycosylation state most likely
involves pretranscriptional mechanism(s) because both cytokine mRNA
levels and NF-B nuclear localization were decreased by CO/FR and
FO/FR in old mice. Recent findings have shown that NF-B upregulates
IFN- (49)
, IL-10 (49
,50)
and TNF-
(51)
expression and is a pivotal transcription factor in
propagating the inflammatory response (44)
. Furthermore, a
recent report showed that mice deficient in NF-B were resistant to
experimental autoimmune encephalomyelitis, establishing a clear link
between NF-B and autoimmunity (52)
. FR has also been
reported to prevent expression of 60–70% of inflammatory and stress
response genes typically elevated in the brains of aging mice
(53)
.
The mechanism by which NF-B is suppressed by CO/FR and FO/FR in old
B/W mice is unclear, but we speculate that it is due to increased
antioxidant enzyme activity. Previously, we found increased antioxidant
enzyme activity and expression in mouse liver and kidney of B/W mice
fed FO/AL compared with CO/AL mice (30)
. Free radicals
have been shown to activate NF-B and other cytokines
(54)
. In the kidney, free radicals derived from resident
kidney cells as well as from the infiltrating immune cells may play a
pivotal role in causing the acute glomerular disease (55)
.
Antioxidant enzymes could reduce free radical levels and thereby block
or down-regulate NF-B activation. This has been observed in
response to in vivo antioxidant administration, which suppressed
NF-B activation and subsequent lung inflammation (56)
.
Indeed, we observed a simultaneous increase in NF-B nuclear levels
and decrease in antioxidant enzyme activity in relatively obese CO/AL
and FO/AL old mice. In the present studies, SOD, CAT and GSH-Px
were increased, but GST was not affected. Interestingly, the CO/FR and
FO/FR treatments increased antioxidant enzyme activity before the onset
of disease in the young mice as well, which may account for the
maintenance of low or normal renal cytokine levels in the old lean
CO/FR and FO/FR mice. These results are in agreement with others and
with our own previous data, which showed that FO/AL and CO/FR increase
antioxidant enzyme activity in both healthy (57)
and
autoimmune-prone mice (58)
and rats (59)
.
An alternative mechanism may involve diet-induced changes in fatty
acid composition (60)
. We showed previously that both
CO/FR and FO/AL decrease arachidonic acid [AA: (n-6) fatty acid]
levels, whereas FO/AL causes a concomitant increase in the (n-3) fatty
acids, EPA and DHA (29
,61)
. It was shown recently that AA,
through its metabolite prostaglandin E2
(PGE2), but not EPA, which inhibits
PGE2 synthesis, could activate NF-B in vitro,
suggesting a mechanism that may be independent of free radical
formation (62)
. The lack of a diet effect on renal
cytokine levels in young mice is important because it suggests that FR
is not immunosuppressive or detrimental to the point that cytokine
steady-state levels are influenced at a young age. It is important
to note also that FR and FO had no adverse effects on antioxidant
enzyme activity.
Data presented herein show that CO/FR and FO/FR acted similarly with
respect to suppressing renal cytokine and NF-B levels, whereas FO/FR
was much more effective at inhibiting renal disease and thereby
increasing life span. Indeed, in this study, the analysis of cytokines
and NF-B was conducted simultaneously in both young and old mice as
a cross-sectional study, whereas life span was followed
longitudinally. The cross-sectional analysis was chosen to allow
direct comparison of all diet groups at the same time. The important
finding of this study is that the age effect of diet most likely
involved increased antioxidant enzyme activity, which was
significantly higher even in the young FO/FR mice relative to the CO/FR
and FO/AL groups, paralleling the pattern of the survival data. This
observation is further supported by a recent report that showed that
increasing CAT expression can extend life span (63)
. Free
radical damage is thought to be a major mechanism contributing to
aging, and FR may delay this by altering multiple genes that are
influenced by age (64)
. Therefore, early increases in
antioxidant enzyme activity in CO/FR and FO/FR mice may represent a key
event, one that ameliorates autoimmune kidney disease. In summary, our
data indicate that renal disease progression could be a result of
stimulation of NF-B by increased free radical species in AL mice.
The increased NF-B could in turn stimulate production of TNF-,
IFN-, IL-10 and IL-12, leading to increased inflammation and failure
of kidney function. Both fish oil feeding and food restriction, and
especially a combination of the two, increase antioxidant enzyme
activity, thereby preventing the rise in NF-B and consequently the
increase in the proinflammatory cytokines, TNF-, IFN-, IL-10, and
IL-12, that occurs in these mice.
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FOOTNOTES |
|---|
3 Abbreviations used: AA, arachidonic acid; AP-1, alkaline phophatase 1; B/W, (NZB x NZW)F(1); CAT, catalase; CO, corn oil; CO/AL, corn oil–based diet, ad libitum intake; CO/FR, corn oil–based diet, restricted intake; DHA, docosahexaenoic acid ; EMSA, electrophoretic mobility shift assay; EPA, eicosapentaenoic acid; FO, fish oil; FO/AL, fish oil–based diet, ad libitum intake; FO/FR, fish oil–based diet, restricted intake; GAPDH, D-glyceraldehyde-3-phosphate dehydrogenase; GSH-Px, glutathione peroxidase; GST, glutathione-S-transferase; IFN-, interferon-; IL, interleukin; NF-B, nuclear factor B; PCR, polymerase chain reaction: PDGF-A, platelet-derived growth factor A; PGE2, prostaglandin E2; PUFA, polyunsaturated fatty acids; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SOD, superoxide dismutase; SS, Sjogren’s syndrome; TGF-ß, transforming growth factor-ß; TNF-, tumor necrosis factor-.
Manuscript received January 12, 2001. Initial review completed February 26, 2001. Revision accepted July 2, 2001.
|
LITERATURE CITED |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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