Dietary supplementation with arachidonic acid increases arachidonic acid content in paw, but does not affect arthritis severity or prostaglandin E2 content in rat adjuvant-induced arthritis model
© Tateishi et al.; licensee BioMed Central. 2015
Received: 17 October 2014
Accepted: 7 January 2015
Published: 16 January 2015
Arachidonic acid (ARA) is an essential fatty acid and a major constituent of biomembranes. It is converted into various lipid mediators, such as prostaglandin E2 (PGE2), which is involved in the development of rheumatoid arthritis (RA). However, the effects of dietary ARA on RA are unclear. Our objective was to clarify the effects of dietary ARA on an experimental rat arthritis model.
Lew rats were fed three contents of ARA diet (0.07%, 0.15% or 0.32% ARA in diet (w/w)), a docosahexaenoic acid (DHA) diet (0.32% DHA), or a control diet. After 4 weeks, arthritis was induced by injection of Freund’s complete adjuvant into the hind footpad. We observed the development of arthritis for another 4 weeks, and evaluated arthritis severity, fatty acid and lipid mediator contents in the paw, and expression of genes related to lipid mediator formation and inflammatory cytokines. Treatment with indomethacin was also evaluated.
The ARA content of phospholipids in the paw was significantly elevated with dietary ARA in a dose-dependent manner. Dietary ARA as well as DHA did not affect arthritis severity (paw edema, arthritis score, and bone erosion). PGE2 content in the paw was increased by arthritis induction, but was not modified by dietary ARA. Dietary ARA did not affect the contents of other lipid mediators and gene expression of cyclooxygenase (COX)-1, COX-2, lipoxgenases and inflammatory cytokines. Indomethacin suppressed arthritis severity and PGE2 content in the paw.
These results suggest that dietary ARA increases ARA content in the paw, but has no effect on arthritis severity and PGE2 content of the paw in a rat arthritis model.
Polyunsaturated fatty acids (PUFAs), such as arachidonic acid (ARA) and docosahexaenoic acid (DHA), are natural nutrients present in common foodstuffs (e.g., egg yolk, meat, and fish oil) and are physiologically important constituents of biomembranes. ARA is an n-6 fatty acid and is converted from Linoleic acid (LA) in vivo. ARA also acts as the substrate for various lipid mediators, such as prostaglandins (PGs), leukotrienes, lipoxins (LX), endocannabinoids, and epoxyeicosatetranoates [1–3]. The recent studies demonstrated that the conversion ability from LA to ARA was decreased with aging  and that dietary ARA supplementation improved cognitive response [5, 6] and cardiovascular function [7, 8] in the elderly people and aged rats.
It has been clarified that dietary ARA affects the ARA content of phospholipids in humans and animals [9–14]. An ex vivo study using cells prepared from animals in which dietary fatty acid intake was manipulated showed that different diets impacted the production of PGs and leukotrienes [15–18]. We reported that ARA supplementation in healthy Japanese elderly individuals increased plasma ARA but did not increase ARA-derived lipid mediators or clinical parameters, including inflammatory parameters such as C-reactive protein, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) . We recently studied the effects of dietary ARA on acute inflammation and reported that dietary ARA increased the ARA and LXA4 contents in the colon but did not affect the severity of inflammation or PGE2 content in a murine colitis model .
Rheumatoid arthritis (RA) is one of the major autoimmune diseases and is associated with chronic inflammation of the joints and bones. Biological disease-modifying antirheumatic drugs are frequently recommended for RA therapy, indicating that inflammatory cytokines are important molecules in the pathology of RA [19–21]. Non-steroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase (COX) inhibitors are no longer first-line drugs for RA, but before the advent of biologic therapy, these agents were widely used for RA because lipid mediators produced from ARA by COX, such as PGE2, are involved in the development of RA [22, 23]. Therefore, ARA metabolism is still important in the treatment of RA, but the effects of dietary ARA on chronic inflammation, such as RA, are not fully understood.
In the present study, to clarify the effects of dietary ARA on chronic inflammation and PGE2 status, we evaluated the effects of ARA at various doses on the severity of an adjuvant-induced arthritis (AIA) model in rats, and determined the contents of ARA and ARA-derived lipid mediators and the expression of genes related to these lipid mediators and inflammatory cytokines.
Materials and methods
Animals, diets, and experimental design
Experiments were approved by the Animal Care and Use Committee of Suntory Holdings Ltd. (Osaka, Japan), and we followed the Guidelines for Animal Care and Use of Suntory Holdings Ltd. Seventy 4-week-old male Lew rats were obtained from Charles River Japan (Yokohama, Japan). Rats were housed under standard conditions and had free access to water and diet.
Fatty acid composition of the diets
g/100 g fatty acids
16:0 palmitic acid
18:0 stearic acid
18:1(n-9) oleic acid
18:2(n-6) linoleic acid
18:3(n-3) α-linolenic acid
20:3(n-6) dihomo-γ-linolenic acid
20:4(n-6) arachidonic acid
20:5(n-3) eicosapentaenoic acid
22:6(n-3) docosahexaenoic acid
Induction and evaluation of AIA
Fatty acid analysis
Lipids in the diets, paws, and plasma were extracted and purified by the method of Folch et al. . Lipids in the paw and plasma were separated into phospholipids (PL) and other lipid fractions by thin-layer chromatography using silica gel 60 (Merck, Darmstadt, Germany). The solvent system consisted of hexane/diethyl ether (7/3, v/v). Fatty acid residues in extracted lipids or separated phospholipids were analyzed by the method of Sakuradani et al. . Briefly, each lipid fraction was incubated with an internal standard (pentadecanoic acid) in methanolic HCl at 50°C for 3 h to transmethylate fatty acid residues to fatty acid methyl esters, which were extracted with n-hexane and analyzed by capillary gas–liquid chromatography.
Analysis of lipid mediators of footpad homogenates
PGE2, PGE2-d4, leukotriene B4 (LTB4), LTB4-d4, LXA4, and LXA4-d5 were obtained from Cayman Chemical (Ann Arbor, MI). The methods for extraction and analysis of lipid mediators were reported previously [28, 29]. Briefly, footpad tissue frozen in liquid nitrogen was ground using a Multi-Beads Shocker MB701(S) (Yasui Kikai, Osaka, Japan) and homogenized with ice-cold ethanol. A fixed amount of PGE2-d4, LTB4-d4, and LXA4-d5 was added to all homogenates as an internal standard. After centrifugation, each supernatant was dried by centrifugal evaporation, and residues were dissolved in methanol, washed, and concentrated with SPE cartridges (Empore disk cartridge C18 SD; 3 M, St. Paul, MN). An Agilent 1200 HPLC system (Agilent Technologies, Santa Clara, CA) equipped with a Cadenza CD-C18 column (3 mm, 2 mm i.d. × 150 mm; Imtakt, Kyoto, Japan) and quadruple linear ion trap hybrid mass spectrometer, 4000 Q TRAP, with an electrospray interface (Applied Biosystems/MDS SCIEX, Concord, Canada) was used for quantification. The mass spectrometer was operated in negative ion mode with selected reaction monitoring. PGE2 and PGE2-d4 were detected by monitoring mass transitions at m/z 351 → 271 for PGE2 and m/z 355 → 275 for PGE2-d4 at a collision energy of −24 V. The quantitative range of PGE2 was 0.3 – 100 ng/injection. LTB4 and LTB4-d4 were detected by monitoring mass transitions at m/z 335 → 195 for LTB4 and m/z 339 → 197 for LTB4-d4 at a collision energy of −24 V. The quantitative range of LTB4 was 0.6 – 200 pg/injection. LXA4 and LXA4-d5 were detected by monitoring mass transitions at m/z 351 → 115 for LXA4 and m/z 356 → 115 for LXA4-d5 at a collision energy of −22 V. The quantitative range of LXA4 was 3 – 1000 pg/injection.
Quantitative real-time polymerase chain reaction (QRT-PCR)
The methods for QRT-PCR were as reported previously , with some modification. In brief, the total RNA from hind-footpad tissues stored at −80°C was extracted using Isogen (Nippon Gene Co., Ltd., Toyama, Japan) and purified with an RNeasy mini kit (Qiagen GmbH, Hilden, Germany). The total RNA (2.0 μ g) was reverse-transcribed with random primers using High-Capacity cDNA Reverse Transcription Kits (Applied Biosystems, Foster City, CA) in accordance with the recommendations of the manufacturer. To quantify the gene expression, cDNA was amplified for various gene targets by QRT-PCR using the ABI PRISM 7900 Sequence Detection System (Applied Biosystems). All primers and probes used were purchased as TaqMan Gene Expression Assays: cytosolic phospholipase A2 (cPLA2, Rn00591916_m1), COX-1 (Rn00566881_m1), COX-2 (Rn01483828_m1), arachidonate 5-lipoxygenase (5-LOX, Rn00563172_m1), arachidonate 12/15-lipoxygenase (12/15-LOX, Rn00696151_m1), TNF-α (Rn01525859_g1), IL-1beta (Rn0058432_m1), IL-6 (Rn01410330_m1) and IL-10 (Rn00566881_m1) (Applied Biosystems). PCR results were analyzed with ABI SDS software (Applied Biosystems). Relative expression levels of the genes in each sample were determined by the Comparative Ct Method. Expression assays for each gene were normalized against glyceraldehyde-3-phosphate dehydrogenase (GAPDH, Rn01775763_g1) and expressed as fold change relative to that of the disease-control group (group 2).
Data are presented as means ± SD. Data were analyzed by the unpaired two-tailed t test or one-way analysis of variance followed by Dunnett or Steel multiple comparisons. Correlation analyses were performed using the Spearman correlation test. P < 0.05 was considered statistically significant.
Fatty acid content of the hind-paw and plasma
Effects of dietary ARA on AIA symptoms
Lipid mediator and gene expression
We assayed the expression of genes related to lipid mediator formation, such as cPLA2, COX-1, COX-2, 5-LOX, and 12/15-LOX (Additional file 5: Figure S4 a-e). Only COX-1 expression in the ADV-/CON group was significantly lower than that in the ADV+/CON group, but no other gene expressions differed between the ADV- and ADV+/CON groups. The ARA or DHA diet had no effect on these gene expressions. Indomethacin treatment increased only ALOX5 gene expression. In addition, to determine the effects of diets on cytokine production related to inflammation, we also analyzed gene expression of IL-1beta, IL-6, TNF-α, and IL-10. There were no differences between these groups in these genes (Additional file 6: Figure S5 a-d).
In the present study, dietary ARA supplementation significantly increased the ARA content in the inflamed paw in a dose-dependent manner, but did not affect the severity and content of lipid mediators in an AIA rat model. This is the first study to demonstrate the effect of dietary ARA on AIA in rats.
Some studies have reported that dietary n-6 fatty acids, mainly LA, exacerbated the symptoms of arthritis models compared to n-3 fatty acids [31–34]. It might be believed that dietary ARA also exacerbates arthritis because ARA is the major n-6 PUFA in the body and is converted to various proinflammatory lipid mediators. However, it remains unknown whether dietary ARA itself exacerbates arthritis or not. To detect the effect of ARA accurately, we carefully designed the experimental conditions and adjusted the severity of AIA to moderate levels (Additional file 1: Table S1). Therefore we could detect both suppression and exacerbation of AIA if ARA had such potential and aimed to prevent a false-negative misjudgement of the potential of ARA. In the present study, dietary ARA significantly increased ARA in phospholipids of the inflamed paw and plasma in a dose-dependent manner in AIA (Figure 2 and Additional file 2: Figure S1), which is consistent with previous studies in humans [9–12] and animals [13–15]. Despite local and systemic increases in ARA, dietary ARA did not exacerbate any AIA parameters, such as paw edema, arthritis score, or bone erosion. Our data in this study are supported by the previous papers. Severity of murine colitis, a typical acute bowel inflammatory model, was also unchanged by dietary ARA . Conversely, there was a report that ARA ethyl ester improved some parameters (body weight loss and diarrhea) in a similar colitis model . A human study revealed that dietary ARA did not affect inflammatory parameters (plasma CRP, IL-6, and TNF-α) in healthy participants . Ultimately, there has been a lack of information regarding whether dietary ARA exacerbates the severity of the inflammatory diseases. The present results suggest that dietary ARA did not affect chronic inflammatory diseases like arthritis, as well as acute inflammatory diseases in previous studies mentioned above. Furthermore, interestingly, ARA content in ADV+/CON group was higher and DHA content in this group was lower compared with ADV-/CON group (Figure 2). Similar tendency was observed in plasma (Additional file 2: Figure S1). Total n-6 and n-3 contents also showed the similar tendency (Additional file 3: Figure S2). The animals in both groups have been fed the same diet (CON) without either ARA or DHA, suggesting that some kind of ARA and DHA metabolism might be modified by chronic inflammation. The reason is unclear at this stage.
Considering the reason why dietary ARA did not affect AIA severity, it is important to examine the changes in lipid mediators from ARA. This is the first study to demonstrate a relationship between ARA composition and ARA-derived lipid mediators in an AIA model. In particular, PGE2 is well known to be a proinflammatory cytokine for various types of inflammation and a key factor in RA. In fact, NSAIDs have been one of the important pharmaceutical treatments against RA due to their suppression of PGE2 formation through COX inhibition [1, 22, 23]. The COX-PGE2 axis dependency was confirmed also in the present results, that is, an 8-time elevation of paw PGE2 content was evoked by arthritis induction, and indomethacin treatment clearly suppressed PGE2 production and AIA parameters (Figure 6). Surprisingly, the PGE2 content in the paw was not increased in either the ARA(L), ARA(M), or ARA(H) groups, although the ARA content in the paw was significantly increased in a dose-dependent manner (Figure 2). These findings may seem unreasonable because ARA is a precursor of PGE2. However, in the previous studies, dietary ARA did not affect the content of PGE2 and/or its metabolites in serum and urine in healthy human participants  and in the colon of a murine colitis model . Taken together, it is suggested that dietary ARA does not affect the PGE2 content in vivo, and that lack of elevation of the PGE2 content is one of the reasons for no change in arthritis severity. These hypotheses are also supported by the correlation results for PGE2 and arthritis parameters (Figure 7), and seem to be different to the results of previous ex vivo or in vitro studies which indicated an increase in eicosanoid production with ARA level [15–17, 36]. The reasons for these differences are unclear, but may be related to the fact that intensive and unphysiological stimuli are used in ex vivo or in vitro experiments. PGE2 metabolism may be also involved. Ex vivo or in vitro experimental conditions for PGE2 production may need to be carefully considered to understand in vivo situations.
Another ARA-derived lipid mediator, LXA4, is produced by 15- and 5-lipoxygenases and is clarified to have an anti-inflammatory role . In the animal arthritis model, 12/15-lipoxigenase–deficient mice showed enhanced inflammatory effects and decreased levels of LXA4, and a lipoxin receptor agonist could modulate the immune response and reduce the severity of murine arthritis . In the present study, the LXA4 content in the ARA groups was slightly higher compared with the control group but no significant differences or dose-dependency was found (Figure 6), although dietary ARA increased the LXA4 content in the colon in our previous study using a murine colitis model . These results suggest that the effects of dietary ARA on LXA4 production differ depending on the inflammation model. LTB4, one of the major leukotrienes, was shown to be produced in the joints of RA patients [40, 41]. In the present study, the LTB4 content in the paw tended to be increased by arthritis induction and were not affected by dietary ARA. These results are similar to those for the colitis model , and suggest that dietary ARA has little effect on LTB4 production.
Gene expression of COX-1 and COX-2 is related to PGE2 synthesis, that of 15-LOX and 5-LOX is related to LXA4 and LTB4 synthesis, and that of cPLA2 is related to all of these mediators through release of ARA from membrane phospholipids. Gene expression of these mediators was unchanged by dietary ARA (Additional file 5: Figure S4). This is consistent with the results showing that the PGE2, LXA4, and LTB4 contents were unchanged by dietary ARA (Figure 6). However, because we could not observe increases in gene expression by arthritis induction except for COX-1, we cannot draw a firm conclusion about its effects on gene expression. Further studies, for example a time course experiment [42, 43], are necessary to determine the effects of dietary ARA on gene expression related to lipid mediators. These results are similar to the case of gene expression of inflammatory cytokines. In the present study, dietary ARA did not affect the gene expressions of these cytokines in vivo (Additional file 6: Figure S5). However, we could not observe increases of gene expression by arthritis induction, and further studies are needed to determine the effect of dietary ARA on gene expression of inflammatory cytokines.
In this study, we showed the amounts of lipid mediators in paws, but their contribution to the disease state is not fully confirmed. Although PGE2, LXA4 and LTB4 are known to be important as described above, it remains unclear whether their contents in the present experiment are enough to show physiological/pathological activities or not. It may be revealed by local injection of PGE2, LXA4 and LTB4 or the specific antagonists for example. The amount of lipid peroxides, free radical generation and anti-oxidant content in the tissues and cells might help the clarification. Furthermore, it has been well-known that lipid mediators might affect the amount of TGF-β beta . The cytokine profile is also expected to be clarified by further studies.
DHA, EPA, or fish oil was reported to be effective against arthritis in both animal and clinical studies [31–34, 45], while some studies failed to show any benefit [32, 46]. In the present study, DHA administration significantly increased the contents of DHA and EPA in the paw, but did not affect either inflammatory parameters or the amounts of PGE2, LXA4, and LTB4. One of the reasons may be that the experimental diets in the present study were designed to have similar n-6/n-3 ratio, and that therefore n-6/n-3 ratio was almost the same in the control (2.0) and DHA (2.2) diets. The n-6/n-3 ratios in the previous studies seem different between the control and DHA, EPA or fish oil groups or unclear [31–34], and it might cause the difference of DHA efficacy.
To the best of our knowledge, there is one study in 1997 regarding the effects of ARA on AIA in essential fatty acid-deficient (EFAD) rats. ARA supplementation could increase the ARA content in EFAD and recover the suppressed inflammatory response in EFAD rats compared with normal rats . This was an early and important report, but it does not necessarily reflect the situation for general arthritis. The fatty acid profile in EFAD is quite abnormal, that is, ARA and LA are extremely reduced. Furthermore, Mead acid, which was clarified to have anti-inflammatory properties [48–50], was endogenously synthesized instead of ARA in EFAD and was reduced by ARA administration . It is also reported that Mead acid is detected in articular cartilage of newborn animals, suggesting that Mead acid might have unknown roles in cartilage development . Therefore, it is difficult to estimate the effects of ARA on AIA from the previous report under the EFAD condition.
Dietary ARA intakes for the ARA(L), ARA(M), and ARA(H) groups were estimated to be approximately 35, 73, and 156 mg/kg/day, respectively, on the assumption that rats consumed a diet about 10% of their body weight daily. In humans, the average ARA intake from daily foods is approximately 150–200 mg ARA per day . Compared to the ARA intake of humans, the ARA doses used in the present study are markedly higher. The results in the present study may thus be regarded as those under excess ARA administration.
Dietary ARA supplementation significantly increased the content of ARA in the inflamed paw in a dose-dependent manner, but did not affect arthritis inflammatory parameters or the content of lipid mediators in an AIA rat model.
This work was supported by Suntory Wellness Ltd. We thank laboratory members of institute for Health Care Science for stimulating discussions and comments of this work. We are also grateful to Shigenobu Shibata, the professor of department of physiology and pharmacology, school of advanced science and engineering, Waseda University, for helpful discussions.
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