Download Modulatory effects of dietary lipids on immune system functions

Immunology and Cell Biology (2000) 78, 31–39
Special Feature
Modulatory effects of dietary lipids on immune system functions
M A N U E L A D E PA B L O a n d G E R A R D O Á LVA R E Z D E C I E N F U E G O S
School of Experimental Sciences, Department of Health Sciences, University of Jaén, Jaén, Spain
Summary Dietary lipid manipulation may affect a great number of immune parameters, such as lymphocyte
proliferation, cytokine synthesis, natural killer (NK) cell activity, phagocytosis and so on. The immunomodulation
induced by dietary fatty acids may be applied in the amelioration of inflammatory disorders, such as autoimmune
diseases. However, the mechanisms that participate in these processes are still poorly understood. It is probable that
modulation of immune system by fatty acids of the diet may occur by alteration of membrane fluidity, lipid peroxide formation, eicosanoid production or regulation of gene expression. However, recent studies have reported the
effects of several free fatty acids on apoptosis induction of in vitro cultures. In fact, a possible explanation of the
effects that fatty acids promote on the immune system cells could be associated with an apoptotic process performed in an irreversible way. In vivo studies have demonstrated the ability of fatty acids to alter the survival of
animals fed diets containing oils and infected with a pathogenic bacterium. Experimental infection in animals fed
dietary lipids produces a modification of resistance to micro-organisms. The present review analyses all of these
parameters that dietary fatty acids are capable of altering in order to modify the immune response. Further studies
will be needed to establish the mechanisms involved in immune system regulation, reduction of symptoms derived
from autoimmune pathologies and so on.
Key words: cytokine, dietary lipid, fish oil, immunomodulation, lymphocyte, macrophage/monocyte, monounsaturated fatty acid, n-3 polyunsaturated fatty acid, natural killer cell, olive oil.
Introduction
According to current understanding, the immune response of
both humans and animals may be influenced by several
essential nutrients, which modify the immune system functions. In fact, it is generally accepted that many of the important infections of human populations have been associated
with a nutritional deficiency. From this point of view, we can
affirm that dietary fatty acids may be able to modulate the
immune system through several mechanisms that include
reduction of lymphocyte proliferation, reduction of cytokine
synthesis, phagocytic activity increase, modification of
natural killer (NK) cell activity and so on. Such modulation
of immune functions may be produced as a consequence of
several factors, but in general the main event involved in this
process may be associated with changes in the cell membrane
due to dietary fatty acid manipulation. Fatty acids may be
incorporated into the plasma membrane after dietary lipid
administration, so that the composition of lipids in this cellular structure will reflect the composition of dietary lipids.1
Because of this incorporation, the phospholipid profiles associated with plasma membrane of lymphocytes, monocytes/macrophages or polymorphonuclear cells may be
altered by dietary lipids.2,3 However, phospholipid changes in
the plasma membrane depend on many factors (which affect
the modulation of the immune response by fatty acids), such
as the amount, type or time of dietary lipid administration;
sex; and the species of animals or humans fed dietary lipids.
Correspondence: Dr Manuel Antonio de Pablo Martínez, University of Jaén, School of Experimental Sciences, Department of Health
Sciences, E-23071-Jaén, Spain. Email: [email protected]
Received 26 August 1999; accepted 26 August 1999.
Dietary lipids or free fatty acids not only affect the
immune system directly, but also interfere in the production
of other substances. When fatty acids are released from the
plasma membranes or when they are incorporated from the
extracellular medium, they may suffer biochemical degradation through the eicosanoid pathways. In fact, fatty acids may
also influence eicosanoid production, because they modify
the activity of enzymes involved in the synthesis of these substances, which participate as secondary messengers within
the cytoplasm. Overall, these events will be responsible for
the modulation of immune system functions by fatty acid
action.
In this scenario, the main substances that participate are
the fatty acids, which are divided into two great families.
These are classified as essential fatty acids for mammalian
cells and should be administered in the diet. Essential fatty
acids include the n-3 series, derived from linolenic acid, and
the n-6 series, derived from linoleic acid. Both polyunsaturated fatty acids are not interconvertible in animals. Likewise,
another family of fatty acids (not essential fatty acids), such
as the n-9 series derived from oleic acid (monounsaturated
fatty acid), also seems to play an important role in the
immunomodulatory process.4,5
As mentioned previously, dietary fatty acid manipulation
is involved in immune system modulation and a large
number of studies has demonstrated the potential benefits of
dietary unsaturated fatty acids on the immune system of both
humans and animals. However, it is noteworthy that the n-3
polyunsaturated fatty acids are present in marine oils,
because fish oils have been well documented due to their
immunosuppressive effects. Classical studies have reported
that the n-3 polyunsaturated fatty acid family is able to
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reduce lymphocyte proliferation, neutrophil chemotaxis and
secretion of several cytokines, such as IL-1, IL-2, TNF and so
on.6,7 Subsequently, these and other studies have indicated
that several parameters of the immune response are modulated by other unsaturated fatty acids and hence they may be
applied in the prevention of several disorders. Thus, an epidemiological study carried out among Greenland Eskimos,
who consume large amounts of fish oil in their diets, has
demonstrated the effects of n-3 polyunsaturated fatty acids on
the immune response. The results from this study indicate a
low incidence of inflammatory and autoimmune diseases in
this population.8
Therefore, the present review will focus on the current
status of the relationship between dietary fatty acids and the
immune system, the molecular mechanisms by which dietary
lipids or free fatty acids exert their effects on the immune
system and the possible application of dietary fatty acids contained in the oils as substances capable of acting in the prevention of autoimmune disorders or as agents that promote
the modulation of the immune system in order to efficiently
eliminate different micro-organisms or biological agents
involved in infectious processes.
Modulatory effects of lipids on immune cell functions
Influence of fatty acids on lymphocyte proliferation
Several studies have demonstrated the ability of unsaturated
fatty acids to reduce the proliferation of T lymphocytes. Such
studies have been performed in both animals and humans fed
dietary lipids or have been carried out in cellular cultures
incubated with free fatty acids. Therefore, it should be noted
that diets containing polyunsaturated fatty acids, such as
eicosapentaenoic or docosahexaenoic acids, suppress the
mitogenic response of lymphocytes to a greater extent than
diets rich in saturated fatty acids.9 However, another fatty
acid, oleic acid (a monounsaturated fatty acid), also plays an
important role in this process.4 Despite the fact that oleic acid
(the most important fatty acid in olive oil) is involved in the
immunomodulatory process, its regulatory effect on immune
functions is lower than that carried out by n-3 polyunsaturated fatty acids, such as eicosapentaenoic or docosahexaenoic acids (the most important fatty acids in fish oil).9
Mitogen-stimulated lymphocytes from mice fed a diet containing olive oil show a significant reduction in lymphocyte
proliferation in comparison with mitogen-stimulated lymphocytes from mice fed sunflower oil or hydrogenated
coconut oil,4 but this reduction is lower than that found from
diets containing eicosapentaenoic or docosahexaenoic fatty
acids.9 Neverthless, a recent study has examined the effects
of dietary docosahexaenoic acid (in absence of eicosapentaenoic acid) on the immune response of human volunteers
and has reported that docosahexaenoic acid consumption
does not inhibit many of the lymphocyte functions modified
by fish oil consumption.10 This fact indicates that a diet containing fish oil modulates the immune response by the action
of eicosapentaenoic acid rather than docosahexaenoic acid.
This argument suggests that it is necessary to find the lipid
component responsible for immune system modulation from
diets containing different fatty acids.
The effect of dietary lipids on lymphocyte proliferation
also depends on lymphocyte subpopulations. A comparative
study in rats fed diets containing unsaturated fatty acids has
shown that there is a significant difference between the lymphocyte suppression found in spleens isolated from rats and
suppression observed in lymphocytes from thymi of rats, in
which lymphocyte proliferation is much lower.11 The fatty
acid composition of lymphocytes that recirculate by the lymphatic system is affected by lipids and the immunological
function of these lymphocytes is also influenced by dietary
lipid manipulation.12 Ex vivo studies have suggested that the
effect of fatty acids on the immune system depends on the
fatty acid concentration. In fact, several studies have reported
a significant reduction of lymphocyte proliferation in
mitogen-stimulated lymphocytes isolated from both humans
and animals fed diets containing a high concentration of
unsaturated fatty acids belonging to the n-3 or n-9 fatty acid
series.4–6,11,13 Diets containing a high concentration of olive
oil have been administered to experimental animals and the
hypothetical effects of olive oil on immune cell function previously reported could be related first to the oleic acid action
and second to other components isolated from the olive oil.
However, it has been reported recently that the immunosuppressive effects of olive oil incorporated into diets are most
likely related to oleic acid action rather than to other components of olive oil.5 Regardless of the effect of fatty acid concentration on lymphocyte function, other authors have
pointed out that the reduction of lymphocyte proliferation by
n-3 polyunsaturated fatty acids, such as eicosapentaenoic or
docosahexaenoic acid, has been shown to be equipotent,14
although sometimes the results obtained depend on the type
of serum used in the cellular cultures.11,15 Hence, many
authors have reported contradictory results, because the previously explained effects have been demonstrated when cells
were cultured in autologous serum.16 However, when cells
were cultured in foetal calf serum, contradictory results
appeared or no effect at all was found.17 Table 1 reflects the
discrepancies found regarding immunomodulation and
dietary fatty acids in both humans and animals.
It is interesting to remark here on the biological consequences in the clinical application of the lymphocyte proliferation regulation by fatty acids. As we will detail in the last
section of the present review, these processes seem to play a
fundamental role in the amelioration of patients suffering
from autoimmune diseases who are characterized by an overactivation of the immune system, such as rheumatoid arthritis,18 psoriasis,19 multiple sclerosis20 and so on.
Effects of fatty acids on cytokine production
Fatty acids may regulate cytokine production and in fact
cytokine modulation by fatty acids seems to be responsible
for the reduction of lymphocyte proliferation in both animals
and humans. This affirmation is based on the study carried
out by Soyland et al., who found that the inhibitory effects of
n-3 polyunsaturated fatty acids may, at least in part, be mediated by the inhibition of the expression of the CD25 molecule
that constitutes an IL-2 receptor.21 However, other studies
have reported that the mechanisms by which n-3 fatty acids
exert suppression of cytokine synthesis remain unknown.
Cytokines such as IL-1 and TNF are important mediators of
Dietary fatty acids and immunomodulation
Table 1
33
Influence of different families of fatty acids on immune system functions in both experimental animals and humans
Immune functions
Dietary fatty acids
n-6
n-3
Lymphocyte proliferation
IL-1 production
IL-2 production
TNF production
NK cell activity
↓ Humans and animals4,6,11,13
↓ Patients suffering from rheumatoid
arthritis18
↓ Human volunteers6,13
↓ Humans and animals13,21,87
↓ Humans6
↑ Macrophages from mice24
↓ Rats16
↓ Humans37,38
NE Rats12,16
NE Rats28
↑ Mice87
↓ Rats28
↓ Rats35
n-9
↓ Rats5
↓ Patients suffering from
rheumatoid arthritis18
↓ Balb/c mice23
NE Rats87
↓ Mice23
NE Balb/c mice23
↓ Balb/c mice4
↓ Rats35
↑, Increase; ↓, decrease; NE, no effect.
inflammation and dietary fatty acids have been demonstrated
to be substances capable of reducing the pro-inflammatory
response induced by IL-1 and TNF.6,22,23 The effects promoted
by n-3 (present in fish oil) fatty acids on IL-1 and TNF production in human volunteers fed a diet containing these fatty
acids have demonstrated a significant reduction in these
cytokines. Moreover, the levels of these biological substances
returned to baseline values after stopping administration of
the diet.6 In contrast, the reduction of cytokine production,
such as IL-1 and IL-2, promoted by a diet containing olive oil
depends on the time of dietary administration.23 Nevertheless,
many studies have reported contradictory effects of dietary
fatty acids on pro-inflammatory cytokine production22–25 and
these discrepancies may be associated with the different
polyunsaturated fatty acid actions on cell populations of
various species.26 The mechanisms involved in the modification of cytokine synthesis remain unclear as yet, but a possible explanation could be found in the regulation at the
transcriptional level, that is, reduction of cytokine mRNA
production by polyunsaturated fatty acids.27 Animal studies
have suggested that the effects of dietary fatty acids on production of macrophage-derived cytokines are different and
that these depend on several factors, such as duration of
feeding, the species of experimental animal, the type and
state of activation of macrophages and so on.25,28–31 For
example, fish oil and olive oil are capable of suppressing
IL-1 production after 4 weeks of dietary supplementation in
rats, whereas olive oil enhances IL-1 production after
8 weeks of dietary administration.31 The regulation of other
cytokines by dietary fatty acids is also very important. In
fact, the cytokine IL-10 suppresses LPS-induced production
of pro-inflammatory cytokines. In this way, a recent study has
demonstrated low TNF production in mice fed a diet containing coconut oil, whereas IL-10 production is significantly
increased.32 Dietary fats also modulate IFN-γ production in
assays in vivo during active infection with Listeria monocytogenes in fish oil-fed mice. Results from this study have
described a higher concentration of this cytokine in serum
compared with results from mice fed soybean oil or lard,33 but
in vitro studies have not demonstrated a significant change in
IFN-γ production. This discrepancy may be explained by
modification of ΙFN-γ receptors, which have been reported
recently to be reduced by dietary n-3 polyunsaturated fatty
acids.34
Modulation of natural killer cell activity by fatty acids
Natural killer cells participate in protection against virus,
intracellular bacteria or tumoral cells. Activity of NK cells is
also modulated by dietary fatty acids.4,35 Previous studies in
animals have demonstrated that dietary lipids reduce the
activity of these cells. In fact, these authors have described
that a decrease in the total fatty acid consumption in the diet
produces an increase in NK cell activity.36 Animal studies
have revealed that diets containing fish oil or olive oil
produce the greatest percentage of NK cell activity inhibition
in comparison with diets rich in saturated fatty acids or n-6
polyunsaturated fatty acids.4,16,35 However, few studies have
investigated the influence of dietary lipids on human NK cell
activity, although it has been demonstrated that intravenous
injection of triacylglycerol containing eicosapentaenoic acid
is related to the suppression of peripheral blood NK cell
activity from human volunteers.37 In addition, a diet containing docosahexaenoic acid has been demonstrated to reduce
NK cell activity from humans, as reported by a recent study.38
Several studies have suggested different mechanisms by
which fatty acids modulate NK cell activity, reporting that
NK cell activity is modulated by production of eicosanoids
such as prostaglandins,39 leukotrienes40 or lipoxins.41
However, the mechanism involved in the fatty acid modulation of NK cell activity remains unknown, because a significant reduction of prostaglandin E 2 and leukotriene B4
production has been recently reported in cells from humans
fed a diet containing docosahexaenoic acid, which produced
a significant decrease in NK cell activity.38
Effects of fatty acids on phagocytic activity and on inflammatory response
Phagocytosis is an important mechanism in many cells for
the elimination of micro-organisms or foreign particles,
mediated by production of endocytic vesicles. Therefore,
membrane fluidity plays an important role in this process.
Plasma membranes of macrophages and other phagocytic
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Figure 1 Schematic representation of different mechanisms of
regulation of the immune system
by dietary fatty acids. NFκB,
nuclear factor kappa B; DCm,
mitochondrial
transmembrane
potential.
cells may be altered by dietary lipids. In fact, several studies
have reported that unsaturated fatty acids increase phagocytosis.23,42 Peritoneal macrophages stimulated with zymosan
particles have shown a significant increase of phagocytosis in
cells isolated from mice fed diets enriched in olive oil23 and
polyunsaturated fatty acids as eicosapentaenoic or docosahexaenoic acids.42 This effect may be due to the increase of
hydrogen peroxide production, which enhances superoxide
release.43 Again, eicosanoid production could be involved in
this process; however, in vitro studies have suggested that
eicosanoid inhibitors have no effect on alterations of chemiluminescence of peritoneal macrophages incubated with
either arachidonic or eicosapentaenoic acid.44 Animal studies
offer some results that reveal the effects of n-3 fatty acids on
phagocytosis. Dietary n-3 fatty acids inhibit45 or do not
affect46 phagocytosis promoted by macrophages, although
this function has not been demonstrated in humans.
In monocytes, a reduction of stearic and arachidonic acid
and an increase of eicosapentaenoic and docosahexaenoic
acid content have been associated with a reduction in superoxide production, as well as the action of other free radicals.47
Chemotaxis has also been reduced by dietary n-3 polyunsaturated fatty acids in a study carried out for long-term supplementation.48 In contrast, short-term supplementation and a
low concentration of n-3 polyunsaturated fatty acids do not
show any significant effect on monocyte chemotaxis.49 This
effect seems to be attributed to a deficiency of docosahexaenoic acid,49 although, as previously mentioned, a recent
study has revealed that this polyunsaturated fatty acid does
not promote any inhibitory effect on different functions of
immune system.10
Mechanisms involved in fatty acid modulation
As discussed previously, the quantity and nature of lipids are
important factors in the process of immune system modulation. Several mechanisms have been involved in the modulation of the immune system by fatty acids: (i) membrane
fluidity; (ii) production of lipid peroxides; (iii) eicosanoid
synthesis; and (iv) influence on gene regulation. It is possible that fatty acid immunomodulation occurs not only by the
individual, but also by the collective action of these factors.
Figure 1 shows the different mechanisms proposed by which
dietary lipid manipulation or free fatty acids added into
cellular cultures may modulate the immune system.
Membrane fluidity
As a consequence of changes in the phospholipid fatty acid
composition due to dietary lipid manipulation, the fluidity of
the cell membrane may change. Fatty acids from dietary
lipids may be incorporated into any of the different phospholipids within the plasma membrane and they are clearly
altered by the availability of dietary lipids. The changes in
fatty acid composition of this structure have great importance
because of the alteration of plasma membrane characteristics.
This fact may be attributed to changes produced in the activity of proteins associated with the membrane, which act as
receptors, form ion channels or are related to enzymatic functions. As a result, binding of cytokines to their respective
receptors on the cell membrane surface may be altered.50,51
Specific macrophage functions may also be altered by lipids,
mainly due to changes in membrane fluidity. In fact, unsaturated fatty acid incorporation is associated with an increase
in the phagocytosis of zymosan particles and the correlation
between phagocytosis and membrane phospholipid has been
demonstrated to be very high.42 It is possible that the changes
in the expression of surface proteins may be due to a vertical
displacement of the membrane proteins by lipid action.52
Expression of surface molecules such as adhesion and major
histocompatibility molecules from human monocytes are
inhibited by eicosapentaenoic acid.53 Instead, a significant
increase in the expression of human lymphocyte antigen
(HLA) is observed in monocytes incubated with docosahexaenoic acid.53
Dietary fatty acids and immunomodulation
Lipid peroxidation
The inhibitory effects of fatty acids on cellular proliferation
may be related to lipid peroxidation. Lipid peroxides are toxic
to cells; in fact, polyunsaturated fatty acids derived from the
n-3 family are incorporated into the cell membrane and
increase the requirements for antioxidant nutrients, such as
tocopherol, which protects membrane polyunsaturated fatty
acids from lipid peroxidation.54 Several reports, however,
have suggested that the lipid peroxidation is not responsible
for the inhibitory effects of fatty acids on lymphocytes
because the addition of antioxidant substances does not avoid
the suppression of mitogen lymphocyte proliferation performed by fatty acids.55,56 Dietary fish oil has been described
as enhancing antioxidant enzyme mRNA levels and decreasing free radical-induced tissue damage in vivo.57 Hence, this
argument (which points out the possibility of increasing the
activity of antioxidant enzymes) and the importance of incorporating an antioxidant, such as tocopherol, in diets containing fish oil produce the reduction of thiobarbituric
acid-reactive substance (TBARS) production.58 In addition,
polyunsaturated fatty acids are more sensitive to lipid peroxidation than are monounsaturated or saturated fatty acids.
Incorporation of polyunsaturated fatty acids into membranes
increases lipid peroxidation and this affects the expression of
surface molecules. This fact may be related to the suppression of HLA-DR expression due to free radical production.59
This argument is confirmed by a recent study reporting that
dietary supplementation with β-carotenes increases the
expression of histocompatibility and adhesion molecules on
human peripheral blood monocytes.60
Eicosanoid production
Classical studies have described that several members
belonging to the eicosanoid family derived from arachidonic
acid participate in inflammatory processes and are also
related to immunomodulatory effects.61 Fatty acids are
released from the phospholipids that compose the plasma
membrane and undergo enzymatic degradation to yield
eicosanoids, which act as lipid mediators. For example,
prostaglandin E2 or leukotriene B4 (derived from arachidonic
acid) exert a great number of functions, such as modulation
of lymphocyte proliferation,62 cytokine production63,64 and
cytotoxicity.40 However, dietary n-3 polyunsaturated fatty
acids reduce the levels of arachidonic acid in the cell membrane and as a consequence, the levels of prostaglandins
derived from arachidonic acid are reduced. The products
derived from n-3 fatty acids (as eicosapentaenoic acid) show
different biological properties in comparison with those
derived from arachidonic acid. Prostaglandin E3 is derived
from eicosapentaenoic acid and several studies have demonstrated that in vitro mitogen-stimulated lymphocyte proliferation is inhibited by the action of this prostaglandin.62
Similarly, leukotriene B5 is also derived from eicosapentaenoic acid and it is generally assumed that its biological
activities are lower than leukotrienes derived from arachidonic
acid. However, leukotriene B5, as well as prostaglandin E3, are
more potent than eicosanoids derived from arachidonic acid
in inhibiting lymphocyte proliferation.62 In contrast, assays
carried out with inhibitors of eicosanoid synthesis have
35
reported that these substances are unable to retain the
inhibitory effect of fatty acids exerted on lymphocyte proliferation. Based on this fact, several authors have suggested
that unsaturated fatty acids inhibit lymphocyte proliferation
by a mechanism independent of eicosanoid synthesis.65,66
Regardless of these observations, eicosanoids regulate a great
number of inflammatory effects, such as induction of fever,
vasodilatation and production of macrophage- and lymphocyte-derived cytokines64 and their effects depend on each
precursor. This is because, as discussed previously,
eicosanoids produced from eicosapentaenoic acid show
different biological activities than eicosanoids produced
from arachidonic acid.
Regulation of gene expression
In addition to participation in the production of eicosanoids
(which also modulate signal transduction through an indirect
pathway), fatty acids are of major relevance because they are
key determinants of membrane-bound enzyme and receptor
expression. The influence of fatty acids on gene expression is
still poorly understood. Nevertheless, fatty acids released
from membrane phospholipids are important second messengers or substitute for the classical second messengers, such as
inositide phospholipid or cyclic AMP signal transduction
pathways, because they act in a reversible manner at a precise
intracellular location for a very short time in order to amplify,
attenuate or deviate a signal in a direct or indirect (by conversion from arachidonic acid to eicosanoids) pathway.67
Several studies have shown that administration of fish oil in
the diet of autoimmune disease-prone mice produces an
increase in the levels of mRNA for several cytokines, such as
IL-2, IL-4 and transforming growth factor (TGF)-β.68 In the
same way, dietary fish oil reduces mRNA production of
IL-1, IL-6 and TNF-α.69 These findings confirm the important role of fatty acids as substances capable of modifying
and influencing signal transduction pathways, mainly through
modulation of protein kinase C (PKC) activity.70
In vitro and in vivo studies of fatty acids as inducers of
apoptosis
Irrespective of the data that support the important role of the
previously cited mechanisms involved in the modulation of
the immune system by fatty acids, recent studies have
reported the effects of several fatty acids on apoptosis induction of in vitro cultured cells. Palmitic acid (a saturated fatty
acid) induces cell death by dissipation of the mitochondrial
transmembrane potential (∆ψm), the process that precedes
nuclear apoptosis. These data show that palmitate-induced
apoptosis involves a direct effect on mitochondria and an
important regulation by anti-apoptotic proto-oncogene
product Bcl-2 occurs.71 In fact, a cell-free system assay has
demonstrated that the induction of apoptosis occurs via a
direct effect on mitochondria, so that palmitate causes the
release of soluble factors capable of inducing the apoptosis of
isolated nuclei.71 Another study has demonstrated that
palmitic and stearic acid induce apoptosis by de novo synthesis of ceramide and, in fact, etomoxir (an inhibitor of mitochondrial protein as carnitine palmitoyl transferase, CPT I)
enhances palmitate-induced cell death. As a consequence of
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this fact, an increase of ceramide was reported,72 although
some discrepancies have been observed because, as mentioned previously, it is probable that palmitate-induced apoptosis occurs by a direct effect on mitochondria (not mediated
via ceramide).71 Another fatty acid, eicosapentaenoic acid,
has been studied as an apoptosis inducer. This fatty acid promotes apoptosis induction in monocytic U937-1 cells.73 In
contrast, docosahexaenoic acid reduces the apoptotic effects
induced by sphingosine (an important second messenger). In
this case, the inhibition of cytosolic phospholipase A2 could
be involved in the inhibitory activity of this polyunsaturated
fatty acid.74 In addition to influence on in vitro cultures,
dietary fatty acids may induce apoptosis, because a recent
study has demonstrated that splenic cells from mice fed
hyperlipidic diets containing saturated fatty acids were more
susceptible to death by apoptosis than splenic cells from mice
fed unsaturated fatty acids.75 It is noteworthy that these findings may provide another mechanism by which fatty acids
promote immune system modulation. In this discipline,
further studies will be needed in order to know more about
the implication of fatty acids as inducers of apoptosis, as well
as the molecular mechanisms involved in these processes.
Modulation of the immune system by fatty acids
modifies the response to bacterial or viral infection
Clinical studies have demonstrated that experimental animals
fed with diets containing a high concentration of unsaturated
fatty acids show a reduced resistance to different infections or
improve their immune response to micro-organisms. Survival
studies have suggested a direct implication of several fatty
acids in modulation of the immune response in order to
produce an amelioration effect for both humans and animals
suffering from inflammatory disorders. However, these
effects were inefficient in the treatment of infectious diseases.
Experimental infection has been carried out in animals fed
dietary lipids in order to determine the ability of each oil to
promote changes in the modulation of the immune response.
In these studies, contradictory results have been found again.
Whereas eicosapentaenoic, docosahexaenoic or oleic fatty
acids may be applied to the amelioration of autoimmune disorders,18–21 several fatty acids have been shown to be inefficient because they impair resistance to experimental
infection.33,76 Diets supplemented with eicosapentaenoic and
docosahexaenoic acids (present in fish oil) affect resistance
to Mycobacterium tuberculosis.76 Dietary fish oil reduces
survival against L. monocytogenes and it also impairs the
clearance of this bacterium from the spleen,33 while diets containing saturated fatty acids help to eliminate micro-organisms such as L. monocytogenes more efficiently than diets
containing unsaturated fatty acids.33 In the same way, infection of mice fed a diet rich in fish oil with Salmonella
typhimurium has been reported to be more severe, because of
a reduction in these mice in resistance to infection by this
bacterium.77 In contrast, other studies have reported that a
fish oil-enriched diet increases mice survival following
Klebsiella pneumoniae infection25,78 or that a reduction in
development of parasites as Eimeria tenella occurs in chickens fed a diet containing n-3 fatty acids.79 Therefore, as we
have mentioned earlier, several studies have observed that
dietary polyunsaturated fatty acids may promote host resistance against certain infectious pathologies,33,76 whereas
others have suggested that polyunsaturated fatty acids participate in the amelioration of these diseases.25,78 Finally, many
studies have reported the effects of n-3 fatty acids on patients
infected with human immunodeficiency virus. These fatty
acids have been applied as coadjuvant treatment administered
to these patients. Results from this study have demonstrated
an increase in survival and a reduction in inflammatory
responses.80 In the same way, a fish oil-enriched diet has also
been described as able to increase significantly survival of
murine acquired immunodeficiency syndrome in mice fed
this diet.81
Dietary fatty acids and inflammatory disorders
Activated T lymphocytes play an important role in the pathogenesis of many inflammatory diseases. The inflammatory
process is the physiological response of the organism to
stimuli promoted by micro-organisms or immunological
mechanisms. Measurements of IL-2 production derived from
overactivity of T lymphocytes, B lymphocyte activation and
an increase in IL-2 receptor levels have produced contradictory results in patients suffering from these pathologies.82,83
Patients suffering from autoimmune disorders have been fed
diets containing eicosapentaenoic, docosahexaenoic or oleic
acid. The results obtained have revealed a significant
amelioration of the inflammatory processes in these patients.
In fact, patients suffering from rheumatoid arthritis fed with
n-3 polyunsaturated fatty acids or olive oil showed a great
amelioration of typical symptomatology caused by this
disease.18 Psoriasis is another autoimmune disease characterized by elevated levels of arachidonic acid and products
derived from 5-lipoxygenase. Therefore, the dietary supplementation of n-3 polyunsaturated fatty acids should reduce
the levels of these substances and, in particular, eicosapentaenoic acid has been demonstrated as an effective subtance
in the treatment of this disease.19,55 In patients affected by
multiple sclerosis, abnormalities in the fatty acid intake have
been described84 and a controlled trial in multiple sclerosis
patients treated with n-3 polyunsaturated fatty acids for a
very long period has shown some beneficial effects for these
patients.20 Clinical studies have also demonstrated the importance of the dietary supplementation of n-3 fatty acids in
patients suffering from systemic lupus erythematosus. A
significant reduction in the symptomatology of lupus was
reported after dietary lipid administration.82,83
Knowledge of how fatty acids promote immune regulation
and the function of cells involved in host defence will lead to
the development of treatments that may be applied to patients
affected by diseases characterized by an overactivation of the
immune system. However, the beneficial aspect of dietary
fatty acids on the reduction of inflammatory disorders in
these patients must be balanced by the fact that at the same
time they may impair the ability to efficiently eliminate
infectious micro-organisms.
Concluding remarks
The nutritional status of both humans and animals has been
related to alteration of the immune response. Thus, numerous
Dietary fatty acids and immunomodulation
studies have described that several dietary fatty acids or free
fatty acids are involved in the modulation of the immune
system through mechanisms that modify the immune
response. The immune parameters susceptible to modification by fatty acids supplied in the diet or free fatty acids
added into cellular cultures are lymphocyte proliferation,9,13
cytokine production,4,6,22,23 activity of NK cells,4,35,38 phagocytosis,23,42,47 expression of markers in the surface of the
cells52 and so on (Table 1). The immune system modulation
induced by fatty acids depends on several biological and
methodological factors, such as the type and concentration of
fatty acids, cell types, species of experimental animals, serum
used in the ex vivo or in vitro cultures and so on. Thus, the
effects of dietary fatty acids or free fatty acids on the immune
response of ex vivo or in vitro cultures are complex, because
they depend on many factors and several discrepant results
have been reported.85,86 Actually, many mechanisms involved
in modulation of the immune system by fatty acids are
unknown or poorly understood, although current understanding allows us to point out several factors that seem to participate in this process. These factors are: (i) membrane fluidity,
which is modified as a consequence of changes in phospholipid composition; (ii) formation of lipid peroxides, which are
toxic to the cells; (iii) eicosanoid production from long-chain
fatty acids, showing different biological properties depending
on their precursors; and (iv) influence on the regulation of the
expression of genes encoding proteins that participate in cellular responses (Fig. 1). The mentioned immunomodulation
associated with fatty acids may be applied to the amelioration
and prevention of diseases characterized by an overactivation
of the immune system, such as inflammatory or autoimmune
disorders.18–21 In addition to these applications, unsaturated
fatty acids may be used to reduce the susceptibility against
bacterial infections due to the possibility of several lipids
playing important roles in the efficient elimination of different micro-organisms or reducing host resistance against an
infectious process due to the immunosuppression promoted
by dietary unsaturated fatty acids. It should be noted that
immunosuppression promoted by different dietary lipids has
to be balanced, because this process may lead to an impairment of host response33,76 and increase the risk of infections.35
Recently, several reports have described the important role
of fatty acids as apoptosis inducers or as substances capable
of reducing cell death in cellular cultures.71–75 It is very
important to determine the role of free fatty acids in programmed cell death as a possible mechanism of action in the
modulatory activity attributable to fatty acids.
Overall, the studies carried out show that fatty acids play
an important role in immune system regulation through
complex mechanisms and therefore they may be classified as
substances capable of participating in the modulation of
immune response. These substances could be used as therapy
for the treatment of inflammatory disorders.
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