Conjugated linoleic acid and inammatory cell signalling

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C.M. Reynolds, H.M. Roche
n
Nutrigenomics Research Group, UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Beleld, Dublin 4, Ireland
a b s t r a c t
Conjugated linoleic acids (CLA) are a family of polyunsaturated fatty acids (PUFA), some isomers
occurring naturally in beef and dairy products and others being formed as a result of bihydrogenation of
vegetable oils to form margarine. Synthetic and natural sources of CLA may have benecial effects in a
range of inammatory conditions including colitis, atherosclerosis, metabolic syndrome and
rheumatoid arthritis. Most of the biological effects have been attributed to the cis9, trans11-
(c9, t11-) and the trans10, cis12- (t10, c12-) isomers. Evidence suggests that c9, t11-CLA is responsible
for the anti-inammatory effect attributed to CLA while t10, t12-CLA appears to be responsible for anti-
adipogenic effects. This review will focus on the effects of CLA on the inammatory components
associated with insulin resistance, atherosclerosis and Th1 mediated inammatory disease, at a cellular,
systemic and clinical level. Whist CLA may ameliorate certain aspects of the inammatory response,
particularly within cellular and animal models, the relevance of this has yet to be claried within the
context of human health.
& 2010 Elsevier Ltd. All rights reserved.
1. Introduction
Conjugated linoleic acid (CLA) describes positional and geo-
metric isomers of linoleic acid. Twenty eight CLA isomers have
been identied in milk, dairy and beef products [1]. These isomers
have conjugated double bonds which are not separated by a
methylene group (Fig. 1). The predominant isomer in dietary
sources is cis9, trans11-CLA (c9, t11-CLA) which constitutes up to
90% of total CLA [2] and is thought to be responsible for the
positive health benets associated with CLA [35]. Trans10,
cis12-CLA (t10, c12-CLA) is another common isomer which
accounts for 110% of total CLA from dietary sources [6] and is
associated with the anti-obesity effects seen with CLA [79].
CLA is produced as an intermediate in the bacterial
biohydrogenation of linoleic acid to stearic acid in ruminant
animals [10]. It can be incorporated into tissues or biohydroge-
nated further to trans-vaccenic acid (TVA) [11]. TVA is the main
trans fatty acid in ruminant products accounting for approxi-
mately 2% of total fatty acid content in cows milk [12]. The high
abundance of c9, t11-CLA in milk and beef, along with evidence
that non-ruminant animals can endogenously produce c9, t11-
CLA, can be attributed to the conversion of TVA to c9, 11-CLA by
delta 9 desaturase [13]. Bioconversion of TVA to c9, t11-CLA has
been conrmed in humans [14], rats [15] and mice [16].
CLA has potent immunomodulatory effects that are exhibited
in an isomer specic manner. These effects have been demonstrated
in a wide range of inammatory based disorders including
inammatory bowel disease (IBD) [17,18], atherosclerosis [1921]
and diabetes [2225]. This review focuses on the biological effects
of CLA in lipopolysaccharide (LPS) induced inammation, type-2
diabetes mellitus (T2DM), and cardiovascular disease (Fig. 2).
2. CLA and inammation
In response to infection or injury, cells of the innate immune
system secrete an array of inammatory mediators which
inuence the direction of the subsequent adaptive immune
response. Dendritic cells (DCs) are at the forefront of this innate
immune response. Activation of DC with an inammatory
stimulus leads to maturation and subsequent migration to the
lymph nodes where they present antigen to na ve T cells [26]. DC
secrete two unique cytokines IL-10 and IL-12 that elicit opposing
bioactive inammatory effects. IL-12 is a heterodimeric cytokine
composed of a p35 and a p40 subunit. The p40 subunit can bind to
a p19 subunit to form IL-23, a cytokine involved in differentiation
of Th17 cells. IL-12 promotes differentiation of na ve Th cells to
Th1 cells which produce interferon gamma (IFN-g), tumor
necrosis factor beta (TNF-b), and interleukin 2 (IL-2), while
IL-10 promotes regulatory T cell differentiation which produce
transforming growth factor beta (TGF-b) and IL-10 [27,28]. In
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Contents lists available at ScienceDirect
journal homepage: www.elsevier.com/locate/plefa
Prostaglandins, Leukotrienes and
Essential Fatty Acids
0952-3278/$ - see front matter & 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.plefa.2010.02.021
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Funding support: CMR was funded by the Food Institutional Research Measure,
Department of Agriculture and Food, Ireland (Project Number: 5254). The authors
have no nancial conict of interest.
n
Corresponding author. Tel.: +353 1 7166845; fax: +353 1 7166701.
E-mail address: helen.roche@ucd.ie (H.M. Roche).
Prostaglandins, Leukotrienes and Essential Fatty Acids 82 (2010) 199204
ARTICLE IN PRESS
addition IL-10 is known to inhibit DC and macrophage production
of MHC class II and co-stimulatory molecule expression, thereby
preventing migration to lymph nodes and production of pro-
inammatory cytokines and chemokines such as IL-12, TNFa,
IL-1b, MIP-2 and RANTES [29]. It is well established that
overproduction of these cytokines can be instrumental in the
pathogenesis of both acute and chronic inammatory diseases.
Loscher et al. [4] examined the immunomodulatory potential
of c9, t11-CLA on bone marrow derived DC (BMDC). BMDC were
incubated with c9, t-11-CLA for 37 days and then stimulated
with LPS to induce maturation. C9, t11-CLA reduced both protein
and mRNA concentrations of IL-12p70 and IL-12p40 while
increasing protein and mRNA concentrations of IL-10 and
increasing surface expression of the IL-10 receptor. Furthermore,
this study showed that c9, t11-CLA enhanced pERK expression.
C9, t11-CLA mediated effects were reversed in the presence of an
IL-10 neutralizing antibody. This study also established that c9,
t11-CLA decreased nuclear nuclear factor kappa B (NF-kB)
concentrations and increased cytosolic NF-kB and IkBa concen-
trations, suggesting that CLA delays LPS-induced translocation of
NF-kB by preventing degradation of IkBa, a protein which
sequesters NF-kB in the cytosol. This was reversed in the presence
of an IL-10 neutralizing antibody. These ndings suggest that c9,
t11-CLA may have therapeutic potential in the treatment of
Th1 mediated diseases.
To examine the anti-inammatory effects of CLA in response to
LPS, Zhao et al. [30] injected LPS into pigs fed with CLA for 1421
days. TNF-a production and mRNA expression in PBMC was
signicantly reduced in CLA-fed animals. In a complementary
study PBMC were stimulated ex vivo with LPS following treatment
with c9, t11-CLA or t10, c12-CLA. TNF-a secretion and mRNA
expression were reduced by both isomers. Furthermore, the
reduction observed in PBMC TNF-a concentrations were
attributed to the attenuation of NF-kB signalling.
The anti-inammatory potential of c9, t11-CLA has also been
demonstrated in animal models of IBD. In a recent study, colitis
was induced in mice using 2.5% dextran sodium sulphate (DSS)
following dietary CLA supplementation [18]. CLA-fed mice were
protected from colitis-induced weight loss, rectal bleeding and
colonic tissue damage. Further investigation demonstrated that
the mechanism responsible for CLA-mediated protection from
colitis was up-regulation of PPARg and PPARd and a subsequent
reduction in NF-kB mediated inammation. The anti-inamma-
tory potential of CLA was also demonstrated in a pig model of
colitis [17]. Following supplementation with CLA colitis was
induced using DSS. CLA-fed animals had reduced colitis-induced
weight loss and rectal bleeding. Furthermore CLA-fed pigs had
increased PPARg and PGC1-a and decreased UCP3 and TNFa.
3. CLA, the metabolic syndrome and type 2 diabetes
The metabolic syndrome (MetS) describes an array of
metabolic abnormalities including central obesity, insulin resis-
tance, elevated triacylglycerol (TAG) concentrations, microalbu-
minurea and hypertension [31,32]. It is associated with increased
risk of developing T2DM. Obesity and insulin resistance are
associated with chronic low-grade inammation. Adipocytes are
known to produce an array of cytokines such as leptin, resistin,
adiponectin, IL-6, MCP-1, IL-1b and TNF-a. Excessive expression
of these adipokines occurs during obesity, which in turn is
implicated in the induction of insulin resistance [3335]. More
recently obesity-induced insulin resistance has been associated
with the inltration of immune cells such as macrophages and
T lymphocytes [36]. Weisberg et al. [37] demonstrated that these
adipose tissue-derived macrophages were of bone marrow origin.
These cells form crown like structures around dying adipocytes
indicating that their purpose in adipose tissue is to clear away
dead cells [38]. Inammatory mediators produced by these
inammatory cells disrupts insulin signalling pathways in
adipocytes and leads to further accumulation of macrophages
exacerbating insulin resistance in the adipose tissue [39]. The role
of CLA isomers in the alteration of body fat [40] in addition to
anti-inammatory effects [41,4] make CLA a prime candidate for
dietary treatment of insulin resistance. Furthermore several
studies have demonstrated the anti-inammatory effects of CLA
in macrophages [4244] which are thought to inuence the
metabolic abnormalities associated with obesity.
The anti-diabetic effects of CLA were examined by Moloney
et al. [22]. This study aimed to determine whether the anti-
inammatory properties of c9, t11-CLA were responsible for the
resolution of insulin resistance in obese mice. Six week old ob/ob
mice received a high fat diet enriched in c9, t11-CLA or linoleic
acid for 6 weeks. While there was no difference in body weight,
food intake and adipose tissue mass, indicators of insulin
C liti Colitis
Reduced body fat Pro-inflammatory Reduced body fat
accumulation
Pro-inflammatory
cytokine levels y
CLA c9 t11 t10 c12 CLA c9, t11 t10, c12
Liver steatosis
Insulin resistance
Liver steatosis
Atherosclerosis Atherosclerosis
Fig. 2. Health effects of c9, t11-CLA, t10, c12-CLA and mixed CLA isomers.
COOH
Linoleic acid
COOH
c9, t11-CLA
COOH
t10, c12-CLA
Fig. 1. Structure of linoleic acid, c9, t11-CLA and t10, c12-CLA.
C.M. Reynolds, H.M. Roche / Prostaglandins, Leukotrienes and Essential Fatty Acids 82 (2010) 199204 200
ARTICLE IN PRESS
resistance including fasting plasma glucose, insulin and TAG
concentrations were all signicantly reduced in the c9, t11-CLA
group. Furthermore, measures of insulin sensitivity, HOMA-IR and
revised QUICKI and levels of insulin signalling pathway proteins
GLUT4 and IRS-1 were increased in the c9, t11-CLA group. In
addition to positive changes in the metabolic prole of the c9,
t11-CLA group, this study also demonstrated a reduction in
macrophage inltration into the adipose tissue of mice and
decreased adipose tissue mRNA expression of the pro-inamma-
tory molecules MCP-1, CD68, IL-6 and TNF-a. This may result
from the observed decrease in adipose tissue NF-kB
signal transduction. A complementary in vitro study in 3T3-L1
adipocytes demonstrated that treatment with c9, t11-CLA
reduced TNF-a mRNA concentrations and reverses TNF-a-
mediated down-regulation of GLUT4 and IRS-1. These ndings
demonstrate that c9, t11-CLA promotes insulin sensitivity by
reducing adipose tissue inammation.
Several studies have demonstrated that the positive anti-
diabetic effects associated with CLA are isomer specic and while
the c9, t11-CLA isomer has anti-inammatory, insulin sensitising
effect, the opposite is true for the t10, c12-CLA isomer [45]. The
t10, c12-CLA isomer has been associated with weight loss and
reduction of fat stores [46,47], However, recent evidence has
revealed that this isomer may induce liver steatosis and insulin
resistance [48,49]. A recent study by Poirier et al. [50] investigated
the effects of t10, c12-CLA in white adipose tissue. Despite a
reduction in body weight and adipose tissue mass, t10, c12-CLA
treated mice had signicantly increased TNF-a, IL-6 and SOCS3
adipose tissue mRNA expression but reduced adiponectin, leptin,
resistin and PPARg mRNA expression. T10, c12-CLA treated mice
also had increased macrophage inltration. Further investigation
revealed that increased pro-inammatory cytokine production
was due to direct effects of t10, c12-CLA on adipocytes. This
isomer activated NF-kB leading to increased IL-6 production. T10,
c12-CLA mediated inammation of white adipose tissue may lead
to the induction of insulin resistance.
These ndings demonstrate that caution must be taken when
considering the therapeutic potential of CLA in insulin resistance.
C9, t11-CLA has clear benecial effects, reducing macrophage
inltration and inammation and improving insulin sensitivity in
mouse models [22,51,52]. In contrast, the weight loss potential of
t10, c12-CLA is overshadowed by increasing evidence of liver
steatosis and insulin resistance [53,23]. As discussed in more
detail later in the review, supplementing the diet of patients with
T2DM with CLA results in increased fasting glucose concentra-
tions, potentiated oxidative stress and reduced insulin sensitivity
[54,55]
4. CLA and atherosclerosis
Atherosclerosis is another chronic inammatory disorder
resulting from metabolic abnormalities and can lead to stroke
and myocardial infarction [52]. Macrophages are also known to
play a key role in the pathogenesis of atherosclerosis [53,56,57].
CLA has been shown to have benecial effects in animal models of
atherosclerosis. Both mixtures and individual isomers of CLA have
been shown to reduce atherosclerotic lesions and improve plasma
lipid proles in rabbits [58,59], hamsters [60] and mice [61].
Toomey et al. [20] demonstrated that a blend of CLA isomers
(80% c9, t11-CLA and 20% t10, c12-CLA) signicantly reduced pre-
established atherosclerotic lesions in male ApoE decient mice.
Atherosclerosis was induced by feeding animals a 1% cholesterol
chow for eight weeks. This was followed by 8 weeks on
1% cholesterol chow supplemented with either saturated fatty
acid (SFA) or CLA mixture. Animals fed SFA had greater lesion area
and increased macrophage inltration. CLA-fed animals had
signicant regression of atherosclerotic plaque and decreased
macrophage inltration into lesions despite no change in plasma
cholesterol or TAG. This was accompanied by increased
concentrations of PPARg and PPARa in atherosclerotic lesions.
Activation of these nuclear receptors suppresses development of
atherosclerosis [62].
The divergent effects of CLA isomers is also evident in animal
models of atherosclerosis [21,63]. A recent study [64] investigated
the effects of c9, t11-CLA and t10, c12-CLA in ApoE decient mice.
Animals were fed a high-fat, high-cholesterol diet supplemented
with c9, t11-CLA, t10, c12-CLA or linoleic acid for 12 weeks. The
c9, t11-CLA group had reduced plasma TAG, NEFA, glucose and
insulin concentrations while these biomarkers were increased in
the t10, c12-CLA group. Lesion size was signicantly reduced in
the c9, t11-CLA group and increased in the t10, c12-CLA group.
Furthermore macrophage migration inhibitory factor (MIF) was
down-regulated in the c9, t11-CLA group and to a lesser extent
the t10, c12-CLA group.
5. CLA: clinical studies
There have been few studies demonstrating the effects of CLA
isomers on inammation in humans. Furthermore the few studies
that have been conducted do not correlate with the dramatic
effects seen in animal models [6567]. Current evidence suggests
that dietary intakes of CLA from milk, cheese and beef range
between 15 and 430 mg/day [68], falling short of the suspected
amount required for health benets associated with this fatty
acid. Therefore human intervention has relied on supplements or
enriched dietary CLA sources. Several studies have shown
detrimental effects on markers of insulin resistance and cardio-
vascular disease particularly following supplementation with the
t10, c12-CLA isomer. A randomised double-blind placebo-con-
trolled trial in obese men [69] showed that t10, c12-CLA
supplementation over 3 months led to a decrease in insulin
sensitivity which was accompanied by increased pro-insulin,
C-reactive protein, lipid peroxidation and fasting glucose. This
group also investigated the effect of 3 month supplementation
with c9, t11-CLA in obese men [52]. While this isomer did not
exhibit as extreme an effect as the t10, t12-CLA isomer, insulin
sensitivity was decreased. Several studies have demonstrated that
supplementation with mixed CLA isomers does not improve
markers of insulin resistance and CVD in risk prone patients.
Tholstrup et al. [70] demonstrated supplementation of 4.6 g CLA
mixed isomers per day for 16 weeks in post-menopausal women
increased plasma TAG, CRP, brinogen and PAI-1 concentrations
while decreasing plasma HDL concentration. Contrary to this,
Moloney et al. [54] showed that daily supplementation with 3 g of
a 50:50 mixture of c9, t11-CLA and t10, c12-CLA for 8 weeks
had a positive effect on HDL cholesterol and decreased the
pro-thrombogenic factors CRP and brinogen. While there was an
increase in HOMA, the oral glucose insulin sensitivity (OGIS) was
unchanged. As this index incorporates both fasting and post-
prandial data it may serve as a better measure of insulin
sensitivity [71]. Analysis of the plasma lipid concentrations of
these subjects demonstrated increased c9, t11-CLA following
supplementation, however t10, c12-CLA was undetectable in
samples.
Given the conicting evidence in regard to the effects of CLA in
human disease, several groups have investigated the effects of
CLA isomers on healthy volunteers. Similar to studies investigat-
ing the role of CLA in human and animal disease states, effects of
CLA were inconsistent. Noone et al. [72] demonstrated that
supplementation with 3 g/d of 50:50 and 80:20 mixtures of c9,
C.M. Reynolds, H.M. Roche / Prostaglandins, Leukotrienes and Essential Fatty Acids 82 (2010) 199204 201
ARTICLE IN PRESS
t11-CLA and t10, c12-CLA for eight weeks had positive effects on
some CVD risk factors. While there was no effect on plasma
cholesterol, NEFA, glucose and insulin concentrations, CLA
decreased VLDL-TAG and VLDL-cholesterol concentrations. The
50:50 isomer mixture also decreased plasma TAG concentration.
Another study where healthy middle aged men supplemented
their diet for 8 weeks with a mixture of CLA isomers [73] showed
no differences in plasma cholesterol, TAG or glucose concentra-
tions. However this study demonstrated that PBMC stimulated
ex vivo with Con-A have signicantly reduced concentrations of
IL-2, a cytokine with pro-atherogenic effects [74]. Furthermore a
recent study by Nazare et al. [75] demonstrated that feeding CLA
enriched yogurts to healthy humans increased PPARg mRNA
production in adipose tissue, but did not have any signicant
effect on molecular markers of body composition or serum lipid
markers. While these studies provided evidence of a moderately
benecial CLA mediated effect, Smedman et al. [76] showed that a
3 months supplementation with 4.2 g/day CLA mixture increased
plasma CRP levels. However, for the most part CLA supplementa-
tion in healthy humans has a neutral effect on markers of
atherogenesis and immune function [7780].
6. Conclusion
To date there is no clear consensus regarding the role of CLA in
inammatory diseases.
In vitro and in vivo studies have demonstrated a range of
molecular mechanisms through which CLA acts including altera-
tion of eicosanoid synthesis [81], reduction of NF-kB signalling
proteins [82,83], activation of PPARg [17,18,84] and alteration of
cytokine levels [85,4] (Fig. 3). However the clear, and in some
cases, profound effects demonstrated by CLA supplementation
in animal models of T2DM and atherosclerosis have yet to be
veried in humans. Furthermore, the positive effects
demonstrated in animal models of intestinal inammation and
septic shock have yet to be veried in humans. The nature of
in vivo animal experiments may be responsible for the
inconsistencies between human and animal studies whereby
larger amounts of CLA are provided to animals in a closely
controlled setting where disease is articially induced.
Furthermore genetic variability in humans can account for
varied effects in human cohorts and the cell specic effects of
CLA seen in in vitro models may not be reective of the overall
disease state. Indeed there have been limited numbers of human
intervention studies in sub-acute inammatory diseases and the
required amount of CLA from dietary intake has yet to be veried.
Furthermore differences in experimental design may account for
inconsistencies across studies (differences in age, gender, CLA
quantity given, CLA isomer, length of dietary intervention and
composition of controlled placebo groups). Naturally derived CLA
is associated with foods such as beef, milk, butter and cheese
which are rich in saturated fatty acids. This creates an additional
problem as supplementation of CLA through enriched natural
sources may be associated with increased risk of CVD and T2DM
due to the intake of saturated fatty acids. Therefore further
research on the effects, and indeed the safety, of CLA in terms of
human disease must be conducted before CLA can be considered
as a functional food component.
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CLA
CD14
CLA
TLR4
TIRAP
CD14
CLA
TIRAP TOLLIP
M D
COX-2
MyD88
IRAK
Eicosanoids
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