M

Rf

HT

a

ARRAA

KPgID

1

rsaaiacarawc

adipa

0d

Mutation Research 669 (2009) 1–7

Contents lists available at ScienceDirect

Mutation Research/Fundamental and MolecularMechanisms of Mutagenesis

journa l homepage: www.e lsev ier .com/ locate /molmutCommuni ty address : www.e lsev ier .com/ locate /mutres

ini review

ole of PPAR-gamma in inflammation. Prospects for therapeutic intervention byood components

arry Martin ∗

he New Zealand Institute for Plant & Food Research Limited, Palmerston North 4474, New Zealand

r t i c l e i n f o

rticle history:eceived 22 May 2009eceived in revised form 16 June 2009ccepted 20 June 2009vailable online 27 June 2009

eywords:eroxisome proliferator activated receptoramma (PPAR�)

a b s t r a c t

Peroxisome proliferator activated receptor gamma (PPAR�) is a ligand-dependent transcription factorand a member of the nuclear receptor superfamily. Acting as sensors of hormones, vitamins, endoge-nous metabolites and xenobiotic compounds, the nuclear receptors control the expression of a verylarge number of genes. PPAR� has been known for some time to regulate adipocyte differentiation, fattyacid storage and glucose metabolism, and is a target of anti-diabetic drugs. More recently, PPAR� hasbeen recognized as playing a fundamentally important role in the immune response through its abil-ity to inhibit the expression of inflammatory cytokines and to direct the differentiation of immune cellstowards anti-inflammatory phenotypes. A feature of PPAR� is the structural diversity of its ligands, which

nflammatory diseaseiet

encompass endogenous metabolites, dietary compounds and synthetic drugs. The high and increasingincidence of inflammatory and allergic disease, coupled with encouraging results from recent clinicaltrials, suggest that natural PPAR� agonists found in foods may be beneficial to human health by actingas anti-inflammatory molecules. PPAR� is therefore not only a target of the pharmaceutical industry, butalso of great potential interest to the food industry, since it is activated by several natural dietary con-stituents. The prospects for dietary intervention in inflammatory disease have improved somewhat overthe last few years, and are reviewed here.

. Introduction—PPAR� and its role in inflammation

Inflammatory disease is a broad term encompassing a wideange of pathological conditions affecting many organs and tis-ues. Inflammatory diseases include inflammatory bowel disease,therosclerosis, rheumatoid arthritis, multiple sclerosis, asthmand psoriasis. The incidence of atopic illness including asthma hasncreased considerably over recent decades [1]. Ulcerative Colitisnd the less prevalent, but more severe, Crohn’s disease, were bothonsidered to be the diseases of Western societies but the incidencend prevalence of these illnesses in Asia are increasing [2–4]. The

isk of developing colorectal carcinoma is increased for individu-ls with inflammatory bowel disease [5]. In geographical regionshere diets are high in n-3 polyunsaturated fatty acids (PUFAs)

ancer incidence is low [6]. It has been suggested that some of the

Abbreviations: 15d-PGJ2, 15-deoxy-�12,14 prostaglandin J2; 5-ASA, 5-minosalicylic acid; c9, t11, cis-9 trans-11; CLA, conjugated linoleic acid; DHA,ocosahexaenoic acid; EPA, eicosapentaenoic acid; IgA, immunoglobulin A; IL,

nterleukin; PPAR�, peroxisome proliferator activated receptor gamma; PUFA,olyunsaturated fatty acid; t10, c12, trans-10, cis-12; TNF-�, tumour necrosis factorlpha.∗ Tel.: +64 6 953 7747; fax: +64 6 953 7701.

E-mail address: hmartin@hortresearch.co.nz.

027-5107/$ – see front matter © 2009 Elsevier B.V. All rights reserved.oi:10.1016/j.mrfmmm.2009.06.009

© 2009 Elsevier B.V. All rights reserved.

protective effect of dietary n-3 PUFAs may be due to their anti-inflammatory, PPAR� activating properties [7].

The peroxisome proliferator activated receptors (PPARs) are asubset of the nuclear receptor superfamily. Unlike the classicalhormone-activated receptors such as the estrogen receptor, whichis located in the cytoplasm and translocates to the nucleus afterbinding of the activating ligand, the PPAR receptors reside in thenucleus bound to DNA response elements [8]. The nuclear loca-tion of the PPAR receptor is typical of metabolite-activated nuclearreceptors. There are three forms of PPAR receptor: alpha, beta/deltaand gamma [9], all of which form obligate heterodimers with theretinoid-X-receptor (RXR-receptor). PPAR� is the target for hypolip-idaemic drugs known as fibrates. PPAR�/� is now emerging as animportant regulator of bowel cell proliferation/differentiation. Thetissue expression of the three PPAR forms is different but overlap-ping. The functions of PPAR� and PPAR� also overlap somewhat.PPAR� is expressed in a range of tissues including adipocytes,skeletal muscle cells, osteoclasts, osteoblasts and several immune-type cells. Unsurprisingly, germ-line knockout of PPAR� is lethal.

Four transcripts of the PPAR� gene are found in human tissueas a result of tissue specific variations in promoters and splic-ing [10–12]. However in normal cells only two proteins, PPARG-1and PPARG-2 are expressed. PPARG-1 protein can be producedfrom transcripts PPARG-1, PPARG-3 and PPARG-4. PPARG-1 pro-

2 Resea

ta

bsPgtot1Le

essoIthPc[amvdla

fIPdtmcatcm

itwMocaottcPio

srtutmwm

H. Martin / Mutation

ein is widely expressed whereas PPARG-2 is mainly restricted todipocytes [13].

PPAR� is activated, not only by ligand (agonist) binding, but alsoy phosphorylation, which increases the ligand-independent tran-criptional activity [14]. Apart from its role as a transcription factor,PAR� also acts as a trans-repressor of macrophage inflammatoryenes [15]. In this mechanism the ligand-dependent sumoyla-ion of PPAR� represses inflammatory gene expression. Bindingf sumoylated PPAR� to a DNA-bound repressor complex blockshe expression of inflammatory gene products by preventing the9S proteasome-mediated degradation of the repressor complex.igand-independent activation of PPAR�/� can suppress bowel dis-ase by down regulation of inflammatory signalling [16].

Evidence of the role of PPAR� in inflammatory disease is appar-nt from genetic screening of patients suffering from multipleclerosis (MS), an autoimmune disease of the central nervousystem. Various genetic linkages to immune genes have been rec-gnized for MS, notably the receptors for interleukin (IL) 2 and

L7. Very recently a PPAR� polymorphism has been added tohe list of MS-linked genes. In a study of 116 patients and 211ealthy age-matched controls, the Ala/Ala genotype of the PPAR�ro12Ala polymorphism was associated with a 10-year, statisti-ally significantly delayed onset of disease in patients with MS17]. The anti-inflammatory effects of the Pro12Ala polymorphismre corroborated by a recent study of atherosclerosis, a chronic,acrophage-mediated, inflammatory disease of the arterial blood

essels. This 10-year follow-up study of men with coronary arteryisease showed that carriers of the Pro12Ala allele of PPAR� have

ess widespread atherosclerosis and are considerably protectedgainst 10-year vascular morbidity and mortality [18].

The use of PPAR� knockout mice has provided strong evidenceor the role of natural PPAR� ligands in controlling inflammation.n a seminal study, colitis was induced in mice deficient in colonicPAR� by two unrelated mechanisms, either by treatment with oralextran sodium sulfate or by transfer of CD4+CD45RBhi T-cells. Inhe former approach colitis is induced by chemical irritation of the

ucosa and is dependent on macrophage activation and epithelialell apoptosis whereas in the latter method, colitis is mediated byntigen driven TH1-cell activation. In both of these models, wildype mice responded to dietary conjugated linoleic acid (CLA) bylinical amelioration of colitis while the colonic PPAR� knockoutice were unresponsive [19].

The anti-inflammatory effects of PPAR� are closely linked withts anti-diabetic effects. Mice with a macrophage-specific dele-ion of PPAR� were tested for their ability to resist a challengeith Leishmania major, a parasitic infection which requires an1 (cell-mediated) type response from the host for immunity to

ccur. Mice lacking macrophage PPAR� were not only less sus-eptible to Leishmania spp. infection, as expected, but the samenimals were also prone to diabetic illness [20]. Selective knockoutf macrophage PPAR� resulted in a reduced capacity for skele-al muscle to metabolise fatty acids and sugars. The expression ofranscription factors and co-activator proteins necessary for mito-hondrial biogenesis were also greatly reduced. Thus macrophagePAR� activation not only induces differentiation of macrophages

nto the non-inflammatory, M2 type but also has profound effectsn the metabolic status of the whole mouse.

A similar demonstration of the profound physiological effect ofelective knockout (KO) of the PPAR� gene, this time selectivelyemoving the gene from endothelial cells, resulted in the whole-runk hair loss in the offspring of the KO mice. The mechanism

nderlying these bizarre symptoms was traced to the default syn-hesis of toxic, highly inflammatory oxidised lipids in the milk of

ice lacking the endothelial PPAR� gene. These oxidised lipidsere generated due to a huge excess of lipoxygenase activity, nor-ally repressed by the endothelial PPAR� gene. Accumulation of

rch 669 (2009) 1–7

the inflammatory lipid mediators in the skin of the suckling micecaused inflammation and subsequent alopecia. Skin inflammationwas confirmed as the cause of alopecia when topical aspirin curedthe inflammation and prevented the hair loss [21]. These exam-ples suggest that systemic inflammation is the default physiologicalcondition, held in check by PPAR� under normal circumstances.

Animal studies and human trials of PPAR� activating drugs, nor-mally used to treat diabetes, have shown these compounds to havegreat potential as anti-inflammatory drugs. In a mouse model ofasthma, pioglitazone, a PPAR� activator, was found to be as effec-tive as dexamethasone, a corticosteroid commonly used in asthmatreatment [22]. In a rat model of rheumatoid arthritis known asadjuvant induced arthritis, the PPAR� activating drugs pioglita-zone and rosiglitazone, were found to reduce bone erosion andinflammatory bone loss [23]. Using Type II diabetic rats as a modelof inflammatory renal disease, pioglitazone reduced nephropathyby an anti-inflammatory mechanism [24]. The successes of PPAR�activators in animal models of the autoimmune disease multi-ple sclerosis (MS) have given strong support to the use of PPAR�agonists in human trials [25]. The use of rosiglitazone in humaninflammatory bowel disease gave beneficial results in an Ulcera-tive Colitis clinical trial [26]. The US National Institutes of Healthare currently recruiting participants for a trial of pioglitazone inthe inflammatory diseases rheumatoid arthritis and atherosclero-sis (clinical trial identifier NCT00554853). A trial of pioglitazone inasthma (clinical trial identifier NCT00787644) is currently in theplanning phase.

PPAR� is of particular interest to the food industry becausePPAR� activators and their precursors e.g. linolenic and linoleicacid are abundant in several foods. In addition, certain isoformsof linoleic acid, notably the trans-10, cis-12 isoform are normallyrare in the diet but present in higher concentration in certain syn-thetic food supplements used for weight loss [27]. The t10, c12isoform of CLA is effective at inducing weight loss in mice, but itdoes this by antagonising PPAR� and inducing the stress responsein adipocytes [28,29]. On the other hand, the cis-9, trans-11 iso-form of linoleic acid, which is commonly found in natural foodproducts, inhibits allergic airway sensitization and inflammationin mice [30] via a PPAR� dependent mechanism. The mechanismsby which dietary PPAR� activators may ameliorate inflammatorydisease are discussed.

2. Anti-inflammatory effects of PPAR� ligands—syntheticand natural

PPAR� ligands can be divided into various categories: nat-ural/synthetic, endogenous/exogenous or covalent/reversible. Todemonstrate the variety of PPAR� ligands, the structures of theligands discussed in this article are shown in Fig. 1.

PPAR� agonists known as thiazolidinediones are commonly pre-scribed for the treatment of diabetes but have been investigatedfor their anti-inflammatory effects. PPAR� protein was identifiedin the antigen presenting cells, monocytes and macrophages andsynthetic PPAR� agonists including pioglitazone, troglitazone androsiglitazone were shown to suppress production of inflammatorycytokines by these cells [31,32]. Subsequently, PPAR� was identi-fied in dendritic cells which are potent and highly differentiated,professional antigen presenting cells. The same thiazolidinedionecompounds were demonstrated to decrease dendritic cell secre-tion of IL12, a potent TH1-type inflammatory cytokine [33,34].In addition, the synthesis of TH1-cell but not TH2-cell recruit-

ing chemokines was also suppressed by thiazolidinediones [33].An mRNA profiling study using mouse macrophages demonstratedthat rosiglitazone acted via PPAR� as a general repressor of abroad range of lipopolysaccharide and interferon-� target genes.Taken together, these studies provide strong evidence of the anti-

H. Martin / Mutation Research 669 (2009) 1–7 3

sity of

iT[

rC

tarrrrmqiT

Fig. 1. The diver

nflammatory function of PPAR� through its ability to suppressH1-type cytokine production in macrophages and dendritic cells35].

Beneficial effects of the PPAR� activator, rosiglitazone, wereeported in two recent clinical trials for the treatment of Ulcerativeolitis [36,37].

Animal models of inflammation are now being used to explorehe utility of PPAR� agonists in other inflammatory diseases. Inmouse model of systemic lupus erthythematosus, rosiglitazone

educed autoantibody production, renal disease, and atheroscle-osis [38]. The PPAR� agonist troglitazone, a thiazolidinedione,educed renal scarring and inflammation in a mouse model of

enal fibrosis [39]. In a rat model of post-operative brain inflam-

ation, rosiglitazone attenuated myeloperoxidase activity andualitatively decreased expression of the cytokine markers of

nflammation, IL1� and tumour necrosis factor � (TNF-�) [40].he beneficial effects of rosiglitazone in brain inflammation are

PPAR� ligands.

tempered by the fact that it has poor penetrance through theblood–brain barrier. Conceivably its effects are mediated outsidethe brain, perhaps in the brain vasculature. In a mouse modelof gastro-intestinal candidiasis, rosiglitazone prevented gut col-onization by activation of PPAR� [41]. This effect was mediatedby increased expression of the mannose-receptor on mucosalmacrophages. Using a rat model of pancreatitis, it was shown thatthe PPAR� agonists 15-deoxy-�12,14 prostaglandin J2 (15d-PGJ2)and troglitazone both suppress pancreatic inflammation which wasmeasured by reduced pancreatic weight and lowered levels of theinflammatory cytokines IL6 and Transforming-Growth-Factor-1�[42].

5-Aminosalicylic acid (5-ASA) is widely used in the treatmentof inflammatory bowel disease. The anti-inflammatory mechanismof 5-ASA has been shown to be dependent on PPAR� activationin a PPAR� +/− mouse model of colitis [43]. These data were alsoconfirmed by culture of human colonic biopsies.

4 Resea

aieaudcIwlsalimatt

pTawibbbv

bcbobartdctne

3b

iobbdt[lsouetdptao

H. Martin / Mutation

These human clinical trials and animal studies show that PPAR�gonists can have systemic anti-inflammatory effects. Similar stud-es using natural dietary PPAR� ligands corroborate the drug-basedvidence. The dietary PUFAs and PPAR� ligands, docosahexaenoiccid (DHA), eicosapentaenoic acid (EPA) and �-linolenic acid weresed to treat the human enterocyte cell line, Caco-2 and humanendritic cells, during exposure of the cells to IL1� and lipopolysac-haride. Not only was secretion of the pro-inflammatory cytokines,L6 and IL8, reduced by these PUFAs, but the expression of PPAR�

as itself enhanced [44]. The central role of PPAR� in these cellu-ar responses to PUFAs was confirmed by the use of GW 9662, aynthetic PPAR� antagonist, which blocked the anti-inflammatoryctions of the PUFAs. In a recent animal feeding trial in pigs,inseed oil significantly reduced the expression of TNF-�, a pro-nflammatory cytokine and marker of inflammation, and increased

uscle mass [45]. Linseed oil’s main components are the PPAR�gonists linoleic and linolenic acid. In this study, PPAR� concentra-ion in the spleen and muscle negatively correlated with TNF-� inhe serum.

X-ray crystallographic studies of PPAR� with bound ligands hasrovided great insight into the mechanism of PPAR� activation.he crystal structures showed that the ligand binding pocket canccommodate two fatty acids simultaneously. More remarkableas the finding that oxo-fatty acid metabolites [46] and the anti-

nflammatory 15-deoxy-�12,14 prostaglandin J2 (15d-PGJ2) [47]ind covalently to the sulfhydryl group of at Cys285 in the ligandinding domain by a Michael addition mechanism. The covalentlyound ligands were shown to be particularly effective PPAR� acti-ators.

The variety and apparent lack of selectivity of the PPAR� ligandinding pocket has led to concern about which ligands should beonsidered physiologically relevant. The discovery of the covalent-inding nature of certain ligands strongly supports the credibilityf these ligands as being physiologically important since reversiblyinding ligands are much more dependant on concentration forctivity than covalent binders. This is because a reversible ligandelies on a having either a high affinity or a high concentrationo achieve appreciable binding to its receptor i.e. to establish aynamic equilibrium in which the receptor function is affected. Byontrast, a covalent binder with only moderate affinity is more ableo influence receptor function since, once covalently bound, it doesot dissociate from the receptor. Penicillin and aspirin, are classicxamples of covalently binding drugs.

. Dietary PPAR� activators, their sources andioavailability

Linoleic acid is a well known component of many foods ands present in vegetables, fruits, nuts, grains and seeds amongther dietary sources. Linoleic and linolenic acids are highly orallyioavailable to the plasma and the brain. Indeed the exceptionalioavailability characteristics of these fatty acids have lead to theiresign as drug-delivery vehicles in emulsions with anti-HIV pro-ease treatments to enhance drug delivery to plasma and brain48], demonstrated using a mouse model. The conjugated form ofinoleic acid cis-9, trans-11, a well researched PPAR� ligand, washown to be produced naturally from linoleic acid by the actionf gut flora, especially probiotic bacteria [49]. In the same studysing human HT-29 colonic carcinoma cells, CLA was also shown tonhance expression of PPAR�. CLA is sold as a dietary supplemento induce weight loss. The safety of this treatment is controversial

ue to the high-content of t10, c12 linoleic acid in some syntheticreparations. Recently, the probiotic bacterium Lactobacillus crispa-us M247, was shown to induce increased PPAR� expression andctivity in the intestinal epithelial cells of mice [50]. The mediatorf the PPAR� inducing activity was identified as bacterially derived

rch 669 (2009) 1–7

hydrogen peroxide. Bacterial strains unable to produce H2O2 werealso unable to induce PPAR� expression while antioxidants andH2O2 scavengers blocked the effect. These data illustrate the impor-tant point that probiotic bacteria can increase PPAR� activity eitherby the metabolism of precursors into PPAR� agonists or by thesynthesis of compounds which enhance PPAR� gene expression.

The dependence of PPAR� function on the colonizing microbiotaof the gut was demonstrated when Enterococcus faecalis isolatedfrom newborn babies was shown to induce phosphorylation ofPPAR� in primary colonic cells and colonic cell lines. Phospho-rylation of PPAR� activated transcription of anti-inflammatorytarget genes, notably including the anti-inflammatory IL10 [51]. ThePPAR� antagonist GW9662 specifically blocked these effects. Theauthors did not identify which product of Enterococcus faecalis wasresponsible for the PPAR� phosphorylation but suggested CLA as alikely mediator.

A meta-analysis of several studies concluded that CLA is mod-erately beneficial for human health [52]. As discussed earlier,macrophage PPAR� has both anti-inflammatory and anti-diabeticactions. It is therefore feasible that the dietary benefits of CLA, seenin the meta-analysis, derive from the transformation of unconju-gated linoleic acid to CLA by gut bacteria. In an in vitro study of 30strains of gram-positive intestinal bacteria, certain species, notablyRoseburia, were capable of converting the unconjugated form oflinoleic acid (cis-9, cis-12, 18:2) to the immediate precursors ofthe health promoting cis-9, trans-11 form. An in vitro, biochemicalstudy showed that the variability among bacterial strains was sub-stantial, some strains having almost none of the required linoleateisomerase activity necessary to perform this metabolic step [53].The implications from this work are that variations in the gut floraamong individuals may well influence their inflammatory and dia-betic status.

CLA isoforms differ in terms of health benefit and PPAR� activa-tion. In primary cultures of human adipocytes the t10–c12 isoformcaused adipocyte delipidation, insulin resistance and inflammationby acting as a PPAR� antagonist. These activities were not associatedwith the more common and natural cis-9, trans-11 (c9, t11) isoformof CLA [54]. The pro-inflammatory effects of the trans-10, cis-12(t10, c12) CLA isoform in human adipocytes were subsequentlyshown to be reversible by resveratrol [55] in an in vitro, cell-basedstudy. A 16-week dietary trial comparing c9, t11 CLA with the syn-thetic form t10, c12 CLA in a group of 75 healthy post-menopausalwomen, found that the t10, c12 isoform increased levels of inflam-matory markers including C-reactive protein and fibrinogen [56].

A study of the effects of long term feeding of c9, t11 CLA torats gave two compelling examples of beneficial immune modu-lation from an analysis of their immune response to ovalbumin[57]. Firstly, the ovalbumin-specific response of the splenocyteswas enhanced 50%, while at the same time, the polyclonal spleno-cyte response to mitogen stimulation was reduced by up to20%. Secondly, the intestinal anti-ovalbumin immunoglobulin A(IgA) response was increased by 75%. Although these effects maybe mediated, in part, by PPAR�, no evidence was presented inthis particular study to test PPAR� involvement in the immuno-logically beneficial effects of dietary c9, t11 CLA. However theanti-lymphoproliferative effects of the dietary PUFAs and PPAR�ligands, linoleic acid and DHA have been demonstrated on humandendritic cells [58]. In this cell-based, in vitro study, specific block-ing of PPAR� activity with the antagonist GW9662, also blocked theanti-inflammatory effects of the PUFAs.

Although the evidence for PPAR� mediated anti-inflammatory

effects is convincing, interpretation of the data from CLA feed-ing trial is complicated by the fact that CLA is also an activatorof PPAR� and PPAR�/� [59,60]. Likewise, in the mRNA profilingstudy using rosiglitazone to stimulate PPAR� receptors in mousemacrophages, it was apparent, using PPAR� deficient macrophages,

Resea

t[tthtpfcteso

phtoaPfirqtlAacttrotmiePsi

wiiapiavboa

4

pmfeamisicl

[

[

[

[

[

[

[

[

[

H. Martin / Mutation

hat PPAR� was activated at higher concentrations of rosiglitazone35]. Similarly, in a study using normal and PPAR� deficient mice,he PPAR� ligand, pioglitazone was shown to suppress inflamma-ion through a PPAR� dependent mechanism [61]. Thus the humanealth benefits of PPAR� agonists, in the diet and from pharmaceu-ical sources, are probably not restricted to their PPAR� activatingroperties. Furthermore the metabolic fate of CLA in humans is not

ully understood but it is apparent that the conversion of CLA toonjugated arachidonic acid is substantially more efficient in ratshan in humans [62]. Differences in CLA metabolism may thereforexplain the apparent disagreement between animal trials whichuggest CLA induces weight loss and human trials which are equiv-cal on this issue [62].

Dietary phytochemicals with quite different structures androperties from the unsaturated fatty acids discussed so far,ave been characterised from oregano by activity-based frac-ionation. Various flavonoids and other phytochemicals fromregano were characterised for their agonist and antagonist PPAR�ctivities. Compounds were first identified as ligands using aPAR� fluorescence-polarization assay and subsequently classi-ed as agonist or antagonist, based on their ability to inhibitosiglitazone-induced cellular responses. The dietary flavonoidsuercetin, luteolin, rosmarinic acid and diosmetin were foundo be PPAR� antagonists, naringenin and apigenin were modu-ators and biochanin A was found to be a PPAR� agonist [63].lthough the bioavailability of these phytochemicals needs to beddressed, the approach demonstrates that many common phyto-hemicals have the potential to influence PPAR� activity, due tohe promiscuous nature of the binding site. The notion of poten-ially harmful over-activation of PPAR� by dietary constituents wasaised by Adapala, who suggested that prolonged consumptionf curcumin, a polyphenol and principal component of the spiceurmeric, suppressed the immune response and exacerbated Leish-ania donovani infection in mice [64]. However, curcumin is not

tself a PPAR� ligand and probably exerts its anti-inflammatoryffects by other mechanisms such as upregulated expression ofPAR� [65,66]. Zingerone, the active ingredient in ginger, which istructurally similar to curcumin, is also anti-inflammatory throughts ability to increase PPAR� expression [67].

Apoptosis delivers anti-inflammatory signals to macrophageshile necrosis is pro-inflammatory [68]. The sumoylation of PPAR�

n mouse macrophages exposed, in vitro, to apoptotic cells resultsn a phenotype shift in the macrophages from pro-inflammatory tonti-inflammatory [69]. Diets which contain pro-apoptotic com-ounds may not only protect against cancer, but also reduce

nflammation [70–72]. The dietary PUFA and PPAR� ligand EPA hasPPAR� mediated apoptotic effect in HT-29 colon cancer cells [7] initro and CLA has been reported to induce apoptosis in the humanreast cancer cell line SKBr3 [73]. A synergistic effect may thereforeccur when cells are exposed to compounds such as these, whichre both pro-apoptotic and also anti-inflammatory.

. Conclusion

The tissue-specific knockout of the PPAR� gene has revealed theivotal role of PPAR� in regulating inflammation and metabolism inice. The importance of PPAR� in inflammatory disease is evident

rom the success of PPAR� activating drugs in animal disease mod-ls and human Ulcerative Colitis trials. Furthermore, the geneticssociation between PPAR� polymorphisms and diseases such asultiple sclerosis and atherosclerosis confirms the role of PPAR�

n human inflammatory disease. These data support the hypothe-is that PPAR� activation in healthy individuals suppresses systemicnflammation. The prospects that dietary factors may have benefi-ial effects in inflammatory disease are good, since various dietaryigands such as conjugated (c9, t11) linoleic acid or DHA, are present

[

rch 669 (2009) 1–7 5

in certain foods. Pre-biotic foods and probiotic bacteria play animportant role in influencing the immune phenotype through theirability to convert food components into PPAR� agonists and tosynthesise compounds de novo which stimulate PPAR� gene expres-sion. The discovery of new dietary PPAR� activators coupled withunderstanding of the subtle mechanisms by which these com-pounds influence PPAR� activity promises to be an exciting fieldin the immediate future—with enormous implications for humanhealth.

Role of funding source

Internal funding from Plant and Food Research.

Conflict of interest

None.

References

[1] S.F. Bloomfield, R. Stanwell-Smith, R.W.R. Crevel, J. Pickup, Too clean, or not tooclean: the hygiene hypothesis and home hygiene, Clinical and ExperimentalAllergy 36 (2006) 402–425.

[2] K.L. Goh, S.D. Xiao, Inflammatory bowel disease: a survey of the epidemiologyin Asia, Journal of Digestive Diseases 10 (2009) 1–6.

[3] E.V. Loftus, Clinical epidemiology of inflammatory bowel disease: inci-dence, prevalence, and environmental influences, Gastroenterology 126 (2004)1504–1517.

[4] B.A. Jacobsen, J. Fallingborg, H.H. Rasmussen, K.R. Nielsen, A.M. Drewes, E.Puho, G.L. Nielsen, H.T. Sorensen, Increase in incidence and prevalence ofinflammatory bowel disease in northern Denmark: a population-based study,1978–2002, European Journal of Gastroenterology & Hepatology 18 (2006)601–606.

[5] A.B. Carter, S.A. Misyak, R. Hontecillas, J. Bassaganya-Riera, Dietary modulationof inflammation-induced colorectal cancer through PPAR�, PPAR Research 2009(2009), Article ID 498352.

[6] C.P.J. Caygill, M.J. Hill, Fish, N-3 fatty-acids and human colorectal and breast-cancer mortality, European Journal of Cancer Prevention 4 (1995) 329–332.

[7] C.D. Allred, D.R. Talbert, R.C. Southard, X. Wang, M.W. Kilgore, PPAR gamma 1as a molecular target of eicosapentaenoic acid in human colon cancer (HT-29)cells, Journal of Nutrition 138 (2008) 250–256.

[8] C.K. Glass, M.G. Rosenfeld, The coregulator exchange in transcriptional func-tions of nuclear receptors, Genes & Development 14 (2000) 121–141.

[9] C.K. Glass, S. Ogawa, Combinatorial roles of nuclear receptors in inflammationand immunity, Nature Reviews Immunology 6 (2006) 44–55.

10] T.T. Wang, J. Xu, X.F. Yu, R.C. Yang, Z.C. Han, Peroxisome proliferator-activatedreceptor gamma in malignant diseases, Critical Reviews in Oncology Hematol-ogy 58 (2006) 1–14.

11] L. Michalik, J. Auwerx, J.P. Berger, V.K. Chatterjee, C.K. Glass, F.J. Gonzalez, P.A.Grimaldi, T. Kadowaki, M.A. Lazar, S. O’Rahilly, C.N.A. Palmer, J. Plutzky, J.K.Reddy, B.M. Spiegelman, B. Staels, W. Wahli, International Union of Pharmacol-ogy. LXI. Peroxisome proliferator-activated receptors, Pharmacological Reviews58 (2006) 726–741.

12] C. Bruedigam, M. Koedam, H. Chiba, M. Eijken, J. van Leeuwen, Evidence for mul-tiple peroxisome proliferator-activated receptor gamma transcripts in bone:fine-tuning by hormonal regulation and mRNA stability, FEBS Letters 582 (2008)1618–1624.

13] P. Escher, O. Braissant, S. Basu-Modak, L. Michalik, W. Wahli, B. Desvergne, RatPPARs: quantitative analysis in adult rat tissues and regulation in fasting andrefeeding, Endocrinology 142 (2001) 4195–4202.

14] C. Diradourian, J. Girard, J.P. Pegorier, Phosphorylation of PPARs: from molecularcharacterization to physiological relevance, Biochimie 87 (2005) 33–38.

15] G. Pascual, A.L. Fong, S. Ogawa, A. Gamliel, A.C. Li, V. Perissi, D.W. Rose, T.M.Willson, M.G. Rosenfeld, C.K. Glass, A SUMOylation-dependent pathway medi-ates transrepression of inflammatory response genes by PPAR-gamma, Nature437 (2005) 759–763.

16] J.M. Peters, H.E. Hollingshead, F.J. Gonzalez, Role of peroxisome-proliferator-activated receptor beta/delta (PPAR beta/delta) in gastrointestinal tract functionand disease, Clinical Science 115 (2008) 107–127.

17] L. Klotz, S. Schmidt, R. Heun, T. Klockgether, H. Kolsch, Association of the PPARgamma gene polymorphism Pro12Ala with delayed onset of multiple sclerosis,Neuroscience Letters 449 (2009) 81–83.

18] J.J. Regieli, J.W. Jukema, P.A. Doevendans, A.H. Zwinderman, Y. van der Graaf, J.J.Kastelein, D.E. Grobbee, PPAR gamma variant influences angiographic outcome

and 10-year cardiovascular risk in male symptomatic coronary artery diseasepatients, Diabetes Care 32 (2009) 839–844.

19] J. Bassaganya-Riera, K. Reynolds, S. Martino-Catt, Y.Z. Cui, L. Hennighausen, F.Gonzalez, J. Rohrer, A.U. Benninghoff, R. Hontecillas, Activation of PPAR gammaand delta by conjugated linoleic acid mediates protection from experimentalinflammatory bowel disease, Gastroenterology 127 (2004) 777–791.

6 Resea

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

H. Martin / Mutation

20] J.I. Odegaard, R.R. Ricardo-Gonzalez, M.H. Goforth, C.R. Morel, V. Subrama-nian, L. Mukundan, A.R. Eagle, D. Vats, F. Brombacher, A.W. Ferrante, A. Chawla,Macrophage-specific PPAR gamma controls alternative activation and improvesinsulin resistance, Nature 447 (2007), pp. 1116-U1112.

21] Y.H. Wan, A. Saghatelian, L.W. Chong, C.L. Zhang, B.F. Cravatt, R.M. Evans, Mater-nal PPAR gamma protects nursing neonates by suppressing the production ofinflammatory milk, Genes & Development 21 (2007) 1895–1908.

22] V.R. Narala, R. Ranga, M.R. Smith, A.A. Berlin, T.J. Standiford, N.W. Lukacs, R.C.Reddy, Pioglitazone is as effective as dexamethasone in a cockroach allergen-induced murine model of asthma, Respiratory Research 8 (2007).

23] M. Koufany, D. Moulin, A. Bianchi, M. Muresan, S. Sebillaud, P. Netter, G.Weryha, J.Y. Jouzeau, Anti-inflammatory effect of antidiabetic thiazolidine-diones prevents bone resorption rather than cartilage changes in experimentalpolyarthritis, Arthritis Research & Therapy 10 (2008).

24] G.J. Ko, Y.S. Kang, S.Y. Han, M.H. Lee, H.K. Song, K.H. Han, H.K. Kim, J.Y.Han, D.R. Cha, Pioglitazone attenuates diabetic nephropathy through ananti-inflammatory mechanism in type 2 diabetic rats, Nephrology DialysisTransplantation 23 (2008) 2750–2760.

25] J.J. Brightt, C.C. Walline, S. Kanakasabai, S. Chakraborty, Targeting PPAR as atherapy to treat multiple sclerosis, Expert Opinion on Therapeutic Targets 12(2008) 1565–1575.

26] J.D. Lewis, G.R. Lichtenstein, J.J. Deren, B.E. Sands, S.B. Hanauer, J.A. Katz, B. Lash-ner, D.H. Present, S. Chuai, J.H. Ellenberg, L. Nessel, G.D. Wu, Rosiglitazone foractive ulcerative colitis: a randomized placebo-controlled trial, Gastroenterol-ogy 134 (2008) 688–695.

27] X.R. Zhou, C.H. Sun, J.R. Liu, D. Zhao, Dietary conjugated linoleic acid increasesPPAR gamma gene expression in adipose tissue of obese rat, and improvesinsulin resistance, Growth Hormone & Igf Research 18 (2008) 361–368.

28] P.C. LaRosa, J.J.M. Riethoven, H. Chen, Y. Xia, Y. Zhou, M. Chen, J. Miner,M.E. Fromm, Trans-10, cis-12 conjugated linoleic acid activates the integratedstress response pathway in adipocytes, Physiological Genomics 31 (2007)544–553.

29] H. Poirier, J.S. Shapiro, R.J. Kim, M.A. Lazar, Nutiritional supplementation withtrans-10, cis-12-conjugated linoleic acid induces inflammation of white adiposetissue, Diabetes 55 (2006) 1634–1641.

30] A. Jaudszus, M. Krokowski, P. Mockel, Y. Darcan, A. Avagyan, P. Matricardi, G.Jahreis, E. Hamelmann, Cis-9, trans-11-conjugated linoleic acid inhibits allergicsensitization and airway inflammation via a PPAR gamma-related mechanismin mice, Journal of Nutrition 138 (2008) 1336–1342.

31] M. Ricote, A.C. Li, T.M. Willson, C.J. Kelly, C.K. Glass, The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation,Nature 391 (1998) 79–82.

32] C.Y. Jiang, A.T. Ting, B. Seed, PPAR-gamma agonists inhibit production of mono-cyte inflammatory cytokines, Nature 391 (1998) 82–86.

33] P. Gosset, A.S. Charbonnier, P. Delerive, J. Fontaine, B. Staels, J. Pestel, A.B. Tonnel,F. Trottein, Peroxisome proliferator-activated receptor gamma activators affectthe maturation of human monocyte-derived dendritic cells, European Journalof Immunology 31 (2001) 2857–2865.

34] C. Faveeuw, S. Fougeray, V. Angeli, J. Fontaine, G. Chinetti, P. Gosset, P. Delerive, C.Maliszewski, M. Capron, B. Staels, M. Moser, F. Trottein, Peroxisome proliferator-activated receptor gamma activators inhibit interleukin-12 production inmurine dendritic cells, FEBS Letters 486 (2000) 261–266.

35] J.S. Welch, M. Ricote, T.E. Akiyama, F.J. Gonzalez, C.K. Glass, PPAR gamma andPPAR delta negatively regulate specific subsets of lipopolysaccharide and IFN-gamma target genes in macrophages, in: Proceedings of the National Academyof Sciences of the United States of America 100, 2003, pp. 6712–6717.

36] J.D. Lewis, G.R. Lichtenstein, J.J. Deren, B.E. Sands, S.B. Hanauer, J.A. Katz, B. Lash-ner, D.H. Present, S. Chuai, J.H. Ellenbergr, L. Nessel, G.D. Wu, Rosiglitazone foractive ulcerative colitis: a randomized placebo-controlled trial, Gastroenterol-ogy 134 (2008) 688–695.

37] H.L. Liang, Q. Ouyang, A clinical trial of combined use of rosiglitazone and5-aminosalicylate for ulcerative colitis, World Journal of Gastroenterology 14(2008) 114–119.

38] T. Aprahamian, R.G. Bonegio, C. Richez, K. Yasuda, L.K. Chiang, K. Sato, K. Walsh,I.R. Rifkin, The peroxisome proliferator-activated receptor gamma agonistrosiglitazone ameliorates murine lupus by induction of adiponectin, Journalof Immunology 182 (2009) 340–346.

39] T. Kawai, T. Masaki, S. Doi, T. Arakawa, Y. Yokoyama, T. Doi, N. Kohno, N. Yorioka,PPAR-gamma agonist attenuates renal interstitial fibrosis and inflammationthrough reduction of TGF-beta, Laboratory Investigation 89 (2009) 47–58.

40] A. Hyong, V. Jadhav, S. Lee, W. Tong, J. Rowe, J.H. Zhang, J.P. Tang, Rosiglitazone,a PPAR gamma agonist, attenuates inflammation after surgical brain injury inrodents, Brain Research 1215 (2008) 218–224.

41] A. Coste, C. Lagane, C. Filipe, H. Authier, A. Gales, J. Bernad, V. Douin-Echinard,J.C. Lepert, P. Balard, M.D. Linas, J.F. Arnal, J. Auwerx, B. Pipy, IL-13 attenuatesgastrointestinal candidiasis in normal and immunodeficient RAG-2(−/−) micevia peroxisome proliferator-activated receptor-gamma activation, Journal ofImmunology 180 (2008) 4939–4947.

42] J.H. Yu, K.H. Kim, H. Kim, SOCS 3 and PPAR-gamma ligands inhibit the expres-sion of IL-6 and TGF-beta 1 by regulating JAK2/STAT3 signaling in pancreas,

International Journal of Biochemistry & Cell Biology 40 (2008) 677–688.

43] C. Rousseaux, B. Lefebvre, L. Dubuquoy, P. Lefebvre, O. Romano, J. Auwerx, D.Metzger, W. Wahli, B. Desvergne, G.C. Naccari, P. Chavatte, A. Farce, P. Bulois,A. Cortot, J.F. Colombel, P. Desreumaux, Intestinal antiinflammatory effectof 5-aminosalicylic acid is dependent on peroxisome proliferator-activatedreceptor-gamma, Journal of Experimental Medicine 201 (2005) 1205–1215.

[

rch 669 (2009) 1–7

44] R. Marion-Letellier, M. Butler, P. Dechelotte, R.J. Playford, S. Ghosh, Comparisonof cytokine modulation by natural peroxisome proliferator-activated receptorgamma ligands with synthetic ligands in intestinal-like Caco-2 cells and humandendritic cells-potential for dietary modulation of peroxisome proliferator-activated receptor gamma in intestinal inflammation, American Journal ofClinical Nutrition 87 (2008) 939–948.

45] F.R. Huang, Z.P. Zhan, J. Luo, S.W. Jiang, J. Peng, Duration of feeding linseeddiet influences peroxisome proliferator-activated receptor gamma and tumornecrosis factor gene expression, and muscle mass of growing-finishing barrows,Livestock Science 119 (2008) 194–201.

46] T. Itoh, L. Fairall, K. Amin, Y. Inaba, A. Szanto, B.L. Balint, L. Nagy, K. Yamamoto,J.W.R. Schwabe, Structural basis for the activation of PPAR gamma by oxidizedfatty acids, Nature Structural & Molecular Biology 15 (2008) 924–931.

47] T. Waku, T. Shiraki, T. Oyama, Y. Fujimoto, K. Maebara, N. Kamiya, H. Jingami,K. Morikawa, Structural insight into PPAR[gamma] activation through covalentmodification with endogenous fatty acids, Journal of Molecular Biology 385(2009) 188–199.

48] T.K. Vyas, A. Shahiwala, M.M. Amiji, Improved oral bioavailability and braintransport of Saquinavir upon administration in novel nanoemulsion formula-tions, International Journal of Pharmaceutics 347 (2008) 93–101.

49] J.B. Ewaschuk, J.W. Walker, H. Diaz, K.L. Madsen, Bioproduction of conjugatedlinoleic acid by probiotic bacteria occurs in vitro and in vivo in mice, Journal ofNutrition 136 (2006) 1483–1487.

50] S. Voltan, D. Martines, M. Elli, P. Brun, S. Longo, A. Porzionato, V. Macchi, R.D’Inca, M. Scarpa, G. Palu, G.C. Sturniolo, L. Morelli, I. Castagliuolo, Lactobacilluscrispatus M247-derived H2O2 acts as a signal transducing molecule activatingperoxisome proliferator activated receptor-gamma in the intestinal mucosa,Gastroenterology 135 (2008) 1216–1227.

51] A. Are, L. Aronsson, S.G. Wang, G. Greicius, Y.K. Lee, J.A. Gustafsson, S. Pet-tersson, V. Arulampalam, Enterococcus faecalis from newborn babies regulateendogenous PPAR gamma activity and IL-10 levels in colonic epithelial cells,in: Proceedings of the National Academy of Sciences of the United States ofAmerica 105, 2008, pp. 1943–1948.

52] L.D. Whigham, A.C. Watras, D.A. Schoeller, Efficacy of conjugated linoleic acidfor reducing fat mass: a meta-analysis in humans, American Journal of ClinicalNutrition 85 (2007) 1203–1211.

53] E. Devillard, F.M. McIntosh, S.H. Duncan, R.J. Wallace, Metabolism of linoleic acidby human gut bacteria: different routes for biosynthesis of conjugated linoleicacid, Journal of Bacteriology 189 (2007) 2566–2570.

54] A. Kennedy, S. Chung, K. LaPoint, O. Fabiyi, M.K. McIntosh, Trans-10, cis-12 con-jugated linoleic acid antagonizes ligand-dependent PPAR gamma activity inprimary cultures of human adipocytes, Journal of Nutrition 138 (2008) 455–461.

55] A. Kennedy, A. Overman, K. LaPoint, R. Hopkins, T. West, C.C. Chuang, K. Mar-tinez, D. Bell, M. McIntosh, Conjugated linoleic acid-mediated inflammationand insulin resistance in human adipocytes are attenuated by resveratrol, Jour-nal of Lipid Research 50 (2009) 225–232.

56] T. Tholstrup, M. Raff, E.M. Straarup, P. Lund, S. Basu, J.M. Bruun, An oil mixturewith trans-10, cis-12 conjugated linoleic acid increases markers of inflamma-tion and in vivo lipid peroxidation compared with cis-9, trans-11 conjugatedlinoleic acid in postmenopausal women, Journal of Nutrition 138 (2008)1445–1451.

57] C. Ramirez-Santana, C. Castellote, M. Castell, M. Rivero, M. Rodriguez-Palmero,A. Franch, F.J. Perez-Cano, Long-term feeding of the cis-9,trans-11 isomer ofconjugated linoleic acid reinforces the specific immune response in rats, Journalof Nutrition 139 (2009) 76–81.

58] F. Zapata-Gonzalez, F. Rueda, J. Petriz, P. Domingo, F. Villarroya, J. Diaz-Delfin,M.A. de Madariaga, J.C. Domingo, Human dendritic cell activities are modulatedby the omega-3 fatty acid, docosahexaenoic acid, mainly through PPAR gamma:RXR heterodimers: comparison with other polyunsaturated fatty acids, Journalof Leukocyte Biology 84 (2008) 1172–1182.

59] S.Y. Moya-Camarena, J.P. Vanden Heuvel, S.G. Blanchard, L.A. Leesnitzer, M.A.Belury, Conjugated linoleic acid is a potent naturally occurring ligand and acti-vator of PPAR alpha, Journal of Lipid Research 40 (1999) 1426–1433.

60] S.Y. Moya-Camarena, J.P. Vanden Heuvel, M.A. Belury, Conjugated linoleic acidactivates peroxisome proliferator-activated receptor a and B subtypes but doesnot induce hepatic peroxisome proliferation in Sprague–Dawley rats, Biochim-ica Et Biophysica Acta: Molecular and Cell Biology of Lipids 1436 (1999)331–342.

61] G. Orasanu, O. Ziouzenkova, P.R. Devchand, V. Nehra, O. Hamdy, E.S. Hor-ton, J. Plutzky, The peroxisome proliferator-activated receptor-gamma agonistpioglitazone represses inflammation in a peroxisome proliferator-activatedreceptor-alpha-dependent manner in vitro and in vivo in mice, Journal of theAmerican College of Cardiology 52 (2008) 869–881.

62] M. Plourde, S. Jew, S.C. Cunnane, P.J.H. Jones, Conjugated linoleic acids: why thediscrepancy between animal and human studies? Nutrition Reviews 66 (2008)415–421.

63] M. Mueller, B. Lukas, J. Novak, T. Simoncini, A.R. Genazzani, A. Jungbauert,Oregano: a source for peroxisome proliferator-activated receptor gamma antag-onists, Journal of Agricultural and Food Chemistry 56 (2008) 11621–11630.

64] N. Adapala, M.M. Chan, Long-term use of an antiinflammatory, curcumin, sup-

pressed type 1 immunity and exacerbated visceral leishmaniasis in a chronicexperimental model, Laboratory Investigation 88 (2008) 1329–1339.

65] A.M. Siddiqui, X.X. Cui, R.Q. Wu, W.F. Dong, M. Zhou, M.W. Hu, H.H. Simms,P. Wang, The anti-inflammatory effect of curcumin in an experimental modelof sepsis is mediated by up-regulation of peroxisome proliferator-activatedreceptor-gamma, Critical Care Medicine 34 (2006) 1874–1882.

Resea

[

[

[

[

[

[

[

H. Martin / Mutation

66] V.R. Narala, M.R. Smith, R.K. Adapala, R. Ranga, K. Panati, B.B. Moore, T. Leff,V.D. Reddy, A.K. Kondapi, R.C. Reddy, Curcumin is not a ligand for peroxisomeproliferator-activated receptor-�, Gene Therapy & Molecular Biology 13 (2009)20–25.

67] S.W. Chung, M.K. Kim, J.H. Chung, D.H. Kim, J.S. Choi, S. Anton, A.Y. Seo, K.Y. Park,T. Yokozawa, S.H. Rhee, B.P. Yu, H.Y. Chung, Peroxisome proliferator-activatedreceptor activation by a short-term feeding of zingerone in aged rats, Journal ofMedicinal Food 12 (2009) 345–350.

68] R.E. Cocco, D.S. Ucker, Distinct modes of macrophage recognition for

apoptotic and necrotic cells are not specified exclusively by phos-phatidylserine exposure, Molecular Biology of the Cell 12 (2001) 919–930.

69] C. Jennewein, A.M. Kuhn, M.V. Schmidt, V. Meilladec-Jullig, A. von Knethen, F.J.Gonzalez, B. Brune, Sumoylation of peroxisome proliferator-activated receptorgamma by apoptotic cells prevents lipopolysaccharide-induced NCoR removal

[

rch 669 (2009) 1–7 7

from kappa B binding sites proinflammatory cytokines, Journal of Immunology181 (2008) 5646–5652.

70] J. Ju, X.P. Hao, M.J. Lee, J.D. Lambert, G. Lu, H. Xiao, H.L. Newmark, C.S. Yang,A gamma-tocopherol-rich mixture of tocopherols inhibits colon inflammationand carcinogenesis in azoxymethane and dextran sulfate sodium-treated mice,Cancer Prevention Research 2 (2009) 143–152.

71] E.H. Jeffery, M. Araya, Physiological effects of broccoli consumption, Phytochem-istry Reviews 8 (2009) 283–298.

72] T. Tanaka, Y. Yasui, R. Ishigamori-Suzuki, T. Oyama, Citrus compounds inhibit

inflammation- and obesity-related colon carcinogenesis in mice, Nutrition andCancer: An International Journal 60 (2008) 70–80.

73] X.L. Yuan, F. He, Q. Chen, X.L. Yang, D.P. Yang, D.M. Wang, L. Zhong, Studieson PPAR gamma signal pathway of conjugated linoleic acid isomers induceapoptosis of human breast cancer cell line SKBr3, Progress in Biochemistry andBiophysics 36 (2009) 491–499.