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Emerging roles of PPARS in inflammation and immunity

Key Points

  • Peroxisome proliferator-activated receptors (PPARs) are ligand-inducible transcription factors that belong to the nuclear-hormone-receptor superfamily.

  • The PPARs can positively regulate gene transcription through their ability to heterodimerize with 9-cis-retinoic acid receptor (RXR) and bind to specific DNA sequences in the promoter regions of selective genes, known as peroxisome proliferator response elements (PPREs).

  • PPARs can negatively regulate gene transcription through their ability to antagonize several important signalling pathways using various transrepression mechanisms.

  • Activated PPARs regulate the inflammatory response through their ability to regulate the expression of several genes that are involved in inflammation.

  • The PPARs are expressed in a wide variety of tissues and cells of the immune system, including macrophages, dendritic cells (DCs), T cells and B cells.

  • The PPARs are important for the regulation of the immune response. This arises through the ability of these receptors to regulate DC and T-cell cytokine production, as well as lymphocyte proliferation.

Abstract

Lipids and lipid metabolism have well-documented regulatory effects on inflammatory processes. Recent work has highlighted the role of the peroxisome proliferator-activated receptors (PPARs) — a subset of the nuclear-hormone-receptor superfamily that are activated by various lipid species — in regulating inflammatory responses. Here, we describe how the PPARs, through their interactions with transcription factors and other cell-signalling systems, have important regulatory roles in innate and adaptive immunity.

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Figure 1: Basic overview of PPAR structure and ligand-induced activation.
Figure 2: Negative regulation of transcription factors by PPARs.
Figure 3: Molecular mechanisms of PPAR-mediated regulation of inflammatory responses.
Figure 4: A model describing a potential role for PPARγ in the inhibition of TH1-cell development.
Figure 5: Mechanisms by which PPARα and PPARγ inhibit the production of IL-2 and IFN-γ after T-cell activation.

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Acknowledgements

This work was supported by grants from the National Institutes of Health, a Browning Foundation grant and DVA Medical Research Funds. D.C.J. is supported by a National Institutes of Health DHHS National Institute of Diabetes and Digestive and Kidney Diseases Hematology Research Training Grant.

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Correspondence to Raymond A. Daynes.

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DATABASES

InterPro

Rel-homology domain

LocusLink

ABCA1

CBP

CD36

CD40

CD40L

CD80

CD86

E-selectin

ETS1

GADD45

HDACs

HSD11B1

ICAM1

IFN-γ

IL-1β

IL-2

IL-4

IL-6

IL-12

iNOS

IP-10

JUN

LXRα

MIP1α

MMP9

MSR1

NFAT

NF-κB

p65

p300

PPARα

PPARβ/δ

PPARγ

RANTES

RXR

SRC1

STATs

T-BET

TLR2

TNF

VCAM1

Medscape DrugInfo

rosiglitazone

OMIM

type-2 diabetes

ulcerative colitis

Glossary

EICOSANOIDS

These are fatty-acid derivatives, derived mainly from arachidonic acid, that have a wide variety of biological activities. There are four main classes of eicosanoid — the prostaglandins, prostacyclins, thromboxanes and leukotrienes — derived from the activities of cyclooxygenases and lipoxygenases on membrane-associated fatty-acid precursors.

TRANSREPRESSION

The process by which nuclear hormone receptors antagonize several signal-transduction pathways through various DNA-dependent and -independent mechanisms.

PEROXISOME

A cytoplasmic organelle that has essential roles in antioxidant defence, cholesterol and bile-acid synthesis, eicosanoid metabolism, and the β- and ω-oxidation of long-chain and very-long-chain fatty acids.

AGONIST-INDUCED ACTIVATION

A process in which ligand binding to an inactive receptor causes conformational changes that give the receptor unique biological properties. Agonist dissociation generally results in the receptor returning to an inactive state.

TRANSCRIPTION CO-ACTIVATORS

These are protein complexes that associate with the ligand-binding domain of the PPARs and other transcription factors; they reorganize chromatin templates and recruit the basal transcriptional machinery to the promoter region.

TRANSCRIPTION CO-REPRESSORS

These are protein complexes, including NCoR and SMRT, that, when associated with nuclear hormone receptors, recruit histone-deacetylase complexes to reverse the actions of histone acetyltransferases and inhibit gene transcription.

PEROXISOMAL β-OXIDATION

An enzyme-catalysed process that occurs in peroxisomes and functions to shorten very-long-chain fatty acids (>22 carbon atoms) so that they can be degraded by the mitochondrial β-oxidation system.

ω-OXIDATION

A fatty-acid oxidation pathway that is catalysed by enzymes in the endoplasmic reticulum (microsomes) and involves fatty-acid hydroxylation by cytochrome P450, which results in medium- and long-chain fatty acids being converted to dicarboxylic acids.

INSULIN SENSITIZATION

A general term that is used to describe various pathways and/or proteins that enhance the activities of insulin in insulin-sensitive tissues.

CD36

CD36 is a highly glycosylated, single-chain, 88-kDa protein that binds oxidized low-density lipoproteins, fatty acids, phospholipids (including phosphatidylinositol and phosphatidylserine) and the proteins collagen and thrombospondin. CD36 is a class-B scavenger receptor with a broad range of ligand specificities that has important roles in fatty-acid and lipoprotein metabolism, clearance of apoptotic cells and anti-angiogenesis.

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Daynes, R., Jones, D. Emerging roles of PPARS in inflammation and immunity. Nat Rev Immunol 2, 748–759 (2002). https://doi.org/10.1038/nri912

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