The Role of PPAR Gamma in Systemic Sclerosis

Table 1

In vitro studies of antifibrotic effects of PPARγ agonists.

Cell type	PPARg Ligand	Effects	References
Healthy human lung fibroblast	15d-PGJ2, CGZ and RGZ	↓ TGF-β-induced myofibroblast differentiation; ↓ TGF-β-induced type I collagen protein production	[40]
Normal lung fibroblasts and fibroblasts; isolated from patients with IIP human fetal lung fibroblast (IMR-90) cells	CGZ and TGZ	↓ Proliferation of human lung fibroblasts; ↓ Proliferative responses of undifferentiated Fibroblasts and myofibroblasts to PDGF; Inhibited TGF-β1-induced myofibroblast differentiation	[47]
MRC-5 cells derived from human lung fibroblasts	PGZ	↓ TGFβ-mediated increase in procollagen I and CTGF expression	[60]
	RGZ	↓ Lung fibroblast migration and proliferation; ↓ Myofibroblast transdifferentiation	[56]
Normal human lung fibroblast cell	15 d-PGJ2, RGZ and CDDO	↓ TGF-β–stimulated differentiation of fibroblasts to myofibroblasts; ↓ TGF-β–induced fibronectin expression	[48]
A549 human; alveolar cell line	RGZ and CGZ	↓ Profibrotic changes (elevation of N-cadherin, CTGF and collagen I) in alveolar epithelial cells	[59]
Primary lung human fibroblasts; Lung fibroblasts from IIP patients	CDDO and 15d-PGJ2	↓ TGFβ-induced phosphorylation of Akt; ↓ myofibroblast differentiation	[49]
SSc lung fibroblasts	RGZ	↑ MMP-1 expression; ↓ Collagen type I expression in white patients; ↓ CTGF and α-SMA expression	[53]
Primary cultures of human dermal; fibroblasts	15d-PGJ2 and TGZ	↑ PPARγ nuclear levels in skin fibroblasts; ↓ type I collagen synthesis and expression by TGFβ-stimulated fibroblasts; ↓ α-SMA expression by TGFβ-stimulated fibroblasts	[25]
	TGZ	↓ TGFβ1, type I collagen and fibronectin expression and secretion	[67]
Human foreskin fibroblasts	15d-PGJ2 and TGZ	↓ Collagen synthesis and of COL1A2 promoter activity induced by TGF-β; ↓ Smad3-dependent transcriptional responses without blocking Smad activation; ↓ TGFβ-induced interaction of p300 with Smad3; ↓ Recruitment of p300 to the DNA-bound transcriptional complex	[39]
Healthy and scleroderma fibroblasts	RGZ	↓ α-SMA, type I collagen and CTGF protein expression in dcSSc fibroblasts; ↑ PPARγ expression	[79]
	Ajulemic acid	↓ Supernatant levels of procollagen type I propeptide and TGFb	[69]
Human scleroderma fibroblasts	RGZ	Reduced CXCL10 secretion induced by IFNγ e TNFα	[86]
	PGZ and RGZ	↓ Cell proliferation and cell viability; Increased apoptosis	[80]
	CDDO	↓ Cellular and secreted type I collagen levels; ↓ COL1A1 and COL1A2 mRNA expression	[27]
Explanted normal human skin; Fibroblasts	CDDO	↓ COL1A2 and aSMA expression induced by TGFb	[27]
Organotypic human skin raft model (epidermal keratinocytes and dermal fibroblasts)	CDDO	↓ COL1A1, COL1A2, and α-SMA expression in fibroblasts	[27]
Human A540 epithelial cells	CDDO	↓ TGF-β-induced epithelial–mesenchymal transition	[27]

CGZ = ciglitazone, RGZ = rosiglitazone, TGF-β = transforming growth factor-β, TGZ = troglitazone, IIP = idiopathic interstitial pneumonia, PDGF = platelet-derived growth factor, PGZ = pioglitazone, CTGF = connective tissue growth factor, CDDO = 2-cyano-3,12-dioxoolean-1,9-dien-28-oic-acid, SSc = systemic sclerosis, MMP-1 = matrix metalloproteinase-1, dSSc = diffuse systemic sclerosis.