Abstract
Previously, the authors found that 4-hydroxy-2-(4-hydroxyphenethyl) isoindoline-1,3-dione (PD1) (a phthalimide analogue) bound to and activated peroxisome proliferator-activated receptor-γ (PPAR-γ). Since PPAR-γ suppresses inflammatory responses, the present study was undertaken to investigate the anti-inflammatory effects of PD1. In lipopolysaccharide (LPS)-stimulated murine RAW264.7 macrophages, PD1 suppressed the inductions of pro-inflammatory factors, including inducible nitric oxide synthase (iNOS), nitric oxide (NO), cyclooxygenase 2 (COX-2), tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6). Concomitantly, PD1 enhanced the expressions of anti-inflammatory factors, such as arginase-1 and interleukin-10 (IL-10), and suppressed LPS-evoked nuclear factor kappa B (NF-κB) p65 subunit phosphorylation in macrophages. In addition, PPAR-γ activated by PD1 was intensively translocated to the nucleus. These observations suggest that the anti-inflammatory mechanism of PD1 involves inhibition of the NF-κB pathway. In a subsequent in vivo animal experiment conducted using a carrageenan-induced acute inflammatory rat paw edema model, intraperitoneal injection of PD1 significantly reduced paw swelling. Histological analysis of rat paw tissue sections revealed less infiltration of immune cells in PD1-pretreated animals. These findings suggest that PD1 be viewed as a lead compound for the development of novel anti-inflammatory therapeutics.
Highlights
Peroxisome proliferator-activated receptor (PPAR)-γ is a member of the nuclear receptor superfamily, which are activated by ligands, such as endogenous 15-deoxy-∆12,14 -prostaglandin J2 and insulin-sensitizing thiazolidinediones [1]
peroxisome proliferator-activated receptor-γ (PPAR-γ) is predominantly present in adipose tissue, colon, skeletal muscle, endothelium, macrophages, and monocytes, and plays important roles in the regulation of insulin sensitivity, lipid metabolism, adipogenesis, and glucose homeostasis [2]
Many inflammatory diseases stem from the activation of macrophages, and it is known that classically activated M1 macrophages induced by infection, tissue damage, or exposure to endotoxins (i.e., lipopolysaccharide (LPS)) secrete large amounts of pro-inflammatory mediators, such as nitric oxide (NO), inducible nitric oxide synthase, cyclooxygenase 2 (COX-2), cytokines interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor α (TNF-α), whereas
Summary
Peroxisome proliferator-activated receptor (PPAR)-γ is a member of the nuclear receptor superfamily, which are activated by ligands, such as endogenous 15-deoxy-∆12,14 -prostaglandin J2 and insulin-sensitizing thiazolidinediones [1]. Activated PPAR-γ translocates to the cell nucleus and binds to peroxisome proliferator response element (PPRE) on target DNA to regulate gene transcription. PPAR-γ is predominantly present in adipose tissue, colon, skeletal muscle, endothelium, macrophages, and monocytes, and plays important roles in the regulation of insulin sensitivity, lipid metabolism, adipogenesis, and glucose homeostasis [2]. PPAR-γ is involved in the regulations of immune and inflammatory responses [3,4].
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