Abstract
IntroductionPeroxisome proliferator-activated receptor (PPAR) agonists are widely used drugs in the treatment of diabetes and dyslipidemia. In addition to their metabolic effects, PPAR isoforms PPARα and PPARγ are also involved in the regulation of immune responses and inflammation. In the present study, we investigated the effects of a dual PPARγ/α agonist muraglitazar on inflammatory gene expression in activated macrophages and on carrageenan-induced inflammation in the mouse.MethodsJ774 murine macrophages were activated by lipopolysaccharide (LPS) and treated with dual PPARγ/α agonist muraglitazar, PPARγ agonist GW1929 or PPARα agonist fenofibrate. The effects of PPAR agonists on cytokine production and the activation of inducible nitric oxide synthase (iNOS) pathway were investigated by ELISA, Griess method, Western blotting and quantitative RT-PCR. Nuclear translocation, DNA-binding activity and reporter gene assays were used to assess the activity of nuclear factor kappa B (NF-kB) transcription factor. Carrageenan-induced paw oedema was used as an in vivo model of acute inflammation.ResultsMuraglitazar as well as PPARγ agonist GW1929 and PPARα agonist fenofibrate inhibited LPS-induced iNOS expression and NO production in activated macrophages in a dose-dependent manner. Inhibition of iNOS expression by muraglitazar included both transcriptional and post-transcriptional components; the former being shared by GW1929 and the latter by fenofibrate. All tested PPAR agonists also inhibited IL-6 production, while TNFα production was reduced by muraglitazar and GW1929, but not by fenofibrate. Interestingly, the anti-inflammatory properties of muraglitazar were also translated in vivo. This was evidenced by the finding that muraglitazar inhibited carrageenan-induced paw inflammation in a dose-dependent manner in mice as did iNOS inhibitor L-NIL and anti-inflammatory steroid dexamethasone.ConclusionsThese results show that muraglitazar has anti-inflammatory properties both in vitro and in vivo and these effects reflect the agonistic action through both PPARα and PPARγ.
Highlights
Peroxisome proliferator-activated receptor (PPAR) agonists are widely used drugs in the treatment of diabetes and dyslipidemia
Muraglitazar and PPARa and PPARg agonists decreased Nitrous oxide (NO) production and inducible nitric oxide synthase (iNOS) expression Resting J774 macrophages did not produce detectable amounts of NO, but when the cells were activated through TLR4 pathway by bacterial endotoxin LPS, NO production and iNOS expression were increased
None of the PPAR agonists did affect the stability of iNOS mRNA when compared to the cells treated with LPS only (Figure 3b)
Summary
Peroxisome proliferator-activated receptor (PPAR) agonists are widely used drugs in the treatment of diabetes and dyslipidemia. In addition to their metabolic effects, PPAR isoforms PPARa and PPARg are involved in the regulation of immune responses and inflammation. Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily and they are strongly linked to the regulation of energy homeostasis in cells. The main interest in PPAR-related studies has been focused on the role of PPARs in energy homeostasis, PPARs, especially PPARa and PPARg, are shown to be involved in the regulation of the immune and inflammatory responses in obesity-linked diseases [8,9,10]. We found only a single study suggesting that a PPARa agonist fenofibrate would have antiinflammatory effects in experimentally induced arthritis [12]
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