IL-17-induced inflammation modulates the mPGES-1/PPAR-γ pathway in monocytes/macrophages

Background and Purpose Recent biochemical and pharmacological studies have reported that in several tissues and cell types, microsomal PGE(2) synthase (mPGES) and PPAR-gamma expression are modulated by a variety of inflammatory factors and stimuli. Considering that very little is known about the biological effects promoted by IL-17 in the context of mPGES-1/PPAR-gamma modulation, we sought to investigate the contribution of this unique cytokine on this integrated pathway during the onset of inflammation. Experimental Approach We evaluated effects of PF 9184 (mPGES-1 inhibitor) and troglitazone (PPAR-gamma agonist) in vitro, using the mouse macrophage cell line J774A.1. In vivo, the dorsal air pouch model in CD1 mice was used, and inflammatory infiltrates were analysed by flow cytometry. Locally produced cyto-chemokines and PGs were assessed using elisa assays. Western blots were also employed to determine the activity of various enzymes involved in downstream signalling pathways. Key Results PF 9184 and troglitazone, in a time- and dose-dependent manner, modulated leukocyte infiltration, myeloperoxidase activity, and the expression of COX-2/mPGES-1, NF-kB/IkB-alpha, and mPTGDS-1/PPAR-gamma, induced by IL-17. Moreover, both PF 9184 and troglitazone modulated PG (PGE(2), PGD(2), and PGJ(2)) production, the expression of different pro-inflammatory cyto-chemokines, and the recruitment of inflammatory monocytes, in response to IL-17. Conclusions and Implications Our data suggest that IL-17 may constitute a specific modulator of inflammatory monocytes during later phases of the inflammatory response. The results of this study show, for the first time, that the IL-17/mPGES-1/PPAR-gamma pathway could represent a potential therapeutic target for inflammatory-based and immune-mediated diseases.

Automated summary

The study suggests that IL-17 may specifically regulate inflammatory monocytes during later stages of inflammation. The IL-17/mPGES-1/PPAR-gamma pathway could be a potential therapeutic target for inflammatory-based and immune-mediated diseases.