IL‐17‐induced inflammation modulates the mPGES‐1/PPAR‐γ pathway in monocytes/macrophages
Federica Raucci, Anella Saviano, Gian Marco Casillo, Miguel Guerra-Rodríguez, Adel Abo Mansour, Marialuisa Piccolo, Maria Grazia Ferraro, Elisabetta Panza, Valentina Vellecco, Carlo Irace, Francesco Caso, Raffaele Scarpa, Nicola Mascolo, Mohammed Alfaifi, Asif Iqbal, Francesco Μaione
Abstract
Background and Purpose Recent biochemical and pharmacological studies have reported that in several tissues and cell types, microsomal PGE 2 synthase (mPGES) and PPAR‐γ 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‐γ 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‐γ 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‐кB/IкB‐α, and mPTGDS‐1/PPAR‐γ, 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‐γ pathway could represent a potential therapeutic target for inflammatory‐based and immune‐mediated diseases. LINKED ARTICLES This article is part of a themed issue on Inflammation, Repair and Ageing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.9/issuetoc