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

Abstract

Background and Purpose Recent biochemical and pharmacological studies have reported that in several tissues and cell types, microsomal prostaglandin E₂ synthase (mPGES) and peroxisome proliferator‐activated receptor‐γ (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 PF 9184 (mPGES‐1 inhibitor) and Troglitazone (PPAR‐γ agonist) activity utilising integrated in vitro and in vivo approaches. The dorsal air pouch model was employed, and inflammatory infiltrates were analysed by flow cytometry. Locally produced cyto‐chemokines and prostaglandins 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, were shown to significantly modulate 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 compounds were found to modulate prostaglandins (PGE₂, PGD₂, and PGJ₂) production, the expression of different pro‐inflammatory cyto‐chemokines and the recruitment of inflammatory monocytes in response to IL‐17. Conclusions and Implications Collectively, the data presented suggests that IL‐17 may constitute a specific modulator of inflammatory monocytes during later phases of the inflammatory response. Therefore, the results of this study show, for the first time, that IL‐17/mPGES‐1/PPAR‐γ “axis” could represent a potential therapeutic target for inflammatory‐based and immune‐mediated diseases.