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Published on: May 31, 2018
IL-17-induced inflammation modulates the mPGES-1/PPAR-γ pathway in monocytes/macrophages
Federica Raucci1, Anella Saviano1, Gian Marco Casillo1
1Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy.
Background And Purpose:
Recent biochemical and pharmacological studies have reported that in several tissues and cell types, microsomal PGE2 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 (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:
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.
Insights
Interleukin-17 (IL-17) influences inflammatory monocytes via the microsomal prostaglandin E2 synthase-1 (mPGES-1) and peroxisome proliferator-activated receptor gamma (PPAR-γ) pathway. This IL-17/mPGES-1/PPAR-γ pathway represents a novel therapeutic target for inflammatory diseases.
Area of Science:
- Biochemistry
- Pharmacology
- Immunology
Background:
- Microsomal prostaglandin E2 synthase-1 (mPGES) and PPAR-γ expression are modulated by inflammatory factors.
- The role of IL-17 in mPGES-1/PPAR-γ pathway modulation during inflammation is largely unknown.
Purpose of the Study:
- To investigate the contribution of IL-17 to the mPGES-1/PPAR-γ pathway during inflammation.
- To explore IL-17's effects on inflammatory monocyte modulation.
Main Methods:
- In vitro studies using J774A.1 macrophages with mPGES-1 inhibitor (PF 9184) and PPAR-γ agonist (troglitazone).
- In vivo studies using a mouse air pouch model.
- Analysis of inflammatory infiltrates, cyto-chemokines, prostaglandins (PGs), and signaling pathways via flow cytometry, ELISA, and Western blots.
Main Results:
- PF 9184 and troglitazone modulated IL-17-induced leukocyte infiltration and inflammatory markers.
- Both compounds affected PG production (PGE2, PGD2, PGJ2) and inflammatory monocyte recruitment in response to IL-17.
- Expression of COX-2/mPGES-1, NF-κB/IκB-α, and mPTGDS-1/PPAR-γ was modulated by IL-17 and the tested compounds.
Conclusions:
- IL-17 acts as a specific modulator of inflammatory monocytes in later stages of inflammation.
- The IL-17/mPGES-1/PPAR-γ pathway is identified as a potential therapeutic target for inflammatory and immune-mediated diseases.
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