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 inflammatorybased and immune-mediated diseases.

IL-17-induced inflammation modulates the mPGES-1/PPAR-gamma pathway in monocytes/macrophages / Raucci, Federica; Saviano, Anella; Casillo, GIAN MARCO; Guerra-Rodriguez, Miguel; Abo Mansour, Adel; Piccolo, Marialuisa; Ferraro, MARIA GRAZIA; Panza, Elisabetta; Vellecco, Valentina; Irace, Carlo; Caso, Francesco; Scarpa, Raffaele; Mascolo, Nicola; Alfaifi, Mohammed; Jilani Iqbal, Asif; Maione, Francesco. - In: BRITISH JOURNAL OF PHARMACOLOGY. - ISSN 1476-5381. - (2021), pp. 1-17. [10.1111/bph.15413]

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

Federica Raucci;Anella Saviano;Gian Marco Casillo;Marialuisa Piccolo;Maria Grazia Ferraro;Elisabetta Panza;Valentina Vellecco;Carlo Irace;Francesco Caso;Nicola Mascolo;Francesco Maione
2021

Abstract

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 inflammatorybased and immune-mediated diseases.
2021
IL-17-induced inflammation modulates the mPGES-1/PPAR-gamma pathway in monocytes/macrophages / Raucci, Federica; Saviano, Anella; Casillo, GIAN MARCO; Guerra-Rodriguez, Miguel; Abo Mansour, Adel; Piccolo, Marialuisa; Ferraro, MARIA GRAZIA; Panza, Elisabetta; Vellecco, Valentina; Irace, Carlo; Caso, Francesco; Scarpa, Raffaele; Mascolo, Nicola; Alfaifi, Mohammed; Jilani Iqbal, Asif; Maione, Francesco. - In: BRITISH JOURNAL OF PHARMACOLOGY. - ISSN 1476-5381. - (2021), pp. 1-17. [10.1111/bph.15413]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/875780
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