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

Federica Raucci; Anella Saviano; Gian Marco Casillo; Miguel Guerra-Rodriguez; Adel Abo Mansour; Marialuisa Piccolo; Maria Grazia Ferraro; Elisabetta Panza; Valentina Vellecco; Carlo Irace; Francesco Caso; Raffaele Scarpa; Nicola Mascolo; Mohammed Alfaifi; Asif Jilani Iqbal; Francesco Maione

doi:10.1111/bph.15413

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

Federica Raucci, Anella Saviano, Gian Marco Casillo, Miguel Guerra-Rodriguez, Adel Abo Mansour, Marialuisa Piccolo, Maria Grazia Ferraro, Elisabetta Panza, Valentina Vellecco, Carlo Irace, Francesco Caso, Raffaele Scarpa, Nicola Mascolo, Mohammed Alfaifi, Asif Jilani Iqbal, Francesco Maione

Cardiovascular Sciences

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Journal	British Journal of Pharmacology
Early online date	17 Feb 2021
DOIs	https://doi.org/10.1111/bph.15413
Publication status	E-pub ahead of print - 17 Feb 2021

Bibliographical note

Funding Information:
This work was supported by MIUR (PRIN 2017; 2017A95NCJ/201795NCJ_002, “Stolen molecules ‐ Stealing natural products from the depot and reselling them as new drug candidates”) and Birmingham Fellowship awarded to A.J.I.

Publisher Copyright:
© 2021 The British Pharmacological Society

Keywords

IL-17A
PGE
PPAR-γ
inflammation
mPGES-1
monocytes/macrophages

ASJC Scopus subject areas

Pharmacology

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Raucci, F., Saviano, A., Casillo, G. M., Guerra-Rodriguez, M., Mansour, A. A., Piccolo, M., Ferraro, M. G., Panza, E., Vellecco, V., Irace, C., Caso, F., Scarpa, R., Mascolo, N., Alfaifi, M., Iqbal, A. J., & Maione, F. (2021). IL-17-induced inflammation modulates the mPGES-1/PPAR-γ pathway in monocytes/macrophages. British Journal of Pharmacology. Advance online publication. https://doi.org/10.1111/bph.15413

@article{e90f35e3881648b58691cbcc1286d930,

title = "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 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. ",

keywords = "IL-17A, PGE, PPAR-γ, inflammation, mPGES-1, monocytes/macrophages",

author = "Federica Raucci and Anella Saviano and Casillo, {Gian Marco} and Miguel Guerra-Rodriguez and Mansour, {Adel Abo} and Marialuisa Piccolo and Ferraro, {Maria Grazia} and Elisabetta Panza and Valentina Vellecco and Carlo Irace and Francesco Caso and Raffaele Scarpa and Nicola Mascolo and Mohammed Alfaifi and Iqbal, {Asif Jilani} and Francesco Maione",

note = "Funding Information: This work was supported by MIUR (PRIN 2017; 2017A95NCJ/201795NCJ_002, “Stolen molecules ‐ Stealing natural products from the depot and reselling them as new drug candidates”) and Birmingham Fellowship awarded to A.J.I. Publisher Copyright: {\textcopyright} 2021 The British Pharmacological Society",

year = "2021",

month = feb,

day = "17",

doi = "10.1111/bph.15413",

language = "English",

journal = "British Journal of Pharmacology",

issn = "0007-1188",

publisher = "Wiley",

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TY - JOUR

T1 - IL-17-induced inflammation modulates the mPGES-1/PPAR-γ pathway in monocytes/macrophages

AU - Raucci, Federica

AU - Saviano, Anella

AU - Casillo, Gian Marco

AU - Guerra-Rodriguez, Miguel

AU - Mansour, Adel Abo

AU - Piccolo, Marialuisa

AU - Ferraro, Maria Grazia

AU - Panza, Elisabetta

AU - Vellecco, Valentina

AU - Irace, Carlo

AU - Caso, Francesco

AU - Scarpa, Raffaele

AU - Mascolo, Nicola

AU - Alfaifi, Mohammed

AU - Iqbal, Asif Jilani

AU - Maione, Francesco

N1 - Funding Information: This work was supported by MIUR (PRIN 2017; 2017A95NCJ/201795NCJ_002, “Stolen molecules ‐ Stealing natural products from the depot and reselling them as new drug candidates”) and Birmingham Fellowship awarded to A.J.I. Publisher Copyright: © 2021 The British Pharmacological Society

PY - 2021/2/17

Y1 - 2021/2/17

N2 - 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.

AB - 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.

KW - IL-17A

KW - PGE

KW - PPAR-γ

KW - inflammation

KW - mPGES-1

KW - monocytes/macrophages

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U2 - 10.1111/bph.15413

DO - 10.1111/bph.15413

M3 - Article

C2 - 33595097

SN - 0007-1188

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

ER -

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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