IL-17 induced inflammation modulates mPGES-1/PPAR-γ pathways 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 these integrated pathways during the onset of
inflammation. Experimental Approach: We evaluated PF 9184 (mPGES-1
antagonist) 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 mPGDS-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.