Human lung fibroblasts (HLFs) act as innate immune sentinel cells that amplify the inflammatory response to injurious stimuli. Here, we use targeted lipidomics to explore the hypothesis that HLFs also play an active role in the resolution of inflammation. We detected cyclooxygenase-2 (COX-2)-dependent production of both pro-inflammatory and pro-resolving prostaglandins (PGs) in conditioned culture medium from HLFs treated with a pro-inflammatory stimulus, IL-1β. Among the pro-resolving PGs in the HLF lipidome were several known ligands for peroxisome proliferator-activated receptor gamma (PPARγ), a transcription factor whose activation in the lung yields potent anti-inflammatory, anti-fibrotic and pro-resolving effects. We next confirmed the ability of HLF supernatants to activate PPARγ using a cell-based luciferase reporter, demonstrating for the first time that HLFs activated with pro-inflammatory IL-1β or cigarette smoke extract (CSE) produce functional PPARγ ligands; this phenomenon is temporally-regulated, COX-2- and lipocalin-type PGD synthase-dependent, and enhanced by arachidonic acid supplementation. Finally, we used luciferase reporter assays to show that several of the PGs in the lipidome of activated HLFs independently activate PPARγ and/or inhibit NFκB. These results indicate that HLFs, as immune sentinels, regulate both pro-inflammatory and pro-resolving responses to injurious stimuli. This novel endogenous resolution pathway represents a new therapeutic target for globally important inflammatory diseases like chronic obstructive pulmonary disease.
- primary human lung fibroblasts
- peroxisome proliferator-activated receptor gamma (PPARγ)
- specialized pro-resolving mediators
- Copyright © 2016, American Journal of Physiology-Lung Cellular and Molecular Physiology