Human lung fibroblasts produce proresolving peroxisome proliferator-activated receptor-γ ligands in a cyclooxygenase-2-dependent manner.
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 proinflammatory and proresolving prostaglandins (PGs) in conditioned culture medium from HLFs treated with a proinflammatory stimulus, IL-1β. Among the proresolving PGs in the HLF lipidome were several known ligands for peroxisome proliferator-activated receptor-γ (PPARγ), a transcription factor whose activation in the lung yields potent anti-inflammatory, antifibrotic, and proresolving effects. Next, we used a cell-based luciferase reporter to confirm the ability of HLF supernatants to activate PPARγ, demonstrating, for the first time, that primary HLFs activated with proinflammatory IL-1β or cigarette smoke extract 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 proinflammatory and proresolving responses to injurious stimuli. This novel endogenous resolution pathway represents a new therapeutic target for globally important inflammatory diseases such as chronic obstructive pulmonary disease.
Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York.
Shannon H
http://orcid.org/0000-0002-8999-4827
SH
Lacy
Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York.
Collynn F
CF
Woeller
Division of Pulmonary Diseases and Critical Care, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York.|Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry, Rochester, New York.
Thomas H
http://orcid.org/0000-0001-7177-3041
TH
Thatcher
Lipidomics Core Facility, Department of Pathology, Bioactive Lipids Research Program, Wayne State University School of Medicine, Karmanos Cancer Institute, Detroit, Michigan; and.
Krishna Rao
KR
Maddipati
Bioactive Lipids Research Program, Department of Pathology, Wayne State University School of Medicine, Karmanos Cancer Institute, Detroit, Michigan.
Kenneth V
KV
Honn
Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York.|Division of Pulmonary Diseases and Critical Care, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York.|Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry, Rochester, New York.
Patricia J
PJ
Sime
Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York; richard_phipps@urmc.rochester.edu.|Division of Pulmonary Diseases and Critical Care, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York.|Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry, Rochester, New York.
Richard P
RP
Phipps
D001095:Arachidonic Acids / Q000494:pharmacology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism; D015777:Eicosanoids / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D053583:Interleukin-1beta / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000378:metabolism; D008024:Ligands; D054834:Lipocalins / Q000378:metabolism; D008168:Lung / Q000166:cytology*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism*; D000071876:Prostaglandin-E Synthases; D012907:Smoking; D015854:Up-Regulation / Q000187:drug effects
D001095:Arachidonic Acids; D017077:Culture Media, Conditioned; D015777:Eicosanoids; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D015850:Interleukin-6; D016209:Interleukin-8; D008024:Ligands; D054834:Lipocalins; D016328:NF-kappa B; D047495:PPAR gamma; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; D015232:Dinoprostone
NFκB; lipidomics; peroxisome proliferator-activated receptor-γ; primary human lung fibroblasts; specialized proresolving mediators