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Prostaglandin D 2  (PGD 2 ) is a potent lipid mediator that controls inflammation, and its dysregulation has been implicated in diverse inflammatory disorders. Despite significant progress made in understanding the role of PGD 2  as a key regulator of immune responses, the molecular mechanism underlying PGD 2  production remains unclear, particularly upon challenge with different and multiple inflammatory stimuli. Interferons (IFNs) potentiate macrophage activation and act in concert with exogenous inflammatory mediators such as toll-like receptor (TLR) ligands to amplify inflammatory responses. A recent study found that IFN-γ enhanced lipopolysaccharide-induced PGD 2  production, indicating a role of IFNs in PGD 2  regulation. Here, we demonstrate that TLR-induced PGD 2  production by macrophages was significantly potentiated by signaling common to IFN-β and IFN-γ in a signal transducer and activators of transcription (STAT)1-dependent mechanism. Such potentiation by IFNs was also observed for PGE 2  production, despite the differential regulation of PGD synthase and PGE synthase isoforms mediating PGD 2  and PGE 2  production under inflammatory conditions. Mechanistic analysis revealed that the generation of intracellular reactive oxygen species (ROS) was remarkably potentiated by IFNs and required for PGD 2  production, but was nullified by STAT1 deficiency. Conversely, the regulation of STAT1 level and activity by IFNs was largely dependent on ROS levels. Using a model of zymosan-induced peritonitis, the relevance of this finding  in vivo  was supported by marked inhibition of PGD 2  and ROS produced in peritoneal exudate cells by STAT1 deficiency. Collectively, our findings suggest that IFNs, although not activating on their own, are potent amplifiers of TLR-induced PGD 2  production  via  positive-feedback regulation between STAT1 and ROS.

frontiers in immunology

Interferon Potentiates Toll-Like Receptor-Induced Prostaglandin D2 Production through Positive Feedback Regulation between Signal Transducer and Activators of Transcription 1 and Reactive Oxygen Species