Interferon Potentiates Toll-Like Receptor-Induced Prostaglandin D(2) Production through Positive Feedback Regulation between Signal Transducer and Activators of Transcription 1 and Reactive Oxygen Species

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.