The Induction of Pro–IL-1β by Lipopolysaccharide Requires Endogenous Prostaglandin E2 Production

Abstract

PGE has been shown to increase the transcription of pro-IL-1β. However, recently it has been demonstrated that PGE can block the maturation of IL-1β by inhibiting the NLRP3 inflammasome in macrophages. These apparently conflicting results have led us to reexamine the effect of PGE on IL-1β production. We have found that in murine bone marrow-derived macrophages, PGE via the cAMP/protein kinase A pathway is potently inducing IL-1β transcription, as well as boosting the ability of LPS to induce IL-1β mRNA and pro-IL-1β while inhibiting the production of TNF-α. This results in an increase in mature IL-1β production in macrophages treated with ATP. We also examined the effect of endogenously produced PGE on IL-1β production. By blocking PGE production with indomethacin, we made a striking finding that endogenous PGE is essential for LPS-induced pro-IL-1β production, suggesting a positive feedback loop. The effect of endogenous PGE was mediated by EP2 receptor. In primary human monocytes, where LPS alone is sufficient to induce mature IL-1β, PGE boosted LPS-induced IL-1β production. PGE did not inhibit ATP-induced mature IL-1β production in monocytes. Because PGE mediates the pyrogenic effect of IL-1β, these effects might be especially relevant for the role of monocytes in the induction of fever. A positive feedback loop from IL-1β and back to PGE, which itself is induced by IL-1β, is likely to be operating. Furthermore, fever might therefore occur in the absence of a septic shock response because of the inhibiting effect of PGE on TNF-α production.

Cell‐intrinsic metabolic regulation of mononuclear phagocyte activation: Findings from the tip of the iceberg

“…has recently been shown to play an important role as a necessary autocrine stimulant for the production of pro-IL-1β by LPS-stimulated macrophages (discussed further below). 18 We found that the PPP plays an important role in these processes by supporting the production of NADPH, an important cofactor for FAS ( Figure 1). In addition, the PPP generates ribose for nucleotide synthesis (Figure 1), which is critical for DNA and RNA synthesis with the latter presumably being important in the strong transcriptional response that results from TLR engagement.…”

Metabolic regulation of NLRP3

“…In a more recent study in murine macrophages, PGE 2 has been identified to promote pro‐IL‐1β processing. PGE 2 can signal through the EP2 receptor, and ablation of the EP2 receptor decreases IL‐1β maturation in an NLRP3‐dependent manner . Furthermore, in primary human monocytes, PGE 2 was shown to boost processing of pro‐IL‐1β by NLRP3.…”

“…PGE 2 can signal through the EP2 receptor, and ablation of the EP2 receptor decreases IL-1β maturation in an NLRP3-dependent manner. 60 Furthermore, in primary human monocytes, PGE 2 was shown to boost processing of pro-IL-1β by NLRP3. The role of PGE 2 -mediated PKA activation on NLRP3 activity however, is not fully elucidated.…”

Metabolic regulation of inflammasomes in inflammation

“…Eicosanoids, including prostaglandins (PGs) and leukotrienes, are derived from AA via the COX and 5‐LOX pathways, respectively . PGE 2 , an abundant eicosanoid present in LPS‐induced BMDMs owing to COX‐2 activation and 15‐hydroxydehydrogenase inhibition, is required for IL‐1 β transcription through interaction with the EP2 receptor, which leads to increased cAMP signalling . It is noteworthy that in macrophages, exogenous PGE 2 added after LPS negatively regulates NLRP3 inflammasome activation, whereas PGE 2 added before LPS promotes this process .…”

“…PGE 2 , an abundant eicosanoid present in LPS‐induced BMDMs owing to COX‐2 activation and 15‐hydroxydehydrogenase inhibition, is required for IL‐1 β transcription through interaction with the EP2 receptor, which leads to increased cAMP signalling . It is noteworthy that in macrophages, exogenous PGE 2 added after LPS negatively regulates NLRP3 inflammasome activation, whereas PGE 2 added before LPS promotes this process . Additionally, a rapid increase in eicosanoids, termed an ‘eicosanoid storm’, is detected during NAIP5/NLRC4 inflammasome activation, which facilitates the recruitment of neutrophils to clear pathogens after pore‐induced intracellular traps are formed following pyroptosis …”