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Differences in PGE2 production between primary human monocytes and differentiated macrophages: role of IL-1β and
Yukinori Endo1, Ksenia Blinova1, Tatiana Romantseva1
1Center for Biologics Evaluation and Research (CBER), Food and Drug Administration (FDA), Bethesda, Maryland, United States of America.
Abstract:
Prostaglandin E2 (PGE2) is induced in vivo by bacterial products including TLR agonists. To determine whether PGE2 is induced directly or via IL-1β, human monocytes and macrophages were cultured with LPS or with Pam3CSK4 in presence of caspase-1 inhibitor, ZVAD, or IL-1R antagonist, Kineret. TLR agonists induced PGE2 in macrophages exclusively via IL-1β-independent mechanisms. In contrast, ZVAD and Kineret reduced PGE2 production in LPS-treated (but not in Pam3CSK4-treated) monocytes, by 30-60%. Recombinant human IL-1β augmented COX-2 and mPGES-1 mRNA and PGE2 production in LPS-pretreated monocytes but not in un-primed or Pam3CSK4-primed monocytes. This difference was explained by the finding that LPS but not Pam3CSK4 induced phosphorylation of IRF3 in monocytes suggesting activation of the TRIF signaling pathway. Knocking down TRIF, TRAM, or IRF3 genes by siRNA inhibited IL-1β-induced COX-2 and mPGES-1 mRNA. Blocking of TLR4 endocytosis during LPS priming prevented the increase in PGE2 production by exogenous IL-1β. Our data showed that TLR2 agonists induce PGE2 in monocytes independently from IL-1β. In the case of TLR4, IL-1β augments PGE2 production in LPS-primed monocytes (but not in macrophages) through a mechanism that requires TLR4 internalization and activation of the TRIF/IRF3 pathway. These findings suggest a key role for blood monocytes in the rapid onset of fever in animals and humans exposed to bacterial products and some novel adjuvants.
Insights
Bacterial products like LPS induce prostaglandin E2 (PGE2) in monocytes via IL-1β, requiring TLR4 internalization and TRIF/IRF3 signaling. Macrophages produce PGE2 independently of IL-1β.
Area of Science:
- Immunology
- Inflammation Research
Background:
- Prostaglandin E2 (PGE2) is a key mediator induced by bacterial products.
- The precise pathways of PGE2 induction in different immune cells remain incompletely understood.
Purpose of the Study:
- To elucidate the distinct mechanisms of PGE2 induction by Toll-like receptor (TLR) agonists in human monocytes and macrophages.
- To investigate the roles of Interleukin-1 beta (IL-1β) and the TRIF signaling pathway in TLR-mediated PGE2 production.
Main Methods:
- Human monocytes and macrophages were stimulated with LPS (TLR4 agonist) or Pam3CSK4 (TLR2 agonist) in the presence of inhibitors (ZVAD, Kineret).
- Gene knockdown using siRNA (TRIF, TRAM, IRF3) and blocking of TLR4 endocytosis were employed.
- Messenger RNA (mRNA) expression of COX-2 and mPGES-1, and PGE2 production were quantified.
Main Results:
- TLR agonists induced PGE2 in macrophages independently of IL-1β.
- In monocytes, LPS-induced PGE2 was partially dependent on IL-1β, involving TLR4 internalization and TRIF/IRF3 pathway activation.
- Pam3CSK4-induced PGE2 in monocytes occurred independently of IL-1β.
Conclusions:
- Monocytes play a critical role in rapid fever onset via IL-1β-dependent PGE2 production triggered by TLR4 agonists.
- Distinct signaling pathways govern PGE2 induction by TLR2 and TLR4 agonists in monocytes.
- Understanding these mechanisms offers insights into inflammatory responses and potential therapeutic targets.
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