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.
Highlights
Fever is a homeostatic response of the host to the infection by microbial and viral pathogens
Effect of caspase-1 inhibitor ZVAD on Prostaglandin E2 (PGE2) production in primary human monocytes and macrophages activated with LPS
To determine whether the TRIF/IRF3 pathway plays a role in IL-1b-induced PGE2 induction in LPS-primed monocytes, we investigated whether IRF3 is phosphorylated in human monocytes and macrophages in response to TLR4 (LPS) vs. TLR2 (Pam3CSK4) agonists and whether IL-1b affected IRF3 phosphorylation in agonist-primed monocytes and macrophages
Summary
Fever is a homeostatic response of the host to the infection by microbial and viral pathogens. According to the conventional view of the mechanism of fever, locally-induced pyrogenic cytokines are transported by the blood stream to the ‘‘fever producing center’’, the ventromedial preoptic area (VMPO) of the anterior hypothalamus, where they activate generation and release of the prostaglandin (PG)E2, a thermogenic lipid mediator [1]. This concept of cytokine-induced fever was challenged by studies showing that neither LPS nor IL-1b administered peripherally crossed the blood-brain barrier and that LPS injected intravenously in animals induced febrile responses and PGE2 in VMPO before cytokines were elevated in the blood [2,3]. Studies in mice genetically engineered to lack pyrogenic cytokines, the ability of PGE2 to cross blood-brain barrier, and observations of clinical fevers that frequently occur without increase of circulating cytokines suggested alternative routes for transmission of febrile signals [3,4,5,6,7]
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