Abstract
Abstract Innate immune activators that are potent inducers of fever also up-regulate plasma PGE2. To determine whether TLR and NOD agonists activate production of PGE2 directly or through IL-1β, human monocytes (Mo) and differentiated macrophages (MF) were cultured with TLR agonists with or without Caspase-1 inhibitor ZVAD, which inhibited LPS-induced IL-1β in both cell types. PGE2 production in MF was not affected by ZVAD, while in Mo, ZVAD reduced PGE2 and COX2 expression by 30-60%. Surprisingly, IL-1β alone did not up-regulate PGE2 in Mo. However, in Mo pretreated with low dose of LPS, PGE2 and COX2 mRNA were up-regulated by IL-1β. LPS (but not TLR2 agonist) induced phosphorylation of IRF3 (Ser 396) in Mo. Knock-down of IRF3 or of TRIF by siRNA abrogated IL-1β induced COX2 mRNA expression in LPS-pretreated U937-CD14 cells. MDP did not induce PGE2 in Mo alone. However, COX2 mRNA and PGE2 protein in MDP-activated Mo was significantly augmented by human CD3 bead-purified T cells or T cell supernatant. Treatment of Mo with inhibitors of autophagy including ATG5 or ATG7 siRNA, inhibited MDP-induced PGE2 production. T cells were also required for PGE2 produced in response to flagellin and IE-DAP but not Poly I:C. In summary, Mo employ multiple pathways to produce PGE2, depending on the type of innate receptors involved: IRF3/TRIF pathway is employed in response to TLR4, while autophagy/ROS and T cell-derived signals are involved in PGE2 production after triggering of NOD1/2 and IPAF.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have