PGE2 released by primary sensory neurons modulates Toll-like receptor 4 activities through an EP4 receptor-dependent process

•In DRG cells, physiological level of PGE2 inhibits LPS-stimulated TNFα via EP4 receptors.•LPS-stimulated COX-2 and TNFα are auto-inhibited by endogenous PGE2 via EP4 receptors.•DRG neurons endogenously produce COX-2-derived PGE2 to regulate TLR4 activity in glia.

Exogenous prostaglandin E2 (PGE2) displays mixed regulatory properties with regard to inflammatory gene expression in dorsal root ganglion (DRG) cells. We show here that endogenously-produced nanomolar concentrations of PGE2, such as that generated in response to Toll-like receptor 4 (TLR4) stimulation, inhibits both cyclooxygenase-2 (COX-2) and tumour necrosis factor alpha (TNFα) mRNA expression in DRG cells in an EP4 receptor-dependent manner. DRG neurons appear to be the major source of PGE2 in the DRG and likely serve as both an autocrine and paracrine system for limiting over-activation of both DRG neurons and glial cells in response to TLR4 stimulation.

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