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

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.