The prostaglandin E2 receptor EP4 is integral to a positive feedback loop for prostaglandin E2 production in human macrophages infected with Mycobacterium tuberculosis

Prostaglandin E-2 (PGE(2)) is an important biological mediator involved in the defense against Mycobacterium tuberculosis (Mtb) infection. Previously, we reported that in macrophages (M phi s), infection with avirulent Mtb H37Ra resulted in inhibition of necrosis by an inhibitory effect on mitochondrial permeability transition via the PGE(2) receptor EP2. However, human M phi s also express EP4, a PGE(2) receptor functionally closely related to EP2 that also couples to stimulatory guanine nucleotide binding protein, but the functional differences between EP2 and EP4 in Mtb-infected M phi s have been unclear. EP4 antagonist addition to H37Ra-infected M phi s inhibited the expression of cyclooxygenase 2 (COX2) and microsomal prostaglandin E synthase-1 (mPGES-1), which are involved in PGE(2) production. Moreover, H37Ra infection induced PGE(2) production through the Toll-like receptor (TLR) 2/p38 mitogen-activated protein kinase (MAPK) signaling pathway. Induction of COX2 and mPGES-1 expression by TLR2 stimulation or Mtb infection was increased after additional stimulation with EP4 agonist. Hence, in Mtb-infected M phi s, PGE(2) production induced by pathogen recognition receptors/p38 MAPK signaling is up-regulated by EP4-triggered signaling to maintain an effective PGE(2) concentration.Nishimura, T., Zhao, X., Gan, H., Koyasu, S., and Remold, H. G. The prostaglandin E-2 receptor EP4 is integral to a positive feedback loop for prostaglandin E-2 production in human macrophages infected with Mycobacterium tuberculosis.