title: The prostaglandin E2 receptor EP4 is integral to a positive feedback loop for prostaglandin E2 production in human macrophages infected with Mycobacterium tuberculosis.
abstract: Prostaglandin E2 (PGE2) is an important biological mediator involved in the defense against Mycobacterium tuberculosis (Mtb) infection. Previously, we reported that in macrophages (Mϕs), infection with avirulent Mtb H37Ra resulted in inhibition of necrosis by an inhibitory effect on mitochondrial permeability transition via the PGE2 receptor EP2. However, human Mϕs also express EP4, a PGE2 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 Mϕs have been unclear. EP4 antagonist addition to H37Ra-infected Mϕs inhibited the expression of cyclooxygenase 2 (COX2) and microsomal prostaglandin E synthase-1 (mPGES-1), which are involved in PGE2 production. Moreover, H37Ra infection induced PGE2 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 Mϕs, PGE2 production induced by pathogen recognition receptors/p38 MAPK signaling is up-regulated by EP4-triggered signaling to maintain an effective PGE2 concentration.
authors.affiliation: Division of Rheumatology, Immunology, and Allergy, Department of Medicine, , Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Tomoyasu
authors.initials: T
authors.lastname: Nishimura
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Zhao
authors.forename: Huixian
authors.initials: H
authors.lastname: Gan
authors.forename: Shigeo
authors.initials: S
authors.lastname: Koyasu
authors.forename: Heinz G
authors.initials: HG
authors.lastname: Remold
mesh_terms: D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D008264:Macrophages / Q000382:microbiology*; D009169:Mycobacterium tuberculosis / Q000472:pathogenicity*; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000737:chemistry / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D058309:Receptors, Prostaglandin E, EP4 Subtype; D051195:Toll-Like Receptor 2; D051546:Cyclooxygenase 2; D048051:p38 Mitogen-Activated Protein Kinases; D015232:Dinoprostone
keywords: Toll-like receptor 2; cyclooxygenase 2; p38 mitogen-activated protein kinase