title: Suppressed microglial E prostanoid receptor 1 signaling selectively reduces tumor necrosis factor alpha and interleukin 6 secretion from toll-like receptor 3 activation.
abstract: Activation of innate immunity via toll-like receptors (TLRs) is associated with neurodegenerative diseases, and some effectors, like tumor necrosis factor alpha (TNFα) and interleukin 6 (IL-6), directly contribute to neurodegeneration. We tested the hypothesis that prostaglandin (PG) E(2) receptor subtype 1 (EP1) was necessary for the induction of microglial cytokines following the activation of innate immunity. Primary murine microglia had cytokine secretion by activators of TLR3 > TLR9 > TLR4 > TLR2. TLR3 activation induced early expression of cyclooxygenase 2 (COX2) and delayed expression of membranous PGE synthase and secretion of PGE(2) . Nonselective and COX2-selective inhibitors blocked TLR3 induction of TNFα and IL-6. Moreover, of the nine of twenty cytokines and chemokines induced by TLR3 activation, only TNFα and IL-6 were significantly dependent on EP1 signaling as determined using microglia from mice homozygous deficient for EP1 gene or wild-type microglia coincubated with an EP1 antagonist. These results were confirmed by blocking intracellular Ca(2+) release with 2-aminoethoxy-diphenyl borate or Xestospongin C, inhibitors of IP3 receptors. Our results show that suppression of microglial EP1 signaling achieves much of the desired effect of COX inhibitors by selectively blocking TLR3-induced microglial secretion of two major effectors of paracrine neuron damage. In combination with the ability of EP1 suppression to ameliorate excitotoxicity, these data point to blockade of EP1 as an attractive candidate therapeutic for neurodegenerative diseases.
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, USA. xli@u.washington.edu
authors.forename: Xianwu
authors.initials: X
authors.lastname: Li
authors.forename: Eiron
authors.initials: E
authors.lastname: Cudaback
authors.forename: C Dirk
authors.initials: CD
authors.lastname: Keene
authors.forename: Richard M
authors.initials: RM
authors.lastname: Breyer
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Montine
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D007113:Immunity, Innate / Q000502:physiology; D015850:Interleukin-6 / Q000378:metabolism*; D051379:Mice; D017628:Microglia / Q000378:metabolism*; D058306:Receptors, Prostaglandin E, EP1 Subtype / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D051196:Toll-Like Receptor 3 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D015850:Interleukin-6; D058306:Receptors, Prostaglandin E, EP1 Subtype; D051196:Toll-Like Receptor 3; D014409:Tumor Necrosis Factor-alpha