Impaired adrenocorticotropic hormone response to bacterial endotoxin in mice deficient in prostaglandin E receptor EP1 and EP3 subtypes.
Sickness evokes various neural responses, one of which is activation of the hypothalamo-pituitary-adrenal (HPA) axis. This response can be induced experimentally by injection of bacterial lipopolysaccharide (LPS) or inflammatory cytokines such as IL-1. Although prostaglandins (PGs) long have been implicated in LPS-induced HPA axis activation, the mechanism downstream of PGs remained unsettled. By using mice lacking each of the four PGE receptors (EP1-EP4) and an EP1-selective antagonist, ONO-8713, we showed that both EP1 and EP3 are required for adrenocorticotropic hormone release in response to LPS. Analysis of c-Fos expression as a marker for neuronal activity indicated that both EP1 and EP3 contribute to activation of neurons in the paraventricular nucleus of the hypothalamus (PVN). This analysis also revealed that EP1, but not EP3, is involved in LPS-induced activation of the central nucleus of the amygdala. EP1 immunostaining in the PVN revealed its localization at synapses on corticotropin-releasing hormone-containing neurons. These findings suggest that EP1- and EP3-mediated neuronal pathways converge at corticotropin-releasing hormone-containing neurons in the PVN to induce HPA axis activation upon sickness.
Matsuoka
Yoko
Y
Department of Pharmacology, Kyoto University Faculty of Medicine, Kyoto 606-8501, Japan.
Furuyashiki
Tomoyuki
T
Bito
Haruhiko
H
Ushikubi
Fumitaka
F
Tanaka
Yasuhiro
Y
Kobayashi
Takuya
T
Muro
Seiji
S
Satoh
Noriko
N
Kayahara
Tetsuro
T
Higashi
Mikito
M
Mizoguchi
Akira
A
Shichi
Hitoshi
H
Fukuda
Yoshihiro
Y
Nakao
Kazuwa
K
Narumiya
Shuh
S
D000324:Adrenocorticotropic Hormone / Q000378:metabolism*; D000818:Animals; D001424:Bacterial Infections; D003346:Corticotropin-Releasing Hormone / Q000032:analysis; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D004731:Endotoxins / Q000633:toxicity*; D005786:Gene Expression Regulation / Q000187:drug effects; D016762:Genes, fos; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000502:physiology; D007527:Isoenzymes / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity*; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000502:physiology; D010286:Paraventricular Hypothalamic Nucleus / Q000502:physiology*; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000502:physiology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058308:Receptors, Prostaglandin E, EP3 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013569:Synapses / Q000502:physiology*
D004731:Endotoxins; D007527:Isoenzymes; D008070:Lipopolysaccharides; D008565:Membrane Proteins; C545636:Ptger1 protein, mouse; C545645:Ptger2 protein, mouse; C545648:Ptger3 protein, mouse; C545651:Ptger4 protein, mouse; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058308:Receptors, Prostaglandin E, EP3 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse