Inducible prostaglandin E2 synthesis interacts in a temporally supplementary sequence with constitutive prostaglandin-synthesizing enzymes in creating the hypothalamic-pituitary-adrenal axis response to immune challenge.
Inflammation-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis has been suggested to depend on prostaglandins, but the prostaglandin species and the prostaglandin-synthesizing enzymes that are responsible have not been fully identified. Here, we examined HPA axis activation in mice after genetic deletion or pharmacological inhibition of prostaglandin E(2)-synthesizing enzymes, including cyclooxygenase-1 (Cox-1), Cox-2, and microsomal prostaglandin E synthase-1 (mPGES-1). After immune challenge by intraperitoneal injection of lipopolysaccharide, the rapid stress hormone responses were intact after Cox-2 inhibition and unaffected by mPGES-1 deletion, whereas unselective Cox inhibition blunted these responses, implying the involvement of Cox-1. However, mPGES-1-deficient mice showed attenuated transcriptional activation of corticotropin-releasing hormone (CRH) that was followed by attenuated plasma concentrations of adrenocorticotropic hormone and corticosterone. Cox-2 inhibition similarly blunted the delayed corticosterone response and further attenuated corticosterone release in mPGES-1 knock-out mice. The expression of the c-fos gene, an index of synaptic activation, was maintained in the paraventricular hypothalamic nucleus and its brainstem afferents both after unselective and Cox-2 selective inhibition as well as in Cox-1, Cox-2, and mPGES-1 knock-out mice. These findings point to a mechanism by which (1) neuronal afferent signaling via brainstem autonomic relay nuclei and downstream Cox-1-dependent prostaglandin release and (2) humoral, CRH transcription-dependent signaling through induced Cox-2 and mPGES-1 elicited PGE(2) synthesis, shown to occur in brain vascular cells, play distinct, but temporally supplementary roles for the stress hormone response to inflammation.
Elander
Louise
L
Division of Cell Biology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, S-581 85 Linköping, Sweden.
Engström
Linda
L
Ruud
Johan
J
Mackerlova
Ludmila
L
Jakobsson
Per-Johan
PJ
Engblom
David
D
Nilsberth
Camilla
C
Blomqvist
Anders
A
D000324:Adrenocorticotropic Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D003345:Corticosterone / Q000037:antagonists & inhibitors / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage; D015232:Dinoprostone / Q000096:biosynthesis*; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology*; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology*; D000071876:Prostaglandin-E Synthases
D052246:Cyclooxygenase 2 Inhibitors; D008070:Lipopolysaccharides; D000324:Adrenocorticotropic Hormone; D051546:Cyclooxygenase 2; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; D015232:Dinoprostone; D003345:Corticosterone