Inducible Prostaglandin E₂Synthesis Interacts in a Temporally Supplementary Sequence with Constitutive Prostaglandin-Synthesizing Enzymes in Creating the Hypothalamic–Pituitary–Adrenal Axis Response to Immune Challenge

Abstract

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.

Interleukin-1β induced activation of the hypothalamus–pituitary–adrenal axis is dependent on interleukin-1 receptors on non-hematopoietic cells

“…Observations in mPGES-1 KO mice, which cannot evoke PGE2 synthesis upon immune challenge (Engblom et al, 2003;Engström et al, 2012), have shown that the induced PGE2 synthesis is involved in the stress hormone release in response to immune insults (Elander et al, 2009), and the present data are consistent with the idea that this PGE2 synthesis occurs in brain endothelial cells. It should be noted however, that this involvement may apply only to the later phases of the stress hormone response, because the immediately occurring corticosterone release, at least when LPS is used as immune stimulus, is unaffected by mPGES-1 deletion (Elander et al, 2009) and seems to be driven by a Cox-1 and not a Cox-2 dependent mechanism (Elander et al, 2010).…”

“…These observations have bearing on the interpretation of the present data on induced c-Fos expression in the PVH, suggestive of activation of hypophysiotropic cells in this nucleus. While we here found that the IL-1β induced c-Fos expression in the PVH was dependent on IL-1R1s on non-hematopoietic cells, this observation does not necessarily imply that the IL-1β signaling that give rise to this response occurs via endothelial cells and induced PGE2 synthesis, because c-Fos expression in PVH upon immune challenge with intraperitoneally injected LPS has been shown to be unaffected by genetic deletion of the prostaglandin synthesizing enzymes Cox-1, Cox-2 and mPGES-1 (Elander et al, 2009). In the work with endothelial specific IL-1R1 knockdown it was shown that such knockdown abolished c-Fos expression in the PVH after intravenous but not after intraperitoneal injection of IL-1β, suggesting a PGE2 dependent pathway for the immune signaling after the former but not after the latter administration route (Ching et al, 2007).…”

“…It should be noted however, that this involvement may apply only to the later phases of the stress hormone response, because the immediately occurring corticosterone release, at least when LPS is used as immune stimulus, is unaffected by mPGES-1 deletion (Elander et al, 2009) and seems to be driven by a Cox-1 and not a Cox-2 dependent mechanism (Elander et al, 2010). These observations have bearing on the interpretation of the present data on induced c-Fos expression in the PVH, suggestive of activation of hypophysiotropic cells in this nucleus.…”

“…The minimum detection concentration was 0.55 ng/ml. By using a 4-PL curve fit, a standard curve with an R value of 1.000 was obtained [for details, see (Elander et al, 2009)]. The concentrations of ACTH in plasma following intraperitoneal injection of IL-1β were determined with a bead-based analysis kit (#MBN1A-41K; Millipore, Billerica, MA), using the Luminex-100 system, as described in detail previously (Ruud and Blomqvist, 2007).…”

“…While there is a strong evidence that brain endothelial cells, by induced prostaglandin (PG) synthesis, are critical for the immune-elicited fever (Engström et al, 2012), it has been suggested that perivascular macrophages, located within the two sheets of the basal membrane of the cerebral blood vessels and hence on the abluminal side of the endothelial cells, mediate IL-1β evoked HPA-axis activation, also by induced PGsynthesis Sawchenko, 2002, 2003;Serrats et al, 2010). Deletion of the gene encoding microsomal prostaglandin E-synthase (Trebino et al, 2003), rending the animals unable to elicit central PGE2 synthesis upon immune stimulation (Engblom et al, 2003), results in attenuated corticosterone release to such stimuli (Elander et al, 2009), showing an important role for immune-induced PGE2 in this response.…”