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The Journal of Neuroscience, February 4, 2009, 29(5):1404-1413; doi:10.1523/JNEUROSCI.5247-08.2009

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Behavioral/Systems/Cognitive
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

Louise Elander,¹ Linda Engström,¹ Johan Ruud,¹ Ludmila Mackerlova,¹ Per-Johan Jakobsson,² David Engblom,¹ Camilla Nilsberth,¹ and Anders Blomqvist¹

¹Division of Cell Biology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, S-581 85 Linköping, Sweden, and ²Division of Rheumatology, Department of Medicine, Karolinska Institute, 171 76 Stockholm, Sweden

Correspondence should be addressed to Dr. Anders Blomqvist, Division of Cell Biology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, S-581 85 Linköping, Sweden. Email: anders.blomqvist{at}liu.se

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 E₂-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 PGE₂ synthesis, shown to occur in brain vascular cells, play distinct, but temporally supplementary roles for the stress hormone response to inflammation.

Key words: CRH; ACTH; corticosterone; mPGES-1; LPS; Fos

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Received Oct. 30, 2008; revised Dec. 19, 2008; accepted Dec. 30, 2008.

Correspondence should be addressed to Dr. Anders Blomqvist, Division of Cell Biology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, S-581 85 Linköping, Sweden. Email: anders.blomqvist{at}liu.se

This article has been cited by other articles:

				B. Garcia-Bueno, J. Serrats, and P. E. Sawchenko Cerebrovascular Cyclooxygenase-1 Expression, Regulation, and Role in Hypothalamic-Pituitary-Adrenal Axis Activation by Inflammatory Stimuli J. Neurosci., October 14, 2009; 29(41): 12970 - 12981. [Abstract] [Full Text] [PDF]

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