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Lipopolysaccharide induces preproenkephalin transcription in hypophysiotropic neurons of the rat paraventricular hypothalamic nucleus suggesting a neuroendocrine role for enkephalins during immune stress
Linköping University, Department of Clinical and Experimental Medicine, Cellbiology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Cellbiology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Cellbiology. Linköping University, Faculty of Health Sciences.
2006 (English)In: Neuroscience, ISSN 0306-4522, Vol. 142, no 3, 781-788 p.Article in journal (Refereed) Published
Abstract [en]

Opioids have impact on stress responses and possess immune modulatory functions. We have previously shown that immune stress elevates the levels of preproenkephalin transcript in a variety of autonomic structures in the rat brain, including the paraventricular hypothalamic nucleus. By using in situ hybridization with an intronic probe recognizing the preproenkephalin heteronuclear RNA combined with retrograde tract tracing, we examined the efferent target of the enkephalinergic neurons in the paraventricular hypothalamic nucleus that display induced transcriptional activity during immune challenge. Rats were first given i.p. injections of the tracer substance Fluoro-Gold, which following this route of administration is taken up only by nerve terminals residing outside the blood–brain barrier, and were then given an i.v. injection of lipopolysaccharide. Neuronal cell bodies retrogradely labeled with Fluoro-Gold were detected by immunohistochemistry, and—using a dual-labeling approach—the same cells were then examined for their expression of preproenkephalin heteronuclear RNA. We found that over 90% of the neurons that expressed preproenkephalin heteronuclear RNA also contained Fluoro-Gold. In addition, approximately 40% of the neurons expressing preproenkephalin heteronuclear RNA co-expressed mRNA for corticotropin-releasing hormone, the main adrenocorticotropic hormone secretagogue. These data show that the paraventricular hypothalamic neurons that display induced preproenkephalin transcription following immune challenge are almost exclusively hypophysiotropic neurons, indicating a role for enkephalin in the hypothalamic control of hormone release during infectious and inflammatory conditions.

Place, publisher, year, edition, pages
2006. Vol. 142, no 3, 781-788 p.
Keyword [en]
opioid; corticotropin-releasing hormone; in situ hybridization; intron; gene expression; retrograde tract tracing
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-12956DOI: 10.1016/j.neuroscience.2006.06.062OAI: oai:DiVA.org:liu-12956DiVA: diva2:17532
Available from: 2008-02-25 Created: 2008-02-25
In thesis
1. Inflammation-Induced Gene Expression in Brain and Adrenal Gland
Open this publication in new window or tab >>Inflammation-Induced Gene Expression in Brain and Adrenal Gland
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The autonomic nervous system serves to maintain a constant inner environment, a process termed homeostasis. Thus, in response to the homeostatic challenge posed by infectious agents, the autonomic nervous system answers to signals from the immune system and elicits adaptive physiological and behavioral reactions. These so called sickness responses include fever, anorexia, hyperalgesia, social avoidance, and the release of stress hormones.

Neuropeptides, used in the communication between neurons, are because of their release properties and sustained actions likely mediators of homeostatic responses. The enkephalinergic system constitutes one of the largest neuropeptidergic systems in the brain, but its involvement in inflammatory conditions has been little studied. We first examined the immune-induced activation of the parabrachial nucleus (paper I), an enkephalinergic autonomic relay center in the brain stem. We found that intravenous injection of bacterial endotoxin, lipopolysaccharide (LPS), activated the external lateral parabrachial subnucleus, as measured in terms of Fos expression, but that the enkephalinergic cell population in this subnucleus was largely separated from the LPS-activated neurons. Because Fos may not always be a reliable activity marker, we next examined by in situ hybridization the immune-induced expression of newly transcribed preproenkephalin (ppENK) heteronuclear RNA (hnRNA), which gives a direct indication of the utilization of enkephalin in a particular neuron (paper II). We detected induced expression of ppENK hnRNA in several autonomic structures in the brain, including the paraventricular hypothalamic nucleus (PVH) but not the parabrachial nucleus, indicating increased enkephalinergic signaling activity in the positively labeled structures during inflammatory condition. We then examined the projections of the immune-induced ppENK transcribing PVH neurons by injecting rats intraperitoneally with the retrograde tracer substance Fluoro-Gold, hence labeling neurons with axonal projections outside the blood-brain barrier, followed by systemic injection of LPS (paper III). Dual-labeling histochemical and hybridization techniques showed that the vast majority of the ppENK hnRNA expressing cells were hypophysiotropic cells, hence being involved in neuroendocrine regulation. These findings suggest that centrally produced enkephalin is involved in the coordination of the sickness responses during systemic immune challenge, including the modulation of the release of stress hormones or other hypothalamic hormones during inflammatory conditions.

We next turned to the role of prostaglandins in the hypothalamic-pituitary-adrenal (HPA) axis response to inflammation. We injected mice deficient for the terminal prostaglandin (PG) E2 synthesizing enzyme mPGES-1 with LPS and studied their stress hormone release (paper IV). The genetically modified mice displayed attenuated plasma levels of adrenocorticotropic hormone (ACTH) and corticosterone during the later phases of the HPA-axis response compared with wild type mice, and this impairment did not depend on a changed activation pattern in the brain, but instead correlated to an early decrease in corticotropin-releasing hormone mRNA expression in the PVH, hence being the likely cause of the blunted ACTH and corticosterone responses at later time-points. Based on these findings we suggest that a neural, mPGES-1-independent pathway, and a humoral, mPGES-1-dependent pathway act in concert but in distinct temporal patterns to initiate and maintain the HPA-axis response during immune challenge.

In addition to activating the central limb of the HPA-axis, inflammatory mediators have been suggested to act directly on the adrenal gland to induce the release of corticosterone, but little is known about the underlying mechanisms. We examined adrenal tissue isolated from rats injected with LPS or interleukin-1β (IL-1β) (paper V), and found that immune stimulation resulted in dynamic changes in the adrenal immune cell population, implying a rapid depletion of dendritic cells in the inner cortical layer and the recruitment of immature cells to the outer layers. These changes were accompanied by an induced production of IL-1β and IL-1 receptor type 1, as well as of cyclo-oxygenase-2 and mPGES-1 in these cells, implying local cytokine-mediated PGE2 production in the adrenals, which also displayed EP1 and EP3 receptors in the cortex and medulla. Additional mechanistic studies using an IL-1 receptor antagonist showed that IL-1β acts locally to affect its own synthesis, as well as that of cyclooxygenase-2. Taken together these data demonstrate a mechanism by which systemic inflammatory agents activate an intrinsically regulated local signaling circuit that may influence the adrenals’ response to immune stress and may help explain the dissociation between plasma levels of ACTH and corticosteroids during chronic immune perturbations.

Place, publisher, year, edition, pages
Linköping University Electronic Press, 2008. 106 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1043
Keyword
Inflammation, brain, adrenal gland, stress, lipopolysaccharide, interleukin-1
National Category
Neurosciences
Identifiers
urn:nbn:se:liu:diva-11089 (URN)978-91-7393-977-5 (ISBN)
Public defence
2008-03-14, Berzeliussalen, Campus US, Linköpings universitet, Linköping, 13:00 (English)
Opponent
Supervisors
Available from: 2008-02-25 Created: 2008-02-25 Last updated: 2015-11-19

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Engström, LindaMackerlova, LudmilaBlomqvist, Anders

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