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Inflammation-Induced Gene Expression in Brain and Adrenal Gland
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
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 [en]
Inflammation, brain, adrenal gland, stress, lipopolysaccharide, interleukin-1
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:liu:diva-11089ISBN: 978-91-7393-977-5 (print)OAI: oai:DiVA.org:liu-11089DiVA: diva2:17535
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
List of papers
1. Preproenkephalin mRNA expression in rat parabrachial neurons: relation to cells activated by systemic immune challenge
Open this publication in new window or tab >>Preproenkephalin mRNA expression in rat parabrachial neurons: relation to cells activated by systemic immune challenge
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2001 (English)In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 316, no 3, 165-168 p.Article in journal (Refereed) Published
Abstract [en]

By using a dual-labeling immunohistochemical/in situ hybridization technique we examined if enkephalin-expressing neurons in the pontine parabrachial nucleus, a major brain stem relay for ascending visceral and homeostatic information, were activated by systemic immune challenge. While rats subjected to intravenous injection of bacterial wall lipopolysaccharide expressed dense labeling for the immediate-early gene product FOS in parts of the parabrachial nucleus that also demonstrated dense preproenkephalin expression, only a small proportion of the enkephalin-positive neurons were FOS-positive. These data indicate that enkephalins, although implicated in a variety of autonomic responses, are not primarily involved in the transmission of immune-related information from the parabrachial nucleus to its different forebrain and brain stem targets.

Place, publisher, year, edition, pages
Elsevier Science B.V., Amsterdam., 2001
Keyword
Parabrachial nucleus, Systemic inflammation, FOS, Enkephalin, In situ hybridization, Feeding
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-12954 (URN)10.1016/S0304-3940(01)02393-X (DOI)000173268200010 ()
Available from: 2008-02-25 Created: 2008-02-25 Last updated: 2017-12-13
2. Systemic immune challenge induces preproenkephalin gene transcription in distinct autonomic structures of the rat brain
Open this publication in new window or tab >>Systemic immune challenge induces preproenkephalin gene transcription in distinct autonomic structures of the rat brain
2003 (English)In: Journal of Comparative Neurology, ISSN 0021-9967, Vol. 462, no 4, 450-461 p.Article in journal (Refereed) Published
Abstract [en]

The involvement of enkephalins in the immune response was investigated in rats injected intravenously with interleukin-1 (2 g/kg). In situ hybridization with a riboprobe complementary to intron A of the preproenkephalin (ppENK) gene showed distinct transcriptional activation within several brain regions known to be activated by immune stimuli, including the nucleus of the solitary tract, the area postrema, the paraventricular hypothalamic nucleus, and the oval nucleus of the bed nucleus of the stria terminalis, and dual labeling confirmed that a large proportion of the intron expressing neurons co-expressed c-fos mRNA. Rats injected with saline (controls) showed little or no heteronuclear transcript in these structures. The induced signal was strongest after 1 hour but was present in some structures 30 minutes after interleukin-1 injection. At 3 hours, transcriptional activity returned to basal levels. High basal expression of the heteronuclear transcript that appeared unchanged by the immune stimulus was seen in regions not primarily involved in the immune response, such as the striatum, the olfactory tubercle, and the islands of Calleja and in the immune activated central nucleus of the amygdala. The heteronuclear transcript colocalized with ppENK mRNA, demonstrating that it occurred in enkephalinergic neurons and was not the result of alternative transcription from the ppENK gene in other cells. These results demonstrated that enkephalin transcription is induced in central autonomic neurons during immune challenge, suggesting that enkephalins are involved in the centrally orchestrated response to such stimuli.

Keyword
interleukin, enkephalin, heteronuclear RNA, brainstem, neuroendocrine, in situ hybridization
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-12955 (URN)10.1002/cne.10770 (DOI)
Available from: 2008-02-25 Created: 2008-02-25 Last updated: 2009-05-12
3. Lipopolysaccharide induces preproenkephalin transcription in hypophysiotropic neurons of the rat paraventricular hypothalamic nucleus suggesting a neuroendocrine role for enkephalins during immune stress
Open this publication in new window or tab >>Lipopolysaccharide induces preproenkephalin transcription in hypophysiotropic neurons of the rat paraventricular hypothalamic nucleus suggesting a neuroendocrine role for enkephalins during immune stress
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.

Keyword
opioid; corticotropin-releasing hormone; in situ hybridization; intron; gene expression; retrograde tract tracing
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-12956 (URN)10.1016/j.neuroscience.2006.06.062 (DOI)
Available from: 2008-02-25 Created: 2008-02-25
4. Impaired hypothalamic-pituitary-adrenal axis response to bacterial endotoxin in mice lacking inducible prostaglandin E synthase-1
Open this publication in new window or tab >>Impaired hypothalamic-pituitary-adrenal axis response to bacterial endotoxin in mice lacking inducible prostaglandin E synthase-1
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Manuscript (Other academic)
Identifiers
urn:nbn:se:liu:diva-12957 (URN)
Available from: 2008-02-25 Created: 2008-02-25 Last updated: 2010-01-13
5. Systemic immune challenge activates an intrinsically regulated local inflammatory circuit in the adrenal gland
Open this publication in new window or tab >>Systemic immune challenge activates an intrinsically regulated local inflammatory circuit in the adrenal gland
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2008 (English)In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 149, no 4, 1436-1450 p.Article in journal (Refereed) Published
Abstract [en]

There is evidence from in vitro studies that inflammatory messengers influence the release of stress hormone via direct effects on the adrenal gland; however, the mechanisms underlying these effects in the intact organism are unknown. Here we demonstrate that systemic inflammation in rats elicited by iv injection of lipopolysaccharide results 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 are accompanied by an induced production of IL-1β and IL-1 receptor type 1 as well as cyclooxygenase-2 and microsomal prostaglandin E synthase-1 in these cells, implying local cytokine-mediated prostaglandin E2 production in the adrenals, which also displayed prostaglandin E2 receptors of subtypes 1 and 3 in the cortex and medulla. The IL-1β expression was also induced by systemically administrated IL-1β and was in both cases attenuated by IL-1 receptor antagonist, consistent with an autocrine signaling loop. IL-1β similarly induced expression of cyclooxygenase-2, but the cyclooxygenase-2 expression was, in contrast, further enhanced by IL-1 receptor antagonist. 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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-12958 (URN)10.1210/en.2007-1456 (DOI)
Available from: 2008-02-25 Created: 2008-02-25 Last updated: 2017-12-13

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