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The Role of Interleukin-6 in the Febrile Response
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Everyone who has been exposed to influenza or a bacterial infection knows how it feels to be sick. Apart from not being willing to participate in social activities, losing your appetite and experiencing pain, you have also most likely suffered from increased body temperature which defines fever, one of the most prominent signs of an acute ongoing infection. Invading the body, the infectious microorganisms are combated by the activated innate and adaptive immune systems, and the impaired balance is thus restored. While fever is an event that is controlled by the central nervous system, it has for long been debated how the inflammatory signals generated in the periphery communicate with the brain that is protected by the bloodbrain barrier which prevents large molecules such as cytokines from entering into the brain parenchyma.

Previous studies from our group have provided evidence in support of the existence of a pathway across the blood-brain barrier by demonstrating that proinflammatory cytokine interleukin-1 transfers the inflammatory message to the brain through binding to its receptors situated in the brain vessels. This will subsequently trigger the production of the prostaglandin E2 (PGE2) that enters the brain and exerts its effect by binding to the receptors located on the thermoregulatory neurons. Interleukin-6 (IL-6) is another cytokine essential for fever signaling; however, the mechanism has not yet been identified. The research on which this thesis is based aimed at elucidating the role of IL-6 in inflammatory induced fever.

In paper I, we demonstrated that mice incapable of producing inflammatory PGE2 still responded with an intact cytokine production in the brain upon peripheral lipopolysaccharide (LPS) stimulation. Thus, although the mice had induced expression of inflammatory cytokines in the brain, this was not sufficient for a fever response without simultaneous production of PGE2. The relationship between IL-6 and PGE2, both essential for fever, was further investigated in paper II, focusing on clarifying the mechanism by which IL-6 controls fever. We demonstrated that mice deficient in IL-6 did not respond with fever upon peripheral LPS administration despite an intact expression of PGE2 in the brain. In contrast, upon intracerebroventricular administration of PGE2 into the brain, a dose-dependent fever response was monitored in IL-6 deficient mice. Thus, we suggest that IL-6 exerts its effect neither up- nor downstream from PGE2, and propose instead that IL-6 may act alongside the PGE2 and regulate the process that deals with the transport of and binding of PGE2 onto its receptors. To further investigate the elusive role of IL-6 in fever, we performed a microarray analysis to identify the genes that were differentially expressed in the brain of LPS-challenged IL-6 deficient mice compared to wild type mice (paper III). We demonstrated that mice lacking IL-6 displayed two-times lower expression of lipocalin-2 in the hypothalamus. IL-6 and lipocalin-2 were directly related to each other since peripherally administrated IL-6 induced the expression of lipocalin-2 in cells associated with the brain vessels. Lipocalin-2 induced by LPS was expressed by brain endothelial cells and partly co-localized with cyclooxygenase-2, one of the enzymes essential for inflammatory PGE2 production in the endothelial cells. We also demonstrated that lipocalin-2 in a sex-dependent and ambient temperature-specific manner may be implicated in thermogenesis. We have thus identified a new factor in the IL-6 regulated fever pathway, but the pathway is still not understood. On important question that remained to be answered was in which  compartment IL-6 was needed for the signaling. This question was studied further in paper IV, where we investigated the role of hematopoietically produced IL-6 in fever by constructing chimeric mice. We concluded that IL-6 produced by cells of non-hematopoietic origin is critical for the LPSinduced fever while hematopoietically produced IL-6 plays only a minor role in contributing to fever.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2013. , 92 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1349
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-87453ISBN: 978-91-7519-722-7 (print)OAI: oai:DiVA.org:liu-87453DiVA: diva2:589420
Public defence
2013-01-30, Berzeliussalen, ingång 64, plan 9, Campus US, Linköpings universitet, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2013-01-18 Created: 2013-01-18 Last updated: 2016-05-04Bibliographically approved
List of papers
1. Peripheral Lipopolysaccharide Administration Induces Cytokine mRNA Expression in the Viscera and Brain of Fever-Refractory Mice Lacking Microsomal Prostaglandin E Synthase-1
Open this publication in new window or tab >>Peripheral Lipopolysaccharide Administration Induces Cytokine mRNA Expression in the Viscera and Brain of Fever-Refractory Mice Lacking Microsomal Prostaglandin E Synthase-1
2009 (English)In: Journal of neuroendocrinology (Print), ISSN 0953-8194, E-ISSN 1365-2826, Vol. 21, no 8, 715-721 p.Article in journal (Refereed) Published
Abstract [en]

We examined the expression of interleukin (IL)-1 beta, IL-6 and tumour necrosis factor (TNF) alpha in mice lacking microsomal prostaglandin E synthase-1 (mPGES-1), which neither produce prostaglandin E-2, nor mount a febrile response upon immune challenge. Intraperitoneal lipopolysaccharide (LPS) injection resulted in a strongly induced expression of all three cytokines in the brain and viscera, similar to wild-type animals. Several brain regions additionally showed modest induction of receptors for these cytokines in both genotypes. Telemetric recordings of body temperature showed that the mPGES-1 deficient mice remained afebrile upon LPS challenge, in contrast to the prominent fever displayed by the wild-type mice. These data demonstrate that LPS-induced cytokine expression occurs independently of prostaglandin E-2, and imply that endogenously expressed IL-1 beta, IL-6, and TNF alpha are not pyrogenic per se, supporting the role of prostaglandin E-2 as the final and obligatory mediator of LPS-induced fever.

Keyword
Fever; prostaglandin E-2; interleukin-6; interleukin-1 beta; tumour necrosis factor alpha
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-20165 (URN)10.1111/j.1365-2826.2009.01888.x (DOI)
Available from: 2009-09-01 Created: 2009-08-31 Last updated: 2017-12-13
2. The Role of Interleukin-6 in Lipopolysaccharide-Induced Fever by Mechanisms Independent of Prostaglandin E-2
Open this publication in new window or tab >>The Role of Interleukin-6 in Lipopolysaccharide-Induced Fever by Mechanisms Independent of Prostaglandin E-2
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2009 (English)In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 150, no 4, 1850-1860 p.Article in journal (Refereed) Published
Abstract [en]

Fever has been shown to be elicited by prostaglandin E-2 (PGE(2)) binding to its receptors on thermoregulatory neurons in the anterior hypothalamus. The signals that trigger PGE(2) production are thought to include proinflammatory cytokines, such as IL-6. However, although the presence of IL-6 is critical for fever, IL- 6 by itself is not or only weakly pyrogenic. Here we examined the relationship between IL-6 and PGE(2) in lipopolysaccharide (LPS)-induced fever. Immune-challenged IL- 6 knockout mice did not produce fever, in contrast to wild-type mice, but the expression of the inducible PGE(2)-synthesizing enzymes, cyclooxygenase-2 and microsomal prostaglandin E synthase-1, was similarly up-regulated in the hypothalamus of both genotypes, which also displayed similarly elevated PGE(2) levels in the cerebrospinal fluid. Nevertheless, both wild-type and knockout mice displayed a febrile response to graded concentrations of PGE(2) injected into the lateral ventricle. There was no major genotype difference in the expression of IL-1 beta and TNF alpha or their receptors, and pretreatment of IL- 6 knockout mice with soluble TNF alpha receptor ip or intracerebroventricularly or a cyclooxygenase-2 inhibitor ip did not abolish the LPS unresponsiveness. Hence, although IL- 6 knockout mice have both an intact PGE(2) synthesis and an intact fever-generating pathway downstream of PGE(2), endogenously produced PGE(2) is not sufficient to produce fever in the absence of IL-6. The findings suggest that IL- 6 controls some factor(s) in the inflammatory cascade, which render(s) IL- 6 knockout mice refractory to the pyrogenic action of PGE(2), or that it is involved in the mechanisms that govern release of synthesized PGE(2) onto its target neurons.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-17620 (URN)10.1210/en.2008-0806 (DOI)
Available from: 2009-04-07 Created: 2009-04-06 Last updated: 2017-12-13
3. Immune-Induced Expression of Lipocalin-2 in Brain Endothelial Cells: Relationship with Interleukin-6, Cyclooxygenase-2 and the Febrile Response
Open this publication in new window or tab >>Immune-Induced Expression of Lipocalin-2 in Brain Endothelial Cells: Relationship with Interleukin-6, Cyclooxygenase-2 and the Febrile Response
2013 (English)In: Journal of neuroendocrinology (Print), ISSN 0953-8194, E-ISSN 1365-2826, Vol. 25, no 3, 271-280 p.Article in journal (Refereed) Published
Abstract [en]

Interleukin (IL)-6 is critical for the febrile response to peripheral immune challenge. However, the mechanism by which IL-6 enables fever is still unknown. To characterise the IL-6-dependent fever generating pathway, we used microarray analysis to identify differentially expressed genes in the brain of lipopolysaccharide (LPS)-treated IL-6 wild-type and knockout mice. Mice lacking IL-6 displayed a two-fold lower expression of the lipocalin-2 gene (lcn2), and this difference was confirmed by real-time reverse transcriptase-polymerase chain reaction. Conversely, the induction of lipocalin-2 protein was observed in brain vascular cells following i.p. administration of recombinant IL-6, suggesting a direct relationship between IL-6 and lipocalin-2. Immunohistochemical analysis also revealed that LPS-induced lipocalin-2 is expressed by brain endothelial cells and is partly co-localised with cyclooxygenase-2 (Cox-2), the rate-limiting enzyme for the production of inflammatory induced prostaglandin E2 (PGE2), which is the key mediator of fever. The direct role of lipocalin-2 in fever was examined in LPS-challenged lipocalin-2 knockout mice. In both male and female mice, normal fever responses were observed at near-thermoneutral conditions (2930 degrees C) but when recorded at normal room temperature (1920 degrees C), the body temperature of lipocalin-2 knockout female mice displayed an attenuated fever response compared to their wild-type littermates. This difference was reflected in significantly attenuated mRNA expression of Cox-2 in the brain of lipocalin-2 knockout female mice, but not of male mice, following challenge with peripheral LPS. Our findings suggest that IL-6 influences the expression of lipocalin-2, which in turn may be involved in the control of the formation of Cox-2, and hence central PGE2-production. We have thus identified lipocalin-2 as a new factor in the pathway of inflammatory IL-6 signalling. However, the effect of lipocalin-2 on fever is small, being sex-dependent and ambient temperature-specific, and thus lipocalin-2 cannot be considered as a major mediator of the IL-6-dependent fever generating pathway.

Keyword
Interleukin-6; lipocalin-2; fever; microarray analysis
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-87451 (URN)10.1111/jne.12000 (DOI)000315398000007 ()23046379 (PubMedID)
Available from: 2013-01-18 Created: 2013-01-18 Last updated: 2017-12-06Bibliographically approved
4. Interleukin-6 produced by non-hematopoietic cells mediates the lipopolysaccharide-induced febrile response
Open this publication in new window or tab >>Interleukin-6 produced by non-hematopoietic cells mediates the lipopolysaccharide-induced febrile response
Show others...
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Interleukin-6 (IL-6) is critical for the lipopolysaccharide (LPS)-induced febrile response. However, the exact source(s) of IL-6 involved in regulating the LPS-elicited fever is still to be identified. One known source of IL-6 is hematopoietic cells, such as monocytes. To clarify the contribution of hematopoietically derived IL-6 to fever, we created chimeric mice expressing IL-6 either in cells of hematopoietic or, conversely, in cells of non-hematopoietic origin. This was performed by extinguishing hematopoetic cells in wild-type (WT) or IL-6 knockout (IL-6 KO) mice by whole-body irradiation and transplanting them with new stem cells. Mice lacking IL-6 in hematopoietic cells displayed normal fever to LPS and were found to have similar levels of IL-6 in the cerebrospinal fluid (CSF) and in plasma as well as similar expression of the IL-6 gene in the brain as WT mice. In contrast, IL-6 KO mice, with intact IL-6 production in cells of hematopoietic origin, only showed a minor elevation of the body temperature after peripheral LPS injection. While they displayed significantly elevated levels of IL-6 both in plasma and CSF compared with control mice, the increase was modest compared with that seen in LPS injected mice on WT background, the latter being approximately 20 times larger in magnitude. These results suggest that IL-6 of nonhematopoietic origin is the main source of IL-6 in LPS-induced fever, and that IL-6 produced by hematopoietic cells only plays a minor role.

Keyword
Interleukin-6, hematopoietic cells, bone marrow transplantation, fever
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-87452 (URN)
Available from: 2013-01-18 Created: 2013-01-18 Last updated: 2016-05-04Bibliographically approved

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