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  • 1.
    Elander, Louise
    et al.
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Avdelningen för medicinsk cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Engström, Linda
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Avdelningen för medicinsk cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Hallbeck, Martin
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Avdelningen för medicinsk cellbiologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Blomqvist, Anders
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Avdelningen för medicinsk cellbiologi. Linköpings universitet, Hälsouniversitetet.
    IL-1β and LPS induce anorexia by distinct mechanisms differentially dependent on microsomal prostaglandin E synthase-12007Ingår i: American Journal of Physiology. Regulatory Integrative and Comparative Physiology, ISSN 0363-6119, E-ISSN 1522-1490, Vol. 292, nr 1, s. R258-R267Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Recent work demonstrated that the febrile response to peripheral immune stimulation with proinflammatory cytokine IL-1β or bacterial wall lipopolysaccharide (LPS) is mediated by induced synthesis of prostaglandin E2 by the terminal enzyme microsomal prostaglandin E synthase-1 (mPGES-1). The present study examined whether a similar mechanism might also mediate the anorexia induced by these inflammatory agents. Transgenic mice with a deletion of the Ptges gene, which encodes mPGES-1, and wild-type controls were injected intraperitoneally with IL-1β, LPS, or saline. Mice were free fed, and food intake was continuously monitored with an automated system for 12 h. Body weight was recorded every 24 h for 4 days. The IL-1β induced anorexia in wild-type but not knock-out mice, and so it was almost completely dependent on mPGES-1. In contrast, LPS induced anorexia of the same magnitude in both phenotypes, and hence it was independent of mPGES-1. However, when the mice were prestarved for 22 h, LPS induced anorexia and concomitant body weight loss in the knock-out animals that was attenuated compared with the wildtype controls. These data suggest that IL-1β and LPS induce anorexia by distinct immune-to-brain signaling pathways and that the anorexia induced by LPS is mediated by a mechanism different from the fever induced by LPS. However, nutritional state and/or motivational factors also seem to influence the pathways for immune signaling to the brain. Furthermore, both IL-1β and LPS caused reduced meal size but not meal frequency, suggesting that both agents exerted an anhedonic effect during these experimental conditions. Copyright © 2007 the American Physiological Society.

  • 2.
    Elander, Louise
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Engström, Linda
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Ruud, Johan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Mackerlova, Ludmila
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Jakobsson, Per-Johan
    Karolinska Institute.
    Engblom, David
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Nilsberth, Camilla
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Blomqvist, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Inducible Prostaglandin E-2 Synthesis Interacts in a Temporally Supplementary Sequence with Constitutive Prostaglandin-Synthesizing Enzymes in Creating the Hypothalamic-Pituitary-Adrenal Axis Response to Immune Challenge2009Ingår i: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 29, nr 5, s. 1404-1413Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    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.

  • 3.
    Engblom, David
    et al.
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Saha, Sipra
    Center for Structural Biochemistry, Karolinska Institute, Huddinge, Sweden.
    Engström, Linda
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Westman, Marie
    Department of Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden..
    Audoly, Laurent
    Inflammation Unit, Pfizer Global Research and Development, Groton Laboratories, Groton, Connecticut, USA..
    Jakobsson, Per-Johan
    Department of Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden..
    Blomqvist, Anders
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Microsomal prostaglandin E synthase-1 is the central switch during immune-induced pyresis2003Ingår i: Nature Neuroscience, ISSN 1097-6256, E-ISSN 1546-1726, Vol. 6, nr 11, s. 1137-1138Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We studied the febrile response in mice deficient in microsomal prostaglandin E synthase-1 (mPGES-1), an inducible terminal isomerase expressed in cytokine-sensitive brain endothelial cells. These animals showed no fever and no central prostaglandin (PG) E2 synthesis after peripheral injection of bacterial-wall lipopolysaccharide, but their pyretic capacity in response to centrally administered PGE2 was intact. Our findings identify mPGES-1 as the central switch during immune-induced pyresis and as a target for the treatment of fever and other PGE2-dependent acute phase reactions elicited by the brain.

  • 4. Beställ onlineKöp publikationen >>
    Engström, Linda
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Inflammation-Induced Gene Expression in Brain and Adrenal Gland2008Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    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.

    Delarbeten
    1. Preproenkephalin mRNA expression in rat parabrachial neurons: relation to cells activated by systemic immune challenge
    Öppna denna publikation i ny flik eller fönster >>Preproenkephalin mRNA expression in rat parabrachial neurons: relation to cells activated by systemic immune challenge
    Visa övriga...
    2001 (Engelska)Ingår i: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 316, nr 3, s. 165-168Artikel i tidskrift (Refereegranskat) 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.

    Ort, förlag, år, upplaga, sidor
    Elsevier Science B.V., Amsterdam., 2001
    Nyckelord
    Parabrachial nucleus, Systemic inflammation, FOS, Enkephalin, In situ hybridization, Feeding
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-12954 (URN)10.1016/S0304-3940(01)02393-X (DOI)000173268200010 ()
    Tillgänglig från: 2008-02-25 Skapad: 2008-02-25 Senast uppdaterad: 2018-03-26
    2. Systemic immune challenge induces preproenkephalin gene transcription in distinct autonomic structures of the rat brain
    Öppna denna publikation i ny flik eller fönster >>Systemic immune challenge induces preproenkephalin gene transcription in distinct autonomic structures of the rat brain
    2003 (Engelska)Ingår i: Journal of Comparative Neurology, ISSN 0021-9967, Vol. 462, nr 4, s. 450-461Artikel i tidskrift (Refereegranskat) 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.

    Nyckelord
    interleukin, enkephalin, heteronuclear RNA, brainstem, neuroendocrine, in situ hybridization
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-12955 (URN)10.1002/cne.10770 (DOI)
    Tillgänglig från: 2008-02-25 Skapad: 2008-02-25 Senast uppdaterad: 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
    Öppna denna publikation i ny flik eller fönster >>Lipopolysaccharide induces preproenkephalin transcription in hypophysiotropic neurons of the rat paraventricular hypothalamic nucleus suggesting a neuroendocrine role for enkephalins during immune stress
    2006 (Engelska)Ingår i: Neuroscience, ISSN 0306-4522, Vol. 142, nr 3, s. 781-788Artikel i tidskrift (Refereegranskat) 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.

    Nyckelord
    opioid; corticotropin-releasing hormone; in situ hybridization; intron; gene expression; retrograde tract tracing
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-12956 (URN)10.1016/j.neuroscience.2006.06.062 (DOI)
    Tillgänglig från: 2008-02-25 Skapad: 2008-02-25
    4. Impaired hypothalamic-pituitary-adrenal axis response to bacterial endotoxin in mice lacking inducible prostaglandin E synthase-1
    Öppna denna publikation i ny flik eller fönster >>Impaired hypothalamic-pituitary-adrenal axis response to bacterial endotoxin in mice lacking inducible prostaglandin E synthase-1
    Visa övriga...
    Manuskript (Övrigt vetenskapligt)
    Identifikatorer
    urn:nbn:se:liu:diva-12957 (URN)
    Tillgänglig från: 2008-02-25 Skapad: 2008-02-25 Senast uppdaterad: 2010-01-13
    5. Systemic immune challenge activates an intrinsically regulated local inflammatory circuit in the adrenal gland
    Öppna denna publikation i ny flik eller fönster >>Systemic immune challenge activates an intrinsically regulated local inflammatory circuit in the adrenal gland
    Visa övriga...
    2008 (Engelska)Ingår i: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 149, nr 4, s. 1436-1450Artikel i tidskrift (Refereegranskat) 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.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-12958 (URN)10.1210/en.2007-1456 (DOI)
    Tillgänglig från: 2008-02-25 Skapad: 2008-02-25 Senast uppdaterad: 2017-12-13
  • 5.
    Engström, Linda
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Björk, Daniel
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Eskilsson, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Vasilache, Ana-Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk immunologi och transfusionsmedicin.
    Elander, Louise
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Engblom, David
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Blomqvist, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Acetaminophen reduces lipopolysaccharide-induced fever by inhibiting cyclooxygenase-22013Ingår i: Neuropharmacology, ISSN 0028-3908, E-ISSN 1873-7064, Vol. 71, s. 124-129Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Acetaminophen is one of the world's most commonly used drugs to treat fever and pain, yet its mechanism of action has remained unclear. Here we tested the hypothesis that acetaminophen blocks fever through inhibition of cyclooxygenase-2 (Cox-2), by monitoring lipopolysaccharide induced fever in mice with genetic manipulations of enzymes in the prostaglandin cascade. We exploited the fact that lowered levels of a specific enzyme make the system more sensitive to any further inhibition of the same enzyme. Mice were immune challenged by an intraperitoneal injection of bacterial wall lipopolysaccharide and their body temperature recorded by telemetry. We found that mice heterozygous for Cox-2, but not for microsomal prostaglandin E synthase-1 (mPGES-1), displayed attenuated fever, indicating a rate limiting role of Cox-2. We then titrated a dose of acetaminophen that did not inhibit the lipopolysaccharide-induced fever in wild-type mice. However, when the same dose of acetaminophen was given to Cox-2 heterozygous mice, the febrile response to lipopolysaccharide was strongly attenuated, resulting in an almost normalized temperature curve, whereas no difference was seen between wild-type and heterozygous mPGES-1 mice. Furthermore, the fever to intracerebrally injected prostaglandin E2 was unaffected by acetaminophen treatment. These findings reveal that acetaminophen, similar to aspirin and other non-steroidal anti-inflammatory drugs, is antipyretic by inhibiting cyclooxygenase-2, and not by inhibiting mPGES-1 or signaling cascades downstream of prostaglandin E2.

  • 6.
    Engström, Linda
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Engblom, David
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Blomqvist, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Systemic immune challenge induces preproenkephalin gene transcription in distinct autonomic structures of the rat brain2003Ingår i: Journal of Comparative Neurology, ISSN 0021-9967, Vol. 462, nr 4, s. 450-461Artikel i tidskrift (Refereegranskat)
    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.

  • 7.
    Engström, Linda
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Engblom, David
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Örtegren (Kugelberg), Unn
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Mackerlova, Ludmila
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Paues, Jakob
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Blomqvist, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Preproenkephalin mRNA expression in rat parabrachial neurons: relation to cells activated by systemic immune challenge2001Ingår i: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 316, nr 3, s. 165-168Artikel i tidskrift (Refereegranskat)
    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.

  • 8.
    Engström, Linda
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Mackerlova, Ludmila
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Blomqvist, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Lipopolysaccharide induces preproenkephalin transcription in hypophysiotropic neurons of the rat paraventricular hypothalamic nucleus suggesting a neuroendocrine role for enkephalins during immune stress2006Ingår i: Neuroscience, ISSN 0306-4522, Vol. 142, nr 3, s. 781-788Artikel i tidskrift (Refereegranskat)
    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.

  • 9.
    Engström, Linda
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Rosén, Khadijah
    Angel, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Utvecklingsbiologi-IKE. Linköpings universitet, Hälsouniversitetet.
    Fyrberg, Anna
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Mackerlova, Ludmila
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Konsman, Jan Pieter
    Engblom, David
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Blomqvist, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Systemic immune challenge activates an intrinsically regulated local inflammatory circuit in the adrenal gland2008Ingår i: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 149, nr 4, s. 1436-1450Artikel i tidskrift (Refereegranskat)
    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.

  • 10.
    Engström, Linda
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Ruud, Johan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Eskilsson, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Larsson, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Mackerlova, Ludmila
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Kugelberg, Unn
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Qian, Hong
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell hematologi. Linköpings universitet, Hälsouniversitetet.
    Vasilache, Ana Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Larsson, Peter
    Linköpings universitet, Institutionen för medicin och hälsa, Medicinsk radiofysik. Linköpings universitet, Hälsouniversitetet.
    Engblom, David
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Sigvardsson, Mikael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell hematologi. Linköpings universitet, Hälsouniversitetet.
    Jönsson, Jan-Ingvar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell hematologi. Linköpings universitet, Hälsouniversitetet.
    Blomqvist, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Lipopolysaccharide-Induced Fever Depends on Prostaglandin E2 Production Specifically in Brain Endothelial Cells2012Ingår i: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 153, nr 10, s. 4849-4861Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Immune-induced prostaglandin E2 (PGE2) synthesis is critical for fever and other centrally elicited disease symptoms. The production of PGE2 depends on cyclooxygenase-2 and microsomal prostaglandin E synthase-1 (mPGES-1), but the identity of the cells involved has been a matter of controversy. We generated mice expressing mPGES-1 either in cells of hematopoietic or nonhematopoietic origin. Mice lacking mPGES-1 in hematopoietic cells displayed an intact febrile response to lipopolysaccharide, associated with elevated levels of PGE2 in the cerebrospinal fluid. In contrast, mice that expressed mPGES-1 only in hematopoietic cells, although displaying elevated PGE2 levels in plasma but not in the cerebrospinal fluid, showed no febrile response to lipopolysaccharide, thus pointing to the critical role of brain-derived PGE2 for fever. Immunohistochemical stainings showed that induced cyclooxygenase-2 expression in the brain exclusively occurred in endothelial cells, and quantitative PCR analysis on brain cells isolated by flow cytometry demonstrated that mPGES-1 is induced in endothelial cells and not in vascular wall macrophages. Similar analysis on liver cells showed induced expression in macrophages and not in endothelial cells, pointing at the distinct role for brain endothelial cells in PGE2 synthesis. These results identify the brain endothelial cells as the PGE2-producing cells critical for immune-induced fever.

  • 11.
    Nilsberth, Camilla
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Elander, Louise
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Hamzic, Namik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Norell, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Lönn, Johanna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Engström, Linda
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Blomqvist, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    The Role of Interleukin-6 in Lipopolysaccharide-Induced Fever by Mechanisms Independent of Prostaglandin E-22009Ingår i: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 150, nr 4, s. 1850-1860Artikel i tidskrift (Refereegranskat)
    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.

  • 12.
    Ruud, Johan
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Nilsson, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Engström, Linda
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Wang, Wenhua
    Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Nilsberth, Camilla
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Iresjö, Britt-Marie
    Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Lundholm, Kent
    Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Engblom, David
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Blomqvist, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    A putative role for Cox-1 in the initiation of cancer anorexia independent of mPGES-1, PGE2 and neuronal EP4 receptorsManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    It is well-established that prostaglandins (PGs) affect tumorigenesis, and evidence indicates that PGs also are important for the reduced food intake and body weight loss, the so called anorexia-cachexia syndrome, in malignant cancer. However, the identity of the PG and the cyclooxygenase (Cox) species responsible for cancer anorexia-cachexia is unknown. Here, we addressed this issue by transplanting mice with a tumor that elicits anorexia. Meal pattern analysis revealed that the reduced food intake in the tumor-bearing animals was due to decreased meal frequency. Treatment with a nonselective Cox inhibitor attenuated the anorexia, and also tumor growth. However, when given at manifest anorexia, the nonselective Cox inhibitors restored appetite and prevented body weight loss without affecting tumor size. Despite the pronounced effect of nonselective Cox-inhibitors, a selective Cox-2 inhibitor had no effect on the anorexia, whereas Cox-1 inhibition delayed its onset. Tumor growth was associated with robust increase of PGE2 levels in plasma - a response blocked by nonselective Cox-inhibition - but not in the cerebrospinal fluid, and there was no rise in body temperature. Neutralization of PGE2 with specific antibodies did not ameliorate the anorexia, and genetic deletion of microsomal PGE synthase-1 (mPGES-1), the inducible terminal isomerase for PGE2 synthesis, affected neither anorexia nor tumor growth. Furthermore, tumor-bearing mice lacking EP4 receptors selectively in the nervous system developed anorexia. These observations suggest that Cox-enzymes, most likely Cox-1, are involved in cancer-elicited anorexia and weight loss, but that these phenomena occur independently of host mPGES-1, PGE2 and neuronal EP4 signaling.

  • 13.
    Ruud, Johan
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Nilsson, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Engström Ruud, Linda
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Wang, Wenhua
    Sahlgrens University Hospital, Sweden .
    Nilsberth, Camilla
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Iresjo, Britt-Marie
    Sahlgrenska University Hospital, Gothenburg, Sweden.
    Lundholm, Kent
    Sahlgrenska University Hospital, Gothenburg, Sweden.
    Engblom, David
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Blomqvist, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Cancer-induced anorexia in tumor-bearing mice is dependent on cyclooxygenase-12013Ingår i: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 29, s. 124-135Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    It is well-established that prostaglandins (PGs) affect tumorigenesis, and evidence indicates that PGs also are important for the reduced food intake and body weight loss, the anorexia–cachexia syndrome, in malignant cancer. However, the identity of the PGs and the PG producing cyclooxygenase (COX) species responsible for cancer anorexia–cachexia is unknown. Here, we addressed this issue by transplanting mice with a tumor that elicits anorexia. Meal pattern analysis revealed that the anorexia in the tumor-bearing mice was due to decreased meal frequency. Treatment with a non-selective COX inhibitor attenuated the anorexia, and also tumor growth. When given at manifest anorexia, non-selective COX-inhibitors restored appetite and prevented body weight loss without affecting tumor size. Despite COX-2 induction in the cerebral blood vessels of tumor-bearing mice, a selective COX-2 inhibitor had no effect on the anorexia, whereas selective COX-1 inhibition delayed its onset. Tumor growth was associated with robust increase of PGE2 levels in plasma – a response blocked both by non-selective COX-inhibition and by selective COX-1 inhibition, but not by COX-2 inhibition. However, there was no increase in PGE2-levels in the cerebrospinal fluid. Neutralization of plasma PGE2 with specific antibodies did not ameliorate the anorexia, and genetic deletion of microsomal PGE synthase-1 (mPGES-1) affected neither anorexia nor tumor growth. Furthermore, tumor-bearing mice lacking EP4 receptors selectively in the nervous system developed anorexia. These observations suggest that COX-enzymes, most likely COX-1, are involved in cancer-elicited anorexia and weight loss, but that these phenomena occur independently of host mPGES-1, PGE2 and neuronal EP4 signaling.

  • 14. Saha, Sipra
    et al.
    Engström, Linda
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Avdelningen för medicinsk cellbiologi.
    Mackerlova, Ludmila
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Avdelningen för medicinsk cellbiologi.
    Jakobsson, Per-Johan
    Blomqvist, Anders
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Avdelningen för medicinsk cellbiologi.
    Impaired febrile responses to immune challenge in mice deficient in microsomal prostaglandin E synthase-12005Ingår i: American Journal of Physiology. Regulatory Integrative and Comparative Physiology, ISSN 0363-6119, E-ISSN 1522-1490, Vol. 288, nr 5 57-5Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Fever is a common, centrally elicited sign of inflammatory and infectious processes and is known to be induced by the action of PGE2 on its specific receptors in the thermogenic region of the hypothalamus. In the present work, using genetically modified mice, we examined the role of the inducible terminal PGE2-synthesizing enzyme microsomal prostaglandin E synthase-1 (mPGES-1) for the generation of immune-elicited fever. Animals with a deletion of the Ptges gene, which encodes mPGES-1, or their wild-type littermates were given either a subcutaneous injection of turpentine-a model for aseptic cytokine-induced pyresis-or an intraperitoneal injection of interleukin-1β. While both procedures resulted in typical febrile responses in wild-type animals, these responses were strongly impaired in the mPGES-1 mutant mice. In contrast, both genotypes showed psychogenic stress-induced hyperthermia and displayed normal diurnal temperature variations. Both wild-type and mPGES-1 mutant mice also showed strongly reduced motor activity following turpentine injection. Taken together with previous observations on mPGES-1 induction in the brain vasculature during various inflammatory conditions and its role in endotoxin-induced pyresis, the present findings indicate that central PGE 2 synthesis by mPGES-1 is a general and critical mechanism for fever during infectious and inflammatory conditions that is distinct from the mechanism(s) underlying the circadian temperature regulation and stress-induced hyperthermia, as well as the inflammation-induced activity depression. Copyright © 2005 the American Physiological Society.

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