Neurons and glial cells of the rat organum vasculosum laminae terminalis directly respond to lipopolysaccharide and pyrogenic cytokines

Ott, Daniela; Murgott, Jolanta; Rafalzik, Sandra; Wuchert, Florian; Schmalenbeck, Babette; Roth, Joachim; Gerstberger, Rüdiger

doi:10.1016/j.brainres.2010.09.083

Cited by 56 publications

(58 citation statements)

References 61 publications

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“…Two days later, the culture medium was exchanged with serum-free culture medium to prevent potentially stimulatory effects by its components and experiments were performed the next day. Cell culture conditions were chosen according to in-house procedures for primary neuro-glial cell cultures of the circumventricular organs [35] and adjusted to protocols for primary pituitary cell cultures, previously utilized by others [36-38]. For each experiment, relative cell density was controlled after immunohistochemical staining (5 predefined areas counted; mean of approximately 500 cells).…”

Section: Methodsmentioning

confidence: 99%

Activation of the inflammatory transcription factor nuclear factor interleukin-6 during inflammatory and psychological stress in the brain

Fuchs

Damm

Gerstberger

et al. 2013

J Neuroinflammation

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BackgroundThe transcription factor nuclear factor interleukin 6 (NF-IL6) is known to be activated by various inflammatory stimuli in the brain. Interestingly, we recently detected NF-IL6-activation within the hypothalamus-pituitary-adrenal (HPA)-axis of rats after systemic lipopolysaccharide (LPS)-injection. Thus, the aim of the present study was to investigate whether NF-IL6 is activated during either, inflammatory, or psychological stress in the rat brain.MethodsRats were challenged with either the inflammatory stimulus LPS (100 μg/kg, i.p.) or exposed to a novel environment. Core body temperature (Tb) and motor activity were monitored using telemetry, animals were killed at different time points, brains and blood removed, and primary cell cultures of the anterior pituitary lobe (AL) were investigated. Analyses were performed using immunohistochemistry, RT-PCR, and cytokine-specific bioassays.ResultsStress stimulation by a novel environment increased NF-IL6-immunoreactivity (IR) in the pituitary’s perivascular macrophages and hypothalamic paraventricular cells and a rise in Tb lasting approximately 2 h. LPS stimulation lead to NF-IL6-IR in several additional cell types including ACTH-IR-positive corticotrope cells in vivo and in vitro. Two other proinflammatory transcription factors, namely signal transducer and activator of transcription (STAT)3 and NFκB, were significantly activated and partially colocalized with NF-IL6-IR in cells of the AL only after LPS-stimulation, but not following psychological stress. In vitro NF-IL6-activation was associated with induction and secretion of TNFα in folliculostellate cells, which could be antagonized by the JAK-STAT-inhibitor AG490.ConclusionsWe revealed, for the first time, that NF-IL6 activation occurs not only during inflammatory LPS stimulation, but also during psychological stress, that is, a novel environment. Both stressors were associated with time-dependent activation of NF-IL6 in different cell types of the brain and the pituitary. Moreover, while NF-IL6-IR was partially linked to STAT3 and NFκB activation, TNFα production, and ACTH-IR after LPS stimulation; this was not the case after exposure to a novel environment, suggesting distinct underlying signaling pathways. Overall, NF-IL6 can be used as a broad activation marker in the brain and might be of interest for therapeutic approaches not only during inflammatory but also psychological stress.

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Section: Methodsmentioning

confidence: 99%

Activation of the inflammatory transcription factor nuclear factor interleukin-6 during inflammatory and psychological stress in the brain

Fuchs

Damm

Gerstberger

et al. 2013

J Neuroinflammation

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“…Evidence against this idea has been presented (Romanovsky et al, 2003); there are recent data, however, that show that neurons and glial cells within the OVLT respond with intracellular calcium signals to lipopolysaccharide, tumor necrosis factor-α, or interleukin-1β or interleukin 6 (Ott et al, 2010).…”

Section: Neuroendocrine Autonomic and Neuroimmune Functionsmentioning

confidence: 99%

Circumventricular Organs

Oldfield

2015

The Rat Nervous System

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“…OVLT and surrounding thermoregulatory neurons are involved in changes in body temperature and inducing fever in response to systemic inflammation. Pyrogenic, proinflammatory cytokines, TNF-α, IL-1β, and IL-6, produced locally in the hypothalamus, or from the circulation via fenestrated capillaries in the OVLT, stimulate thermoregulatory neurons to increase the body temperature [57-60]. We postulate that these cytokines directly regulate GnRH neurons in the proximity to OVLT.…”

Section: Introductionmentioning

confidence: 99%

Leukemia Inhibitory Factor Represses GnRH Gene Expression via cFOS during Inflammation in Male Mice

Lainez

Coss²

2019

Neuroendocrinology

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Background: The mechanisms whereby neuroinflammation negatively affects neuronal function in the hypothalamus are not clear. Our previous study determined that obesity-mediated chronic inflammation elicits sex-specific impairment in reproductive function via reduction in spine density in gonadotropin-releasing hormone (GnRH) neurons. Neuroinflammation and subsequent decrease in GnRH neuron spine density was specific for male mice, while protection in females was independent of ovarian estrogens. Methods: To examine if neuroinflammation-induced cytokines can directly regulate GnRH gene expression, herein we examined signaling pathways and mechanisms in males in vivo and in GnRH-expressing cell line, GT1–7. Results: GnRH neurons express cytokine receptors, and chronic or acute neuroinflammation represses GnRH gene expression in vivo. Leukemia inhibitory factor (LIF) in particular represses GnRH expression in GT1–7 cells, while other cytokines do not. STAT3 and MAPK pathways are activated following LIF treatment, but only MAPK pathway, specifically p38α, is sufficient to repress the GnRH gene. LIF induces cFOS that represses the GnRH gene via the -1,793 site in the enhancer region. In vivo, following high-fat diet, cFOS is induced in GnRH neurons and neurons juxtaposed to the leaky blood brain barrier of the organum vasculosum of the lamina terminalis, but not in the neurons further away. Conclusion: Our results indicate that the increase in LIF due to neuroinflammation induces cFOS and represses the GnRH gene. Therefore, in addition to synaptic changes in GnRH neurons, neuroinflammatory cytokines directly regulate gene expression and reproductive function, and the specificity for neuronal targets may stem from the proximity to the fenestrated capillaries.

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Neurons and glial cells of the rat organum vasculosum laminae terminalis directly respond to lipopolysaccharide and pyrogenic cytokines

Cited by 56 publications

References 61 publications

Activation of the inflammatory transcription factor nuclear factor interleukin-6 during inflammatory and psychological stress in the brain

Activation of the inflammatory transcription factor nuclear factor interleukin-6 during inflammatory and psychological stress in the brain

Circumventricular Organs

Leukemia Inhibitory Factor Represses GnRH Gene Expression via cFOS during Inflammation in Male Mice

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