Endotoxin-Induced Release of Interleukin-6 from Rat Medial Basal Hypothalami*

Spangelo, Bryan L.; Judd, Allan M.; MacLeod, Robert M.; Goodman, D. W.; Isakson, Peter C.

doi:10.1210/endo-127-4-1779

Cited by 109 publications

(39 citation statements)

References 27 publications

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“…Spangelo et al [22] also reported the induction of IL-6 release from rat MBH by endotoxin and suggested that this IL was released from nonneuronal cell type.…”

Section: Discussionmentioning

confidence: 94%

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Hypothalamic Relationships between Interleukin-6 and LHRH Release Affected by Bacterial Endotoxin in Adult Male Rats

Feleder

Wuttke²,

Moguilevsky³

1998

Neurosignals

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Immune system alterations coexist with modifications in the reproductive axis. The bacterial endotoxin lipopolysaccharide (LPS) has inflammatory effects and stimulates cytokine release in the hypothalamus where LHRH neurons are located. LPS inhibition of LHRH release at hypothalamic level appears to be associated with modifications in the cerebral immune system. Central and peripheral LPS administration induces the expression and release of several cytokines in the central nervous system. Hence the present study was designed to investigate a possible function of the interleukin-6 (IL-6) stimulated by LPS in the regulation of LHRH secretion. Male rats were decapitated, and the preoptic mediobasal hypothalamic area (PO/MBH) was dissected and superfused with Earle’s balanced salt solution. Superfusate fractions were collected at 15-min intervals after a 60-min stabilization superfusion period. LPS (100 ng/ml) and IL-6 receptor antagonist (IL-6ra) were then added to the superfusion medium over 1 h in two different experimental designs: (1) LPS only and (2) LPS followed by IL-6ra, performed in different experiments. This was followed by a washout period. The PO/MBH fragments were then subjected to a 56 mM K⁺ stimulus. Control PO/MBH fragments were continuously superfused with Earle’s solution. As expected, LHRH release was significantly reduced (p < 0.05) during and following exposure to LPS. At the same time, IL-6 concentrations significantly increased in the superfusion medium compared with the control group. IL-6ra significantly (p < 0.01) potentiated the inhibitory effect of LPS on LHRH secretion. On the bases of previous papers indicating a stimulatory effect of IL-6 on LHRH release it could be considered that the potentiation of IL-6ra of the inhibitory effect of LPS on LHRH could be the consequence of the lack of the stimulatory effect of IL-6 on LHRH produced by the receptor antagonist. IL-6ra also increased IL-6 levels measured in medium probably due to a decrease in the metabolization induced by the blockage of the receptors and the consequent accumulation of IL-6 in the media. These results could indicate that IL-6 partly attenuates the inhibitory effect of LPS on LHRH release. These observations indicate that there is an increase in IL-6 release that becomes significant at the same time when LHRH release is decreased. Also, depolarizing concentrations of K⁺ (56 mM) did not increase IL-6 release, while LHRH release from the hypothalamic fragments was significantly increased. These data suggest that the inhibitory effect of LPS on LHRH release may be explained by the stimulation of other cytokines than IL-6, meanwhile the augmented levels of IL-6 probably released via a nonneuronal source was shown to be higher when LHRH was decresed. This could confirm the stimulatory role of IL-6 on LHRH release.

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“…Spangelo et al [22] also reported the induction of IL-6 release from rat MBH by endotoxin and suggested that this IL was released from nonneuronal cell type.…”

Section: Discussionmentioning

confidence: 94%

“…IL-6 is synthesized in the mediobasal hypothalamus [22], and although the effect of IL-6 is not well established, some reports demonstrated that this cytokine has stimulatory functions on LHRH secretion suggesting a possible role for this cytokine in the regulation of gonadotropin secretion [23].…”

Section: Introductionmentioning

confidence: 99%

Hypothalamic Relationships between Interleukin-6 and LHRH Release Affected by Bacterial Endotoxin in Adult Male Rats

Feleder

Wuttke²,

Moguilevsky³

1998

Neurosignals

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“…Activation of the HPA axis by proinflammatory cytokines provokes the release of glucocorticoids which, in turn, prevent the continuing immune-inflammatory response [1]and thereby regulates a homeostatic neuroendocrine-immune regulatory loop. For example, proinflammatory cytokines, such as interleukin 1β (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor (TNF-α), are expressed in HPA axis tissues [2, 3, 4]and stimulate the release of corticotropin-releasing hormone (CRH), adrenocorticotropin (ACTH), and corticosterone [5, 6, 7, 8, 9, 10]. This indicates that proinflammatory cytokines play an important role in maintaining neuroendocrine-immune homeostasis through the HPA axis.…”

Section: Introductionmentioning

confidence: 99%

Interleukin-12 p40 Gene Expression Is Induced in Lipopolysaccharide-Activated Pituitary Glands in vivo

Yang

Han

Kim³

et al. 2002

Neuroendocrinology

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Proinflammatory cytokines have several functions including activation of the hypothalamo-pituitary-adrenal (HPA) axis and regulation of the immune system. The present study focuses on the regulation of interleukin 12 (IL-12) and its receptor gene expression in the HPA axis under artificially induced immune stress, brought on by administration of lipopolysaccharide (LPS) to Sprague-Dawley (SD) rats. RT-PCR analyses showed that expression of the IL-12 p40 gene was significantly increased and peaked at 2 h in the pituitary gland, but not in the hypothalamus. LPS-induced IL-12 p40 gene induction in the pituitary gland was suppressed after β-adrenoceptor agonist pretreatment in vivo. Both IL-12 p40 gene induction and IL-12 production were also observed when freshly isolated pituitary glands from non-treated SD rats were incubated with LPS in vitro. Furthermore, CD14, which is known as a LPS receptor, was found to be expressed in the pituitary gland. Gel mobility shift assays using nuclear extracts prepared from the pituitary glands of rats administered LPS showed induction of NF-ĸB and AP-1 DNA-binding activity. These results suggest that LPS stimulates the pituitary gland directly in vivo to increase IL-12 p40 gene expression and IL-12 protein production.

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“…On the other hand, IL-6 inhibits FSH-stimulated progesterone production by rat granulosa cells in vitro (28). This pleiotropic cytokine is produced by many endocrine tissues, such as the anterior pituitary gland (29) and the medial basal hypothalamus (30). It is also produced by ovarian cancer cell lines and primary ovarian tumor cultures (31).…”

mentioning

confidence: 99%

Immunoendocrine Interactions During Chronic Cysticercosis Determine Male Mouse Feminization: Role of IL-6

Morales‐Montor

Baig

Mitchell

et al. 2001

The Journal of Immunology

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Taenia crassiceps cysticercosis results in an impressive feminization in male mice during chronic infection, characterized by increased serum estradiol levels 100 times their normal values, while those of testosterone and dihydrotestosterone are decreased by 85 and 95% respectively. Concomitantly, the levels of follicle-stimulating hormone and IL-6 are increased 70 and 90 times their normal values in the infected male mice. Since a specific Th1/Th2 shift of the immune response has been previously reported during the chronic infection, and this shift may be associated with the feminization process, we proposed that this shift is induced by immunoendocrine interactions during the disease, and this gives way to a change in the initial resistance to the infection in the male mice, which become as susceptible as female mice. To confirm this hypothesis, we depleted immune system activity in two different ways: total body irradiation and neonatal thymectomy. Our results show that when immune system activity is depleted using either strategy, the male mice do not feminize, and the levels of follicle-stimulating hormone and IL-6 are inhibited. Depletion of IL-6 using IL-6−/− knockout mice does not produce the feminization process stated above, while restitution of the IL-6−/− knockout, irradiated, and thymectomized mice with murine recombinant IL-6 restores the feminization process. Expression of the IL-6 gene was found only in the testes and spleen of infected animals. Our results illustrate the importance of immunoendocrine interactions during a parasitic disease and show a possible new mechanism of parasite establishment in an initially resistant host.

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Endotoxin-Induced Release of Interleukin-6 from Rat Medial Basal Hypothalami*

Cited by 109 publications

References 27 publications

Hypothalamic Relationships between Interleukin-6 and LHRH Release Affected by Bacterial Endotoxin in Adult Male Rats

Hypothalamic Relationships between Interleukin-6 and LHRH Release Affected by Bacterial Endotoxin in Adult Male Rats

Interleukin-12 p40 Gene Expression Is Induced in Lipopolysaccharide-Activated Pituitary Glands in vivo

Immunoendocrine Interactions During Chronic Cysticercosis Determine Male Mouse Feminization: Role of IL-6

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