Prostaglandins mediate the ACTH response to lnterleukin-1-Beta instilled into the hypothalamic median eminence

John G. McCoy, Shannon G. Matta, Burt Sharp

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Interleukin-1β (IL-1β) is a potent ACTH secretagogue which activates the release of hypothalamic CRH. Direct injections of IL-1β into the hypothalamic median eminence (ME), a site which lacks a blood-brain barrier, has been shown to rapidly induce ACTH secretion. Therefore, the ME is a likely site whereby circulating IL-1β can access the brain to stimulate CRH and. consequently, ACTH secretion. To further evaluate this hypothesis, an angular stereotaxic approach was developed to localize the spread of IL-1 β to the ME and to optimally separate the injectate from the hypothalamic paraventricular nucleus (PVN), another proposed site of IL-1 action. Studies of the diffusion of [125I]-IL-1 β (100 nl delivered over 60 s) showed that 97% remained within 200 (tm of the ventral surface of the hypothalamus and 87% was contained within a radius of 550 μm of the injection site in the sagittal plane. Additional rats received recombinant human IL-lβ (0.2-25.0 ng in 100 nl) into the ME (intra-ME). Plasma ACTH levels were significantly elevated by a much lower dose (0.5 ng, p < 0.001) of IL-lβ than that previously reported. Responses appeared to be dose-dependent and ACTH was maximally stimulated by 2.0 ng IL-lβ. Also, immunocytochemically labelled CRH in the ME was markedly depleted after intra-ME IL-lβ. Indomethacin, an inhibitor of prostaglandin (PG) synthesis, has been shown to block both the induction of CRH secretion by IL-lβ from hypothalamic explants, as well as the ACTH response to intravenous IL-lβ. Thus, indomethacin was used to determine whether PGs are mediators of the ACTH response to IL-1 β delivered into the ME. The ACTH response was abolished (p < 0.005) when a low dose of indomethacin (1 mg/kg i.v.) was administered 20 min before intra-ME IL-lβ (25 ng). Finally, plasma ACTH was elevated in a dose-dependent manner by the intra-ME administration of PGs. The hierarchy of ACTH responses to PGE2 were: CSF < 0.5 μg (p < 0.001) = 2.0 μg <4.0 μg (p < 0.05). Responses to PGF2α were: CSF<0.5 μg (p < 0.001) <2.0 μg (p < 0.05) = 4.0 μg. Since these PGs appear to activate different second-messenger systems, a submaximal dose of each was administered alone or in combination. Additivity of the response, rather than synergy, was evident, since the overall ACTH level in response to the combination of PGE2 and PGF2α(0.5 μg each) was no greater than the sum of the two separate treatments. In summary, the ACTH response to IL-lβ delivered into the ME appears to be mediated by local prostaglandins.

Original languageEnglish (US)
Pages (from-to)426-435
Number of pages10
JournalNeuroendocrinology
Volume60
Issue number4
DOIs
StatePublished - Jan 1 1994

Fingerprint

Median Eminence
Adrenocorticotropic Hormone
Prostaglandins
Interleukin-1
Indomethacin
Dinoprost
Dinoprostone
Prostaglandin Antagonists
Injections
Paraventricular Hypothalamic Nucleus
Second Messenger Systems
Blood-Brain Barrier
Hypothalamus

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology
  • Endocrine and Autonomic Systems
  • Cellular and Molecular Neuroscience

Cite this

Prostaglandins mediate the ACTH response to lnterleukin-1-Beta instilled into the hypothalamic median eminence. / McCoy, John G.; Matta, Shannon G.; Sharp, Burt.

In: Neuroendocrinology, Vol. 60, No. 4, 01.01.1994, p. 426-435.

Research output: Contribution to journalArticle

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abstract = "Interleukin-1β (IL-1β) is a potent ACTH secretagogue which activates the release of hypothalamic CRH. Direct injections of IL-1β into the hypothalamic median eminence (ME), a site which lacks a blood-brain barrier, has been shown to rapidly induce ACTH secretion. Therefore, the ME is a likely site whereby circulating IL-1β can access the brain to stimulate CRH and. consequently, ACTH secretion. To further evaluate this hypothesis, an angular stereotaxic approach was developed to localize the spread of IL-1 β to the ME and to optimally separate the injectate from the hypothalamic paraventricular nucleus (PVN), another proposed site of IL-1 action. Studies of the diffusion of [125I]-IL-1 β (100 nl delivered over 60 s) showed that 97{\%} remained within 200 (tm of the ventral surface of the hypothalamus and 87{\%} was contained within a radius of 550 μm of the injection site in the sagittal plane. Additional rats received recombinant human IL-lβ (0.2-25.0 ng in 100 nl) into the ME (intra-ME). Plasma ACTH levels were significantly elevated by a much lower dose (0.5 ng, p < 0.001) of IL-lβ than that previously reported. Responses appeared to be dose-dependent and ACTH was maximally stimulated by 2.0 ng IL-lβ. Also, immunocytochemically labelled CRH in the ME was markedly depleted after intra-ME IL-lβ. Indomethacin, an inhibitor of prostaglandin (PG) synthesis, has been shown to block both the induction of CRH secretion by IL-lβ from hypothalamic explants, as well as the ACTH response to intravenous IL-lβ. Thus, indomethacin was used to determine whether PGs are mediators of the ACTH response to IL-1 β delivered into the ME. The ACTH response was abolished (p < 0.005) when a low dose of indomethacin (1 mg/kg i.v.) was administered 20 min before intra-ME IL-lβ (25 ng). Finally, plasma ACTH was elevated in a dose-dependent manner by the intra-ME administration of PGs. The hierarchy of ACTH responses to PGE2 were: CSF < 0.5 μg (p < 0.001) = 2.0 μg <4.0 μg (p < 0.05). Responses to PGF2α were: CSF<0.5 μg (p < 0.001) <2.0 μg (p < 0.05) = 4.0 μg. Since these PGs appear to activate different second-messenger systems, a submaximal dose of each was administered alone or in combination. Additivity of the response, rather than synergy, was evident, since the overall ACTH level in response to the combination of PGE2 and PGF2α(0.5 μg each) was no greater than the sum of the two separate treatments. In summary, the ACTH response to IL-lβ delivered into the ME appears to be mediated by local prostaglandins.",
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N2 - Interleukin-1β (IL-1β) is a potent ACTH secretagogue which activates the release of hypothalamic CRH. Direct injections of IL-1β into the hypothalamic median eminence (ME), a site which lacks a blood-brain barrier, has been shown to rapidly induce ACTH secretion. Therefore, the ME is a likely site whereby circulating IL-1β can access the brain to stimulate CRH and. consequently, ACTH secretion. To further evaluate this hypothesis, an angular stereotaxic approach was developed to localize the spread of IL-1 β to the ME and to optimally separate the injectate from the hypothalamic paraventricular nucleus (PVN), another proposed site of IL-1 action. Studies of the diffusion of [125I]-IL-1 β (100 nl delivered over 60 s) showed that 97% remained within 200 (tm of the ventral surface of the hypothalamus and 87% was contained within a radius of 550 μm of the injection site in the sagittal plane. Additional rats received recombinant human IL-lβ (0.2-25.0 ng in 100 nl) into the ME (intra-ME). Plasma ACTH levels were significantly elevated by a much lower dose (0.5 ng, p < 0.001) of IL-lβ than that previously reported. Responses appeared to be dose-dependent and ACTH was maximally stimulated by 2.0 ng IL-lβ. Also, immunocytochemically labelled CRH in the ME was markedly depleted after intra-ME IL-lβ. Indomethacin, an inhibitor of prostaglandin (PG) synthesis, has been shown to block both the induction of CRH secretion by IL-lβ from hypothalamic explants, as well as the ACTH response to intravenous IL-lβ. Thus, indomethacin was used to determine whether PGs are mediators of the ACTH response to IL-1 β delivered into the ME. The ACTH response was abolished (p < 0.005) when a low dose of indomethacin (1 mg/kg i.v.) was administered 20 min before intra-ME IL-lβ (25 ng). Finally, plasma ACTH was elevated in a dose-dependent manner by the intra-ME administration of PGs. The hierarchy of ACTH responses to PGE2 were: CSF < 0.5 μg (p < 0.001) = 2.0 μg <4.0 μg (p < 0.05). Responses to PGF2α were: CSF<0.5 μg (p < 0.001) <2.0 μg (p < 0.05) = 4.0 μg. Since these PGs appear to activate different second-messenger systems, a submaximal dose of each was administered alone or in combination. Additivity of the response, rather than synergy, was evident, since the overall ACTH level in response to the combination of PGE2 and PGF2α(0.5 μg each) was no greater than the sum of the two separate treatments. In summary, the ACTH response to IL-lβ delivered into the ME appears to be mediated by local prostaglandins.

AB - Interleukin-1β (IL-1β) is a potent ACTH secretagogue which activates the release of hypothalamic CRH. Direct injections of IL-1β into the hypothalamic median eminence (ME), a site which lacks a blood-brain barrier, has been shown to rapidly induce ACTH secretion. Therefore, the ME is a likely site whereby circulating IL-1β can access the brain to stimulate CRH and. consequently, ACTH secretion. To further evaluate this hypothesis, an angular stereotaxic approach was developed to localize the spread of IL-1 β to the ME and to optimally separate the injectate from the hypothalamic paraventricular nucleus (PVN), another proposed site of IL-1 action. Studies of the diffusion of [125I]-IL-1 β (100 nl delivered over 60 s) showed that 97% remained within 200 (tm of the ventral surface of the hypothalamus and 87% was contained within a radius of 550 μm of the injection site in the sagittal plane. Additional rats received recombinant human IL-lβ (0.2-25.0 ng in 100 nl) into the ME (intra-ME). Plasma ACTH levels were significantly elevated by a much lower dose (0.5 ng, p < 0.001) of IL-lβ than that previously reported. Responses appeared to be dose-dependent and ACTH was maximally stimulated by 2.0 ng IL-lβ. Also, immunocytochemically labelled CRH in the ME was markedly depleted after intra-ME IL-lβ. Indomethacin, an inhibitor of prostaglandin (PG) synthesis, has been shown to block both the induction of CRH secretion by IL-lβ from hypothalamic explants, as well as the ACTH response to intravenous IL-lβ. Thus, indomethacin was used to determine whether PGs are mediators of the ACTH response to IL-1 β delivered into the ME. The ACTH response was abolished (p < 0.005) when a low dose of indomethacin (1 mg/kg i.v.) was administered 20 min before intra-ME IL-lβ (25 ng). Finally, plasma ACTH was elevated in a dose-dependent manner by the intra-ME administration of PGs. The hierarchy of ACTH responses to PGE2 were: CSF < 0.5 μg (p < 0.001) = 2.0 μg <4.0 μg (p < 0.05). Responses to PGF2α were: CSF<0.5 μg (p < 0.001) <2.0 μg (p < 0.05) = 4.0 μg. Since these PGs appear to activate different second-messenger systems, a submaximal dose of each was administered alone or in combination. Additivity of the response, rather than synergy, was evident, since the overall ACTH level in response to the combination of PGE2 and PGF2α(0.5 μg each) was no greater than the sum of the two separate treatments. In summary, the ACTH response to IL-lβ delivered into the ME appears to be mediated by local prostaglandins.

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