Stimulation of Thyroid Hormone Secretion by Dibutyryl Cyclic-AMP<sup>1</sup>

Oncostatin-M (OSM), a pluripotent cytokine of the interleukin-6 (IL-6) family, is produced in a number of inflammatory conditions. Known sources of OSM include monocytes-macrophages and T-cells. Here we present microglia, the resident macrophages of the brain, as a source of OSM in the CNS. In this context, we describe a novel inducer of OSM, prostaglandin E(2) (PGE(2)). PGE(2) induces OSM expression in microglia, monocytes, and macrophages of human and murine origin. PGE(2) induction of OSM is mimicked by cholera toxin, an activator of stimulatory G (G(s))-proteins; by forskolin, an activator of adenylate cyclase; and by the cAMP analog, dibutyryl-cAMP. PGE(2) induction of OSM gene expression is inhibited by the adenylate cyclase inhibitor 2',5'-dideoxyadenosine, by the protein kinase A (PKA) inhibitor H-89, and by a dominant-negative PKA construct. These data indicate that PGE(2) signals via G(s)-protein-coupled receptor(s), adenylate cyclase, and PKA to induce OSM expression. Accordingly, other activators of cAMP signaling such as norepinephrine and PGE(1) induce OSM. The ability of PGE(2) to induce OSM expression was tested under more physiological conditions, using cocultures of astrocytes and monocytes. Treatment of the cocultures with IL-1beta or tumor necrosis factor-alpha (TNF-alpha) results in production of PGE(2) and OSM. PGE(2) produced in the cocultures is responsible for OSM induction, because pretreatment with indomethacin, an inhibitor of prostaglandin synthesis, as well as depletion of PGE(2), abrogate OSM expression induced by IL-1beta or TNF-alpha. These data suggest that in the CNS, OSM may be produced through collaboration of astrocytes and macrophages-microglia.

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“…4 B). Finally, dbcAMP, a synthetic, cell-permeable analog of cAMP (Ahn et al, 1969), induced OSM production in THP-1 cells (Fig. 4 B).…”

Section: Pge 2 Treatment Elevates Intracellular Camp Levelsmentioning

confidence: 92%

Prostaglandin E₂Is a Novel Inducer of Oncostatin-M Expression in Macrophages and Microglia

Repovic

Benveniste

2002

J. Neurosci.

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“…Good yields of the O2-monobutyryl derivatives were obtained when the reaction was stopped after 2 h at room temperature or 1-2 days at 0-5 °C, whereas exhaustive butyrylation at room temperature for 7-9 days afforded the dibutyryl derivatives as main products, accompanied by small amounts of other unidentified products, presumably the A^^.O^-tributyryl19 derivatives. The A^monobutyryl-S-substituted analogues, e.g., lV®-butyryl-8-thioadenosine cyclic 3',5'-phosphate (12), JV6butyryl-8-methylthioadenosine cyclic 3',5'-phosphate (15), and S-benzylthio-A^-butyryladenosine cyclic 3',5'-phosphate (17), were produced by partial hydrolysis of the corresponding dibutyryl derivatives in 0.1 N aqueous-alcoholic KOH under carefully controlled conditions (0-5 °C, 1 h). Compounds in which the substituent in position 8 is susceptible to acylation, e.g., 8H2N-CAMP (8) or 8HO-cAMP (6), were butyrylated in the form of a suitable precursor like 8N3-CAMP (7) or a blocked derivative like 8PhCH20-cAMP (5) and subsequently converted to the desired product, i.e., 8-amino-Af®,02-dibutyryladenosine cyclic 3',5'-phosphate (19) or A/^CP-dibutyryl-S-hydroxyadenosine cyclic 3',5'-phosphate (18), respectively.…”

Section: Methodsmentioning

confidence: 99%

“…7"9 In contrast to in vitro studies, the results obtained in in vivo systems are conditional and not clearly positive. Bastomski and McKenzie10 and Ahn et al11,12 have reported that in vivo injections of only very high doses of cAMP (~300 mg/kg) and/or pretreatment of the animals with thyroxine and TSH produced a statistically significant increase in thyroidal radioiodide release or enhanced the synthesis of organically bound iodine in the thyroid.…”

mentioning

confidence: 99%

Synthesis of new cyclic nucleotides and their differential stimulatory effects on thyroid function in mice

Cehovic¹,

Bayer²,

Giao³

1976

J. Med. Chem.

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Various 8-substituted cAMP analogues were converted into the corresponding N6,O2'-dibutyryl, N6-monobutyryl, or O2'-monobutyryl derivatives and the parent compounds as well as the new derivatives were tested for TSH-like stimulation of the thyroid function in mice in vivo by means of the McKenzie bioassay. It was found that a pronounced stimulatory effect on the thyroid secretion can be produced by certain cyclic nucleotides. The most potent compounds, 8H2N-cAMP, 8MeS-cAMP, and 8N3-cAMP at 15-30 mg/kg iv, showed an activity approximately one order of magnitude higher than that of cAMP and comparable to the action of 0.6-1.0 mU of TSH per mouse iv. Radioimmunological determination of thyroxine levels in the serum confirmed these results. Serum T4 levels in mice injected, for instance, with 8MeS-cAMP (30 mg/kg) rose from 4.85 +/- 0.25 to 6.32 +/- 0.41 mug/100 ml in 1 h, the net increase in T4 being comparable to that produced by TSH (1 mU/mouse) under identical experimental conditions. Introduction of one or two butyryl groups (in the N6 and/or O2' position) significantly increased or decreased the biological activity, dependent on the parent compound, but no direct correlation between biological activity and degree of butyrylation was apparent. The effect of these compounds on the thyroid seems to be specific for cyclic nucleotides because 8MeS-5'AMP which resembles 8MeS-cAMP but lacks the cyclic phosphate structure is inactive in the McKenzie bioassay and in the T4 radioimmunoassay.

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Some recent developments in the physiology of the thyroid gland

Stanbury

1972

Ergebnisse Der Physiologie Reviews of Physiology, Volume 65

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Stimulation of Thyroid Hormone Secretion by Dibutyryl Cyclic-AMP¹

Cited by 15 publications

References 0 publications

Prostaglandin E₂Is a Novel Inducer of Oncostatin-M Expression in Macrophages and Microglia

Prostaglandin E₂Is a Novel Inducer of Oncostatin-M Expression in Macrophages and Microglia

Synthesis of new cyclic nucleotides and their differential stimulatory effects on thyroid function in mice

Some recent developments in the physiology of the thyroid gland

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Stimulation of Thyroid Hormone Secretion by Dibutyryl Cyclic-AMP1

Cited by 15 publications

References 0 publications

Prostaglandin E2Is a Novel Inducer of Oncostatin-M Expression in Macrophages and Microglia

Prostaglandin E2Is a Novel Inducer of Oncostatin-M Expression in Macrophages and Microglia

Synthesis of new cyclic nucleotides and their differential stimulatory effects on thyroid function in mice

Some recent developments in the physiology of the thyroid gland

Contact Info

Product

Resources

About

Stimulation of Thyroid Hormone Secretion by Dibutyryl Cyclic-AMP¹

Prostaglandin E₂Is a Novel Inducer of Oncostatin-M Expression in Macrophages and Microglia

Prostaglandin E₂Is a Novel Inducer of Oncostatin-M Expression in Macrophages and Microglia