In vivo effects of the antiglucocorticoid RU 486 on glucocorticoid and cytokine responses to Escherichia coli endotoxin

Hawes, A S; Rock, Craig S.; Keogh, Christopher V.; Lowry, Stephen F.; Calvano, Steve E.

doi:10.1128/iai.60.7.2641-2647.1992

Cited by 63 publications

(16 citation statements)

References 33 publications

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“…This effect has been generally assumed to be due to a reduction in the levels of corticosterone but our data indicate that adrenaline plays a more important regulatory role than corticosterone since TNFa production was enhanced by the fl-adrenoceptor antagonist, propranolol but not by the corticosterone antagonist, RU 486. This result is in agreement with previous studies which demonstrated that RU 486 does not enhance systemic TNFa production in response to LPS at doses which effectively block the action of glucocorticoids (Hawes et al, 1992;Perretti et al, 1993) but is surprising since it is well established that glucocorticoids can inhibit TNFa production in vitro and in vivo. The implication is that the tissues responsible for systemic production of TNFa are more sensitive to the inhibitory action of /3-adrenoceptor agonists than to that of glucocorticoids.…”

Section: Discussionsupporting

confidence: 93%

Regulation of tumour necrosis factor production by adrenal hormones in vivo: insights into the antiinflammatory activity of rolipram

Pettipher

Labasi

Salter

et al. 1996

British J Pharmacology

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The role of adrenal hormones in the regulation of the systemic and local production of tumour necrosis factor (TNFα) was examined in male Balb/c mice. Intraperitoneal injection of 0.3 mg E. coli lipopolysaccharide (LPS, 0111:B4) led to high levels of circulating TNFa without stimulating TNFa production in the peritoneal cavity. Systemic production of TNFα in response to LPS was increased in adrenalectomized animals and in normal animals treated with the β‐adrenoceptor antagonist, propranolol. The glucocortoid antagonist, RU 486, did not modify systemic TNFα production. These results indicate that systemic TNFα production is regulated by adrenaline but not by corticosterone. When mice were primed with thioglycollate, TNFα was produced in the peritoneal cavity in response to low dose LPS (1 μg). The levels of TNFα in the peritoneal cavity were not enhanced by adrenalectomy or by treatment with either propranolol or RU 486, indicating local production of TNFα in the peritoneal cavity is not regulated by adrenaline or corticosterone. The phosphodiesterase type IV (PDE‐IV) inhibitor, rolipram, inhibited both the systemic production of TNFa in response to high dose endotoxin (ED50 = 1.3 mg kg−1) and the local production of TNFα in the peritoneal cavity in response to low dose endotoxin (ED50 = 9.1 mg kg−1). In adrenalectomized mice there was a slight reduction in the ability of rolipram to inhibit the systemic production of TNFα (ED50 = 3.3 mg kg−1) while the ability of rolipram to inhibit the local production of TNFα in the peritoneal cavity was virtually abolished (24% inhibition at 30 mg kg−1). The glucocorticoid antagonist, RU 486, also reduced the ability of rolipram to inhibit local TNFα production while propranolol was without effect. Systemic treatment with rolipram increased the plasma concentrations of corticosterone in normal mice but not in adrenalectomized mice indicating that rolipram can cause adrenal stimulation in vivo. In summary, these data indicate that systemic production of TNFα in response to high dose endotoxin is controlled differently from the local production of TNFα in response to low dose endotoxin. The systemic production of TNFα is regulated by catecholamines, but not by corticosterone, while the local production of TNFα in the peritoneal cavity is not regulated by basal levels of either catecholamines or corticosterone. These data also show that the ability of rolipram to inhibit the local production of TNFα is dependent on the release of corticosterone from the adrenal glands.

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Section: Discussionsupporting

confidence: 93%

Regulation of tumour necrosis factor production by adrenal hormones in vivo: insights into the antiinflammatory activity of rolipram

Pettipher

Labasi

Salter

et al. 1996

British J Pharmacology

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“…8 Consequently, adrenalectomy or treatment with the GR antagonist RU486 results in high mortality in various models of infection. 9,10 In contrast, elevated GR expression is associated with increased resistance to endotoxic shock. 11 GCs modulate the function of leucocytes at different levels including the control of gene expression, enzymatic activity and cellular migration.…”

Section: Introductionmentioning

confidence: 99%

Glucocorticoids exert opposing effects on macrophage function dependent on their concentration

et al. 2007

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SummaryGlucocorticoids (GCs) are involved in the modulation of macrophage function and thereby control the host's immune responses to pathogens. However, neither the role of hormone concentration nor the differential contribution of the glucocorticoid (GR) and the mineralocorticoid receptors (MR) to these activities are known. Here we show that low levels of corticosterone enhance NO production as well as mRNA expression of pro-inflammatory cytokines, chemokines and enzymes required for mediator synthesis. In contrast, at high corticosterone concentrations macrophage function was strongly repressed. Importantly, inactivation of the GR by lentiviral delivery of siRNAs abrogated both the immunostimulatory and the immunosuppressive GC actions whereas inactivation of the MR had no effect. Furthermore, removal of endogenous GCs by adrenalectomy in vivo induced a preactivated state in macrophages that could be modulated by corticosterone. We conclude that GCs exert distinct effects on macrophage function dependent on their concentration, and that they primarily act through the GR despite concomitant expression of the MR.

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“…Endogenous GCs are produced during the course of inflammatory responses, including endotoxin shock [3,5,6]. Inhibition of the biosynthesis or effects of endogenously produced GCs in mice increases LPS-induced TNF production and lethality [4,[6][7][8].…”

Section: Introductionmentioning

confidence: 99%

Methylprednisolone differentially regulates IL-10 and tumour necrosis factor (TNF) production during murine endotoxaemia

Marchant¹,

Amraoui²,

Gueydan

et al. 1996

Clinical and Experimental Immunology

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SUMMARYIL-10 is an endogenous antiinflammatory cytokine that inhibits TNF biosynthesis and protects mice from lipopolysaccharide (LPS)-induced lethality. As synthetic glucocorticoids are widely used as antiinflammatory agents, we analysed the effects of methylprednisolone administration on IL-10 biosynthesis during murine endotoxaemia. We found that low doses of methylprednisolone (2-10 mg/ kg) markedly inhibited TNF production but did not affect serum levels of IL-10, while a high methylprednisolone dose (50 mg/kg) increased LPS-induced IL-10 levels. In parallel, we observed that LPS-induced IL-10 production is TNF-independent in this experimental setting. Experiments conducted in vitro indicated that methylprednisolone (from 0 . 01 to 100

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In vivo effects of the antiglucocorticoid RU 486 on glucocorticoid and cytokine responses to Escherichia coli endotoxin

Cited by 63 publications

References 33 publications

Regulation of tumour necrosis factor production by adrenal hormones in vivo: insights into the antiinflammatory activity of rolipram

Regulation of tumour necrosis factor production by adrenal hormones in vivo: insights into the antiinflammatory activity of rolipram

Glucocorticoids exert opposing effects on macrophage function dependent on their concentration

Methylprednisolone differentially regulates IL-10 and tumour necrosis factor (TNF) production during murine endotoxaemia

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