Receptor-mediated effects of glucocorticoids on inflammation: Enhancement of the inflammatory response with a glucocorticoid antagonist

Laue, Louisa; Kawai, Shinichi; Brandon, David D.; Brightwell, David; Barnes, Kevin M.; Knazek, Richard A.; Loriaux, D. Lynn; Chrousos, George P.

doi:10.1016/0022-4731(88)90156-2

Cited by 72 publications

(29 citation statements)

References 46 publications

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“…RU486 alone did not affect permeability. The antagonism of the dexamethasone effects by RU486 at 100ϫ concentration is consistent with previous results demonstrating RU486 inhibition of known receptor-mediated effects (45,46). The RU486 experiments were also performed using recVPF as the permeability-inducing agent.…”

Section: Resultssupporting

confidence: 92%

Mechanism of dexamethasone suppression of brain tumor-associated vascular permeability in rats. Involvement of the glucocorticoid receptor and vascular permeability factor.

Heiss¹,

Papavassiliou²,

Merrill³

et al. 1996

J. Clin. Invest.

240

139

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Brain tumor-associated cerebral edema arises because tumor capillaries lack normal blood-brain barrier function; vascular permeability factor (VPF, also known as vascular endothelial growth factor, VEGF) is a likely mediator of this phenomenon. Clinically, dexamethasone reduces brain tumor-associated vascular permeability through poorly understood mechanisms. Our goals were to determine if suppression of permeability by dexamethasone might involve inhibition of VPF action or expression, and if dexamethasone effects in this setting are mediated by the glucocorticoid receptor (GR). In two rat models of permeability (peripheral vascular permeability induced by intradermal injection of 9L glioma cell-conditioned medium or purified VPF, and intracerebral vascular permeability induced by implanted 9L glioma), dexamethasone suppressed permeability in a dose-dependent manner. Since 80% of the permeability-inducing activity in 9L-conditioned medium was removed by anti-VPF antibodies, we examined dexamethasone effects of VPF expression in 9L cells. Dexamethasone inhibited FCS-and PDGF-dependent induction of VPF expression. At all levels (intradermal, intracranial, and cell culture), dexamethasone effects were reversed by the GR antagonist mifepristone (RU486). Dexamethasone may decrease brain tumor-associated vascular permeability by two GR-dependent mechanisms: reduction of the response of the vasculature to tumor-derived permeability factors (including VPF), and reduction of VPF expression by tumor cells. ( J. Clin. Invest . 1996. 98:1400-1408.)

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Section: Resultssupporting

confidence: 92%

Mechanism of dexamethasone suppression of brain tumor-associated vascular permeability in rats. Involvement of the glucocorticoid receptor and vascular permeability factor.

Heiss¹,

Papavassiliou²,

Merrill³

et al. 1996

J. Clin. Invest.

240

139

View full text Add to dashboard Cite

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“…Seven hours later, the rats were sacrificed by CCL inhalation and the content of the inflammatory pouch was evacuated by aspiration. This time point was selected because previous time-course studies have demonstrated that peak inflammatory activity is observed at that time [12]. The effect of dif ferent treatments was assessed by measuring the volume of the inflammatory exudate and by determining the number of leukocytes per mm3 of the exudate[l 1].…”

Section: Introductionmentioning

confidence: 99%

Increased Arginine Vasopressin Secretion May Participate in the Enhanced Susceptibility of Lewis Rats to Inflammatory Disease

et al. 1993

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Lewis (LEW/N) and Fischer (F344/N) rats are histocompatible inbred strains characterized respectively by susceptibility and resistance to inflammatory disease. LEW/N rats have deficient corticotropin-releasing hormone (CRH), ACTH and corticosterone responses to inflammation, and increased circulating and hypothalamic concentrations of arginine vasopressin (AVP). CRH is produced locally at inflammatory sites, where it acts as a proinflammatory agent, while AVP has been reported to exert immunopotentiating effects in vivo and in vitro. In order to further investigate the mechanism of increased AVP secretion in LEW/N rats, we measured AVP and CRH mRNA in several hypothalamic nuclei in LEW/N and F344/N rats, using in situ hybridization histochemistry. LEW/N rats had increased AVP mRNA concentrations in the supraoptic (SON) and paraventricular (PVN), but not in the suprachiasmatic (SCN) nuclei. CRH mRNA, on the other hand, was decreased in the PVN of LEW/N rats. To examine the potential role of AVP and CRH in the exaggerated inflammatory responses of LEW/N rats, we pretreated young female Lewis and Fischer rats with AVP- and/or CRH-neutralizing rabbit antisera and elicited subsequently an inflammatory response by a nuchal subcutaneous injection of carrageenin. We demonstrated that both antisera decreased significantly the leukocyte concentration in the inflammatory exudate in LEW/N rats, but found no synergistic or additive effects between them. We conclude that previously observed differences in hypothalamic AVP and CRH contents between LEW/N and F344/N rats correspond to differences in the steady state mRNA levels of the two neuropeptides and that both AVP and CRH participate in the excessive inflammatory response of Lewis rats as locally active proinflammatory agents.

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“…Indeed, it has been shown that androgen replacement in male patients with RA and low serum testosterone levels is able to improve the clinical features of the disease (3). There is considerable evidence that the hypothalamic±pituitary±adrenal (HPA) axis contributes to the inhibition of in¯ammation and that adrenalectomy and glucocorticoid antagonists exacerbate in¯ammation in animal models (4,5). It is well known that hypothalamic and pituitary factors such as corticotropin-releasing hormone (CRH), arginine vasopressin (AVP) and adrenocorticotropin (ACTH) are involved in the regulation of the HPA axis.…”

Section: Introductionmentioning

confidence: 99%

Desmopressin and low-dose ACTH test in rheumatoid arthritis

Foppiani

Cutolo²,

Sessarego³

et al. 1998

European Journal of Endocrinology

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Objective: To ascertain whether a different regulation and sensitivity of the hypothalamic±pituitary± adrenal axis exists and whether a type of cortisol resistance is present in rheumatoid arthritis (RA) patients, a chronic disease in whose pathogenesis modi®cations of the steroid milieu are involved. Design: We studied the basal and dynamic response of ACTH and adrenal steroids to various stimuli acting on the hypophysis or directly on the adrenal gland. Methods: We studied ten RA patients (39.8 6 7.4 (S.D.) years), de®ned according to the American Rheumatism Association, and seven healthy control patients (34.1 6 9.6 (S.D.) years). All subjects underwent testing, in random order, with placebo, desmopressin (DDAVP) (10 mg i.v.), ovine corticotropin-releasing hormone (oCRH) (1 mg/kg body weight) and low-dose ACTH (5 mg i.v.), during the follicular phase of two different menstrual cycles. Blood samples were collected at different times for ACTH and adrenal steroids assay. Baseline estradiol (E2), testosterone and IGF-I levels were also evaluated. All subjects collected urine specimens for 24 h urine free cortisol (UFC). Results: No difference in E2, testosterone or UFC was found between RA patients and controls. IGF-I levels were signi®cantly (P < 0.01) lower in RA patients (110.6 6 6.4 mg/l) than in controls (207.0 6 37.9 mg/l). Mean baseline dehydroepiandrosterone (DHEA) and D4-androstenedione levels of the four tests were signi®cantly (P < 0.05) lower in RA patients than in controls. In RA, a negative correlation was found between mean DHEA levels, class of disease (r À 0.67, P < 0.05) and erythrocyte sedimentation rate (r À 0.63, P < 0.05). After placebo no difference in ACTH and cortisol area under curves (AUCs) was found between RA patients and controls. After DDAVP no cortisol or ACTH response was found in RA patients, while a signi®cant (P < 0.05) ACTH release was found in controls. Only in RA patients was DDAVP able to induce a signi®cant (P < 0.01) DHEA increase. After oCRH a similar signi®cant response in ACTH (P < 0.05), cortisol (P < 0.01), and DHEA (P < 0.01) was found in both groups. After low-dose ACTH, a similar signi®cant (P < 0.01) cortisol response was found in both RA patients and controls; indeed in RA patients DHEA AUC (2196.0 6 321.8 nmol/l per 90 min) was signi®cantly lower (P < 0.01) than DHEA AUC (4280.8 6 749.0 nmol/l per 90 min) in controls. A similar signi®cant (P < 0.01), though not abnormal, 17-hydroxyprogesterone response to ACTH was found in both groups. Conclusions: Our study underlines reduced adrenal steroid and IGF-I levels, but not the previously described cortisol resistance in RA patients; it shows that baseline and dynamic cortisol levels arè normal' but inadequate in the setting of a sustained in¯ammatory disease like RA. The reduced basal and low-dose ACTH-induced DHEA levels could re¯ect both a reduced sensitivity of the adrenal gland to exogenous corticotropin and a decreased steroid synthesis due to a partial adrenal enzymatic defect (P450 17,20 lyase). Europ...

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Receptor-mediated effects of glucocorticoids on inflammation: Enhancement of the inflammatory response with a glucocorticoid antagonist

Cited by 72 publications

References 46 publications

Mechanism of dexamethasone suppression of brain tumor-associated vascular permeability in rats. Involvement of the glucocorticoid receptor and vascular permeability factor.

Mechanism of dexamethasone suppression of brain tumor-associated vascular permeability in rats. Involvement of the glucocorticoid receptor and vascular permeability factor.

Increased Arginine Vasopressin Secretion May Participate in the Enhanced Susceptibility of Lewis Rats to Inflammatory Disease

Desmopressin and low-dose ACTH test in rheumatoid arthritis

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