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Biomedical subjects

L Parente

Publications and source records attributed to L Parente.

At least 37 records · Page 2Linked to original sources
PubMed1995

Interleukin-1 receptor antagonist displays intrinsic agonist activity on rat gastric fundus motility in vitro.

It has been shown previously that both forms of interleukin-1, 1 alpha and 1 beta, produce dose-dependent relaxation of the rat gastric fundus in vitro, accompanied by an increased production and release of eicosanoids. This effect appears to be mediated, at least in part, by leukotrienes, since the inhibition of 5-lipoxygenase by specific drugs counteracts interleukin-1-induced gastric relaxation. In the present study, we attempted to antagonize interleukin-1-induced inhibition of gastric fundus motility with a interleukin-1 receptor antagonist. Surprisingly, the interleukin-1 receptor antagonist itself possessed interleukin-1-like agonist activity, since: (a) it produced rapid, dose-dependent relaxation of the rat gastric fundus, with an estimated EC50 of 70 pg/ml and a maximal effect at 10 ng/ml; (b) interleukin-1 receptor antagonist-induced relaxation was dose dependently inhibited by N-(3-phenoxycinnamyl)acetohydroxamic acid (BW A4c), a specific inhibitor of 5-lipoxygenase; (c) in the first 5 min after its addition to the bath solution, interleukin-1 receptor antagonist produced a significant increase in prostaglandin E2 release from the gastric strips. This evidence suggests that, shortly after receptor occupancy, in this experimental model interleukin-1 and interleukin-1 receptor antagonist share the same pattern of mechanical and biochemical activities.

Analysis of Variance↗
PubMed1995

Evidence that the interleukin-1 beta-induced prostaglandin E2 release from rat hypothalamus is mediated by type I and type II interleukin-1 receptors.

Interleukin-1 beta (IL-1 beta) has been shown to specifically increase the release of prostaglandin (PG) E2 from rat hypothalamic explants in short-term experiments. In this study we attempted to characterize the receptor subtype(s) involved in this response. Rat hypothalamic explants were incubated with mouse monoclonal antibodies (mAbs) raised against human IL-1 type I or type II receptors, IL-1 receptor antagonist (IL-1ra) and alpha-melanocyte-stimulating hormone (alpha-MSH) (which appears to antagonize certain IL-1 induced inflammatory effects in vivo), alone and in the presence of IL-1 beta. PGE2 released into the incubation medium was measured by radioimmunoassay. The anti-type I mAb reduced both basal and IL-1 beta-stimulated PGE2 release at 10 micrograms/ml, but not at lower concentrations. The anti-type II mAb also produced a significant decrease in stimulated release but had no effect on basal release. IL-1ra mimicked the effects of the anti-type I mAb, while alpha-MSH failed to alter either basal or stimulated PGE2 release. These findings suggest that IL-1 beta controls production and release of PGE2 by the rat hypothalamus via both type I and type II receptors, although the latter appear to be involved only in the response to high levels of IL-1.

Animals↗
PubMed1995

Gastric antisecretory and anti-ulcer actions of IL-1 in rat involve different IL-1 receptor types.

Limited knowledge exists concerning the interleukin-1 (IL-1) receptor type (IL-1RT) mediating the potent antisecretory and gastro-protective actions of IL-1. In the present study, the gastric actions of IL-1 beta and two related mutant proteins, yIL-1 beta delta 4, an analogue that preferentially binds to IL-1-RTII, and mutant yIL-1 beta N7/Q, an analogue that has equal affinity as IL-1 beta for IL-1RTI and IL-1RTII, have been compared. Modulation of IL-1 gastric actions were also investigated using monoclonal antibody (MAb) preparations raised against IL-1RTI or IL-1RTII. In the pylorus-ligated rat, yIL-1 beta delta 4, yIL-1 beta N7/Q, and IL-1 beta (all at 1 microgram/kg ip) reduced gastric acid secretion (50, 79, and 78%, respectively), indicating the importance of IL-1RTII binding for antisecretory activity. This was further substantiated in experiments using the MAb preparations, which showed that IL-1 beta (1 microgram/kg ip) antisecretory activity was reversed by MAb IL-1RTII (10-50 micrograms/kg sc) but not by MAb IL-1RTI (50 micrograms/kg sc). In contrast, at dosages 10-fold higher (10 micrograms/kg ip) than that used in the study to inhibit acid secretion, IL-1 beta and yIL-1N7/Q equally reduced (approximately 80%) indomethacin-induced gastric damage, but yIL-1 beta delta 4 was ineffective. The results using yIL-1 beta delta 4 indicated that impairment of IL-1RTI binding capacity appeared to be paralleled by a decreased gastroprotective effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Evidence that interleukin-1 beta and tumor necrosis factor inhibit gastric fundus motility via the 5-lipoxygenase pathway.

In this study, we compared the effects of interleukin-1 beta and tumor necrosis factor (TNF) on in vitro rat gastric fundus motility. Interleukin-1 beta produced rapid, concentration-dependent relaxation of rat gastric fundus strips, similar to that seen with TNF, with a maximal effect at 30 U/ml and an estimated EC50 at 0.9 U/ml. The relaxant effects of interleukin-1 beta and TNF were not influenced by the inhibition of cyclooxygenase or nitric oxide-synthase activities. Interleukin-1 beta- and TNF-induced gastric relaxations were concentration dependently inhibited by BW 755c, which inhibits both cyclooxygenase and lipoxygenase, BW A4, which selectively inhibits the 5-lipoxygenase pathway, and SC 41930, a selective leukotriene B4 receptor antagonist, providing pharmacological evidence that leukotriene B4 is involved in the relaxant effects of both cytokines. The interleukin-1 beta- and TNF-induced activation of 5-lipoxygenase pathway did not appear to be triggered by phospholipase A2. An alternative pathway could involve the following steps: (i) activation of phospholipase C and the formation of diacylglycerol; (ii) diacylglycerol-induced activation of protein kinase C; (iii) formation of free arachidonic acid from diacylglycerol by diacylglycerol-lipase. This mechanism is suggested by the finding that leukotriene B4 is able to mimic cytokine-induced strip relaxation only in the presence of phorbol 12-myristate 13-acetate, which selectively activates protein kinase C.

Animals↗
PubMed1994

Effect of steroids on brain lipocortin immunoreactivity.

LCT-1, LCT-2 and LCT-5 were assessed in uninjured rats and rats subjected to a cortical freezing injury or middle cerebral artery (MCA) occlusion. Apart from animals receiving no treatment, other uninjured or injured animals received methylprednisolone (2 or 30 mg/kg) or the 21-aminosteroid U-74389F (10 mg/kg) one day and 2 hours before killing. The animals were killed by decapitation 1 hour after the freezing injury or the MCA occlusion and the area containing the lesion was removed and frozen in Freon. Frozen sections were treated with rabbit polyclonal anti-LCT antibody; binding of antibody was visualized by horseradish peroxidase-conjugated swine antirabbit antibody. Without steroid pretreatment, in the uninjured brain LCT immunoreactivity was absent in the greater part of the brain, except in sporadic microglia. In steroid-pretreated animals and in the freezing lesion of both pretreated and untreated animals there was extensive immunostaining; in the freezing lesion it may be due to passage of systemic LCT across the impaired blood-brain barrier in the lesion. The cellular elements showing immunostaining were meningeal cells, neurons, ependyma, choroid plexus, oligodendroglia and capillary endothelium. It implies that also in the brain the steroid effect is consistent with LCT formation.

Animals↗
PubMed1994

Interleukin-1 beta- and tumour-necrosis-factor-induced inhibition of rat gastric fundus motility in vitro.

In this study, we compared the effects of interleukin-1 beta (IL-1 beta) and tumour necrosis factor (TNF) on in vitro rat gastric fundus motility. IL-1 beta and TNF produced rapid, concentration-dependent relaxation of the rat gastric fundus strips with maximal effect at 300 pg ml-1 and 10 ng ml-1, and estimated EC50S at 10 and 450 pg ml-1, respectively. The relaxant effects of IL-1 beta and TNF were not influenced by the inhibition of cyclo-oxygenase or NO-synthase activities. IL-1 beta- and TNF-induced gastric relaxations were inhibited by BW 755c, which inhibits both cyclo-oxygenase and lipoxygenase (LO), BW A4c, which selectively inhibits the 5-LO pathway, and SC 41930, a selective leukotriene B4 (LTB4) receptor antagonist, providing pharmacological evidence that LTB4 is involved in the relaxant effects of both cytokines. The IL-1 beta- and TNF-induced activation of 5-LO pathway did not appear to be triggered by phospholipase A2. An alternative pathway could involve the activation of a phospholipase C, specific for phosphatidylcholine, from which, in sequence: the formation of diacylglycerol (DAG), DAG-induced activation of protein kinase C and the formation of free arachidonic acid from DAG would ensue. This mechanism is suggested by the finding that LTB4 is able to mimic cytokine-induced strip relaxation only in the presence of phorbol 12-myristate 13-acetate, which selectively activates protein kinase C.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1994

Dexamethasone-induced translocation of lipocortin (annexin) 1 to the cell membrane of U-937 cells.

Lipocortin (annexin) 1 is a putative mediator of the inflammatory effects of glucocorticoids. By flow cytometric analysis (FACS) we have studied the effect of dexamethasone on the cellular localization of lipocortin 1. U-937 cells were incubated with or without 10 nM phorbol 12-myristate 13-acetate (PMA) to induce cell differentiation. Then 1 microM dexamethasone was added and incubation carried out for increasing times (1-24 h). Dexamethasone caused a time-dependent biphasic translocation of lipocortin 1 from the intracellular compartment to the cell membrane with maximal membrane expression at 4 and 24 h. In differentiated U-937 cells the steroid-induced membrane accumulation of lipocortin 1 was significantly higher than that of undifferentiated cells. The accumulation of the protein in the cell membrane may precede its release which is stimulated by dexamethasone in differentiated U-937 cells. Since extracellular lipocortin 1 has anti-inflammatory properties the modulation of the translocation/secretion process of the protein by glucocorticoids may be part of their mechanism of action.

Annexin A1↗
PubMed1994

Increase of extracellular brain calcium involved in interleukin-1 beta-induced pyresis in the rabbit: antagonism by dexamethasone.

1. This study investigates the role of extracellular brain calcium in the hyperthermia induced by interleukin-1 beta (IL-1 beta). 2. Intracerebroventricular (i.c.v.) injection of IL-1 beta (12.5 ng kg-1) in rabbits caused a prompt and sustained rise in cerebrospinal fluid (CSF) Ca2+ concentration ([Ca2+]) followed by enhanced prostaglandin E2 (PGE2) release and hyperthermia. 3. A linear and significant correlation was observed between the increase in [Ca2+] induced by IL-1 beta and the rise in body temperature. 4. Ventriculo-cisternal perfusion with artificial CSF containing the calcium chelator EGTA (1.3 mM) blocked the IL-1-induced PGE2 release and countered the febrile response. 5. I.c.v. administration of dexamethasone (Dex) (2.4 and 24 micrograms kg-1) 100 min prior to IL-1 beta, dose-dependently antagonized the cytokine-induced Ca2+ increase, the PGE2 release and the febrile response. 6. These results suggest that changes in extracellular brain calcium are involved in the regulation of body temperature. In this light, the antipyretic action of Dex may be related to its effect on Ca2+ uptake.

Animals↗
PubMed1993

Pharmacology of interleukin-1-induced neutrophil migration.

Neutrophil (PMN) accumulation induced by interleukin-1 beta (IL-1 beta, 5-20 ng) into the mouse air pouch was inhibited in a dose-dependent manner (2-200 micrograms) by concomitant injection of IL-1 receptor antagonist (IL-1RA). Similarly, co-administration of the neuropeptide alpha-melanocyte-stimulating hormone (alpha-MSH) resulted in a reduction of the number of migrated PMN but only at the highest dose tested (200 micrograms). Although IL-1RA does not select between the two types of receptors so far described for IL-1, the effectiveness of alpha-MSH suggests that this property of the cytokine may occur through IL-1 type I receptor. This observation was confirmed by using a specific monoclonal antibody (mAb) raised against this receptor type, and which strongly inhibited (87%) IL-1-induced PMN recruitment.

Animals↗
PubMed1993

Macrophage-specific eicosanoid synthesis inhibition and lipocortin-1 induction by glucocorticoids.

It has been suggested that the induction of lipocortin-1, a phospholipase A2-inhibitory protein, may mediate the anti-inflammatory action of glucocorticoids. We assessed the production of prostaglandin E2, thromboxane B2, and leukotriene B4 and the expression of lipocortin-1 in different populations of blood leukocytes and in alveolar macrophages (obtained by bronchoalveolar lavage) from patients with inflammatory lung diseases (bronchial asthma, n = 21; interstitial lung disease, n = 6) undergoing glucocorticoid treatment at clinically effective doses. No inhibition of eicosanoid production was observed in either whole blood or single populations of blood leukocytes (granulocytes and monocytes) stimulated with ionophore A-23187, N-formyl-L-methionyl-L-leucyl-L-phenylalanine, or zymosan. Conversely, eicosanoid production from alveolar macrophages (assessed in 9 cases) was significantly inhibited by glucocorticoids. After ionophore stimulation, eicosanoid production was as follows (in ng/ml): prostaglandin E2, 0.19 +/- 0.06 and 0.06 +/- 0.01; thromboxane B2, 2.9 +/- 0.9 and 0.5 +/- 0.1; leukotriene B4, 6.6 +/- 1.1 and 3.6 +/- 1.0, before and after treatment, respectively (P < 0.05 for all differences). Lipocortin-1 expression, determined by Western blot and enzyme immunoassay, was significantly (P < 0.05) stimulated in alveolar macrophages, but not in blood leukocytes, by glucocorticoid treatment. These results indicate that alveolar macrophages, at variance from blood leukocytes, are the most likely cell target for glucocorticoid-induced eicosanoid inhibition and lipocortin expression. We suggest that cell responsiveness to glucocorticoids is acquired during differentiation from monocyte to tissue macrophage.

Adolescent↗
PubMed1993

Prostaglandin E2 and bacterial lipopolysaccharide stimulate bioactive interleukin-1 release from rat hypothalamic explants.

While interleukin-1 (IL-1) is intimately involved in locally modulating the acute inflammatory response, it is also able to influence processes at remote sites, i.e., in an endocrine manner. While there is as yet little evidence that IL-1 can cross the blood-brain barrier, many effects such as fever, increased slow-wave sleep, anorexia and the modulation of neuroendocrine function suggest an action of circulating IL-1 at regulatory sites within the hypothalamus. However, there is accumulating evidence for IL-1 originating within the central nervous system (CNS), and it is currently unclear as to whether the neurally mediated manifestations of the acute inflammatory response are due to activation of central or peripheral (circulating) IL-1. In this study we have characterized the release of IL-1 from rat hypothalamic explants, and we have investigated the effects of putative modulators of IL-1 release, lipopolysaccharide (LPS) and the prostaglandins E2 (PGE2) and F2 alpha (PGF2 alpha). After 1 h of incubation, IL-1-like activity in hypothalamic supernatants ranged between 175 and 2,304 munits/mg of protein; this was substantially inhibited by the addition to the bioassay system of antibodies (1:200) against IL-1 alpha, but not against IL-1 beta. LPS and PGE2 significantly stimulated IL-1 release at 100 and 1 ng/ml respectively, whereas PGF2 alpha had no effect in the range of doses tested. It is therefore concluded that the control of hypothalamic IL-1 release may be investigated by means of acute rat hypothalamic explants.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Studies on the induction of lipocortin-1 by glucocorticoids.

Part of the anti-inflammatory efficacy of glucocorticoids has been ascribed to the inhibition of eicosanoid formation which is brought about by lipocortins (LC, phospholipase A2 inhibitory proteins) whose synthesis is induced by corticosteroids. We have investigated the effect of glucocorticoids on eicosanoid formation and lipocortin-1 induction in a human cell line in vitro and in patients with inflammatory lung disease in vivo. Human promyelocitic U-937 cell line was differentiated by 24 h incubation with phorbol myristate acetate (PMA, 6 ng/ml), then dexamethasone (1 microM) was added for further 16 h. In these conditions the steroid treatment caused both the release of lipocortin-1 in the cellular supernatant and the inhibition of eicosanoid release. These results suggest that the responsiveness of these cells to steroids is dependent on the phase of cell activation-differentiation. The selective release of the lipocortin-1 may explain the inhibition of eicosanoid formation. Patients with inflammatory lung disease underwent glucocorticoid treatment at clinically effective doses. LC-1 expression was significantly stimulated in alveolar macrophages, but not in blood-derived lympho-monocytes. These results suggest that also in vivo cell responsiveness to glucocorticoids is acquired during cell differentiation from blood monocyte to tissue macrophage.

Annexin A1↗
PubMed1992

Evidence that endogenous interleukin-1 is involved in leukocyte migration in acute experimental inflammation in rats and mice.

As a putative mediator of inflammation interleukin-1 has been implicated in the recruitment of leukocytes during the early stages of the inflammatory reaction. In the present report we have investigated the release of endogenous IL-1 in the rat zymosan pleurisy and in the mouse zymosan peritonitis. In both cases the release of the cytokine was maximal 4 hours after zymosan injection and appeared to be time-related to neutrophil migration into the inflammatory site. The effect of in vivo treatment with dexamethasone in rat pleurisy and with polyclonal anti-murine IL-1 beta antibody in mouse peritonitis was also assessed. The steroid reduced both cell migration and the release of IL-1-like activity as well as the formation of exudate and the release of eicosanoids. The anti-IL-1 beta serum inhibited selectively the number of neutrophil that migrated to the inflamed site (approximately 40%) and the IL-1 activity recovered in (approximately 70%) the exudate. In vitro incubation of the inflammatory exudate with polyclonal anti-murine IL-1 alpha or anti-murine IL-1 beta sera allowed the identification of the IL-1 species present. In the rat pleurisy IL-1 biological activity was mainly due to the alpha species, whereas IL-1 beta was the only species apparently present in the mouse peritoneal exudate.

Animals↗
PubMed1992

Peptide 204-212 of lipocortin 5 inhibits the generation of a prostacyclin-like factor from rat aorta preparations in vitro.

The release of an endogenous prostacyclin-like factor (PLF) from rat thoracic aorta rings was evaluated through inhibition of platelet ADP-induced aggregation and assessed with a micro-method using 96-multiwell plates. Aggregation was assessed in an ELISA reader by measuring changes of optical density at 620 nm in each well. The generation of endogenous PLF by aortic rings was time-dependent and was inhibited by indomethacin (3 microM). ADP-induced aggregation was inhibited by iloprost in a dose-dependent manner. Incubation of rat aorta rings with peptide 204-212 of human lipocortin 5 (1-100 micrograms/ml) resulted in a dose-dependent inhibition of PLF release with a maximal inhibition of 90-95%. The effect of peptide 204-212 was reversible. A control peptide (amino-acids 104-112 of lipocortin 5) was without any significant effect. Peptide 204-212 (100 micrograms/ml) did not modify PLF release from rat aorta preparations challenged with arachidonic acid (10(-6)-10(-4) M).

Amino Acid Sequence↗