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Biomedical subjects

D Rotondo

Publications and source records attributed to D Rotondo.

28 records · Page 2Linked to original sources
PubMed1992

The role of inositol lipids in the activation of monocytes by interleukin-1 and bacterial endotoxin.

The effect of interleukin-1 (IL-1) and bacterial endotoxin (lipopolysaccharide, LPS) on the activation of phosphoinositidase C (PIC) and on prostaglandin E2 release was studied in monocytes (M phi). Both IL-1 alpha and IL-1 beta increased the release of PGE2 in a concentration-dependent manner, with EC50s of 0.48 nM and 0.12 nM, respectively. Intact M phi were prelabelled with [3H]inositol and the formation of inositol phosphates (IPs) was estimated by ion exchange chromatography. PIC activity was estimated directly by measuring the conversion of [3H]phosphatidylinositol-4,5-bisphosphate to aqueous soluble radioactivity by M phi homogenates. IL-1 alpha (5.8 nM) increased the accumulation of IPs within 1-4 minutes and increases in IP3 and IP4 occurred before the increase in IP1+2 whereas LPS only increased the IPs level after at least 30 min. IL-1 alpha increased PIC activity in M phi homogenates within 15 min with an EC50 of 0.58 nM and IL-1 beta (0.1 nM) also increased activity. Neither IL-1 alpha nor IL-1 beta affected the PIC activity of membrane or cytosolic fractions. LPS decreased activity in all fractions. These data indicate that IL-1, but not LPS, can directly lead to an increased activity of PIC which may be involved in eicosanoid formation in M phi.

Animals↗
PubMed1992

Alpha-melanocyte-stimulating hormone suppresses fever and increases in plasma levels of prostaglandin E2 in the rabbit.

1. The effect of alpha-melanocyte-stimulating hormone (alpha-MSH) on changes in body temperature and plasma levels of prostaglandin E2 (PGE2) were measured in the rabbit following intravenous injection of bacterial lipopolysaccharide (LPS), rabbit endogenous pyrogen (EP), human recombinant tumour necrosis factor-alpha (TNF-alpha), human recombinant interleukin-1 beta (IL-1 beta) and intracerebroventricular injection of PGE2. 2. LPS (25 ng kg-1), EP (25 microliters kg-1), TNF-alpha (11 micrograms kg-1) and IL-1 beta (5 ng kg-1) produced increases in body temperature simultaneously with increases in plasma PGE2 levels. alpha-MSH (5 or 10 micrograms kg-1) attenuated both the increase in body temperature and increases in plasma levels of PGE2. 3. Intracerebroventricular injection of PGE2 (500 ng) produced a monophasic increase in body temperature. alpha-MSH (5 micrograms kg-1) administered 20 min after PGE2 had no effect on the hyperthermic response. 4. alpha-MSH (10 micrograms kg-1) had no effect on either body temperature or plasma levels of PGE2 in response to I.V. injection of sterile saline. 5. These data demonstrate that alpha-MSH inhibits both the pyrogenic actions of LPS, EP, TNF-alpha and IL-1 beta and their ability to increase PGE2 release without affecting the direct actions of PGE2, suggesting the possibility that alpha-MSH may prevent the synthesis of PGE2 either by preventing the actions or release of mediators such as TNF-alpha and IL-1 in response to LPS.

Animals↗
PubMed1991

Antipyretic actions of human recombinant lipocortin-1.

The effect of human recombinant lipocortin-1 (hrLC-1) on the pyrogenic actions of the synthetic polyribonucleotide polyinosinic:polycytidylic acid (poly I:C) has been studied in conscious rabbits. Poly I:C (2.5 micrograms kg-1) given i.v. produced a biphasic fever with a first peak after 90-105 min and a second peak between 225-240 min. hrLC-1 (50 micrograms kg-1) given i.v. simultaneously with the poly I:C produced a significant reduction in the febrile response but without complete suppression. The thermal response index over 5 h (TRI5) was 4.69 +/- 0.51 for poly I:C given with saline and the TRI5 for poly I:C given with hrLC-1 was 2.66 +/- 0.45 (values are for n = 5 +/- s.e. mean, P less than 0.05). hrLC-1 administered alone had no effect on body temperature and its antipyretic activity was lost on heating. In a separate series of experiments 1 h pretreatment with dexamethasone (1 mg kg-1) given i.v. reduced the pyrogenic response (TRI5) to poly I:C (2.5 micrograms kg-1) from 4.87 +/- 0.54 without dexamethasone to 2.00 +/- 0.25 (n = 5, P less than 0.05) and dexamethasone given alone had no effect on body temperature. These data demonstrate that LC-1 possesses antipyretic actions and raises the possibility that the antipyretic actions of dexamethasone are mediated through the induction of LC-1.

Animals↗
PubMed1990

A study of the pyrogenic actions of interleukin-1 alpha and interleukin-1 beta: interactions with a steroidal and a non-steroidal anti-inflammatory agent.

1. The pyrogenic effects of intravenously administered human recombinant interleukin-1 alpha (IL-1 alpha) and IL-1 beta were studied in the rabbit. 2. Both cytokines produced dose-related increases in body temperature. At all doses studied (100-5000 u kg-1) both cytokines elicited a monophasic increase in body temperature, beginning 15 min and reaching a maximum 45 min after administration. 3. A comparison of thermal response index (TRI2, the magnitude of febrile responses over 2 h obtained by integrating the change in temperature in degrees C against time in hours) values indicated that IL-1 beta (500 u kg-1, TRI2 = 0.69 +/- 0.04, n = 4) was approximately 5 fold more potent than IL-1 alpha (2500 u kg-1, TRI2 = 0.73 +/- 0.07, n = 4, all values are means +/- s.e.means) in elevating body temperature. delta Tmax values for the above doses of IL-1 beta and IL-1 alpha were 0.60 +/- 0.06 and 0.61 +/- 0.03 respectively. When IL-1 alpha and IL-1 beta were heated for 30 min at 60 degrees C prior to administration no biological activity was observed. 4. A cyclo-oxygenase inhibitor, ketoprofen (3 mg kg-1) administered 15 min before either cytokine completely abolished the fever induced by both IL-1 alpha (2500 u kg-1) and IL-1 beta (500 u kg-1). 5. Intravenous administration of the steroidal anti-inflammatory agent dexamethasone (3 mg kg-1) 1 h before either cytokine attenuated the fever induced by IL-1 alpha (2500 u kg-1) and IL-1 beta (500 u kg-1). 6. The effects of ketoprofen and dexamethasone on IL-I pyrogenicity indicate that prostanoids are almost certainly involved in the responses. The different potencies of IL-l alpha and IL-1 beta may be related to their relative ability to stimulate prostanoid biosynthesis.

Animals↗
PubMed1989

Lipopolysaccharide, muramyl dipeptide and polyinosinic: polycytidylic acid induce the accumulation of inositol phosphates in blood monocytes and lymphocytes.

Rabbit macrophages (Mø) and lymphocytes (Ly) incubated with three structurally dissimilar immunomodulators, lipopolysaccharide (bacterial endotoxin, LPS), polyinosinic: polycytidylic acid (poly-I:C) and muramyl dipeptide (MDP), were found to accumulate inositol phosphates (IPs) in a concentration- and time-dependent manner. The threshold concentration of LPS necessary for an increase in IPs in both cell types was less than 1 ng/ml and a maximum effect was observed between 1 and 10 micrograms/ml. The threshold concentrations for poly-I:C and MDP were between 0.1 and 1 microgram/ml for both cell types. Significant increases in the concentration of inositol phosphates occurred between 30 and 60 min after challenge of either cell type with any of the three agents studied. In addition, all three immunomodulators produced a greater accumulation of IPs in macrophages than in mixed lymphocytes and after 2 h appeared to approach a maximum in macrophages, whereas the IPs level in lymphocytes appeared to be still rising after 2 h. In Mø and Ly the IPs level was increased within 10 min of incubation in the presence of either PGE2 or medium previously obtained from cells incubated with LPS. In addition, anisomycin (a protein synthesis inhibitor) and ketoprofen (a cyclo-oxygenase inhibitor) inhibited the LPS-stimulated increase of IPs accumulation in both cell types. These two observations suggest that the LPS-stimulated increase in IPs in macrophages and lymphocytes is mediated by a protein intermediate and possibly a prostanoid.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1988

Pyrogenic immunomodulators increase the level of prostaglandin E2 in the blood simultaneously with the onset of fever.

Blood prostaglandin E2 (PGE2) levels, estimated by radioimmunoassay, and body temperatures of conscious rabbits were measured simultaneously during fever in response to polyinosinic: polycytidylic acid, lipopolysaccharide and interleukin 1/endogenous pyrogen. The effects of the antipyretic agent ketoprofen on both parameters was also studied. Significant rises (in the order of 6- to 8-fold) in the PGE2 level were observed after injection of either of the three pyrogens and occurred simultaneously with the rise in temperature. Ketoprofen given after the onset of fever in response to the pyrogens produced an immediate defervescence and a simultaneous decrease in plasma PGE2. Ketoprofen given before the pyrogens prevented any rise in either body temperature or plasma PGE2 level. When animals were subjected to an environmental temperature of 34 degrees C a hyperthermia was observed without any change in the blood PGE2 level. These results suggest that an increase in the blood PGE2 level may contribute to the pathogenesis of fever.

Animals↗
PubMed1988

A study of cyclic AMP-dependent protein phosphorylation in Schistocerca gregaria CNS: a comparison to that in mammalian CNS.

1. The effect of cyclic AMP (10 microM) on the incorporation of 32P into protein was studied in cell-free preparations of Schistocerca gregaria cerebral ganglia. 2. Cyclic AMP-dependent phosphorylation of total protein was maximal after 60 sec, had a pH optimum of 7 to 8, was not affected by temperature (22-37 degrees C) and had a Km of 77 microM ATP. 3. Cyclic AMP increased the phosphorylation of total and specific protein in soluble fractions greater than synaptosomal greater than microsomal greater than crude membrane fractions. 4. In a direct comparison of locust brain to rat cerebral cortex, cyclic AMP stimulated the increased phosphorylation of only three protein bands, whereas in identical fractions of locust brain the phosphorylation of at least 12 protein bands was observed.

Animals↗
PubMed1987

The pyrogenic actions of the interferon-inducer, polyinosinic:polycytidylic acid are antagonised by ketoprofen.

The effect of various doses of polyinosinic:polycytidilic acid (Poly I:C) in the range (0.25-250 micrograms/kg) administered i.v. on the body temperature of rabbits was investigated. The effect of ketoprofen on the febrile responses was also studied. The threshold dose of Poly I:C administered which produced a fever was between 0.25 and 0.5 micrograms/kg and a double-sigmoidal dose-response relationship was observed. A sigmoidal relationship was obtained with lower doses from 0.25 micrograms/kg to an apparent maximum with 2.5 micrograms/kg and another with higher doses from 5 micrograms/kg to another apparent maximum with 250 micrograms/kg. Ketoprofen (3 mg/kg) given s.c. 15 min prior to Poly I:C inhibited the production of fever. Ketoprofen administered after the onset of fever resulted in an immediate deffervescence. These results suggest that febrile responses to Poly I:C involve prostaglandin biosynthesis.

Animals↗
PubMed1987

Dexamethasone pre-treatment is antipyretic toward polyinosinic: polycytidylic acid, lipopolysaccharide and interleukin 1/endogenous pyrogen.

The effect of intravenously injected dexamethasone on the febrile response of rabbits to Polyinosinic: Polycytidylic acid (Poly I:C), lipopolysaccharide (LPS) and interleukin 1/endogenous pyrogen (IL1/E.P.) was studied. Dexamethasone (1 mg/kg) attenuated the febrile response to Poly I:C (5 micrograms/kg) but only if administered between 0.5 to 2 h before Poly I:C. If it was given after Poly I:C this resulted in a potentiation of the fever. Antagonism of the febrile response to Poly I:C by dexamethasone pre-treatment was dose-dependent and a maximal effect was observed with 3 mg/kg, a higher dose (6 mg/kg) resulted in a lesser effect on the Poly I:C fever. DEX injected alone (0.5-6 mg/kg) did not have any effect on body temperature. Fevers in response to LPS (50 ng/kg) and IL1/E.P. were also attenuated by dexamethasone. It is concluded that Poly I:C, LPS and IL1/E.P. induce fever by a common mechanism which is either directly or indirectly inhibited by dexamethasone.

Animals↗