Interleukin-15 strongly inhibits interleukin-8 and monocyte chemoattractant protein-1 production in human colonic epithelial cells.
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Interleukin-15 (IL-15) is a novel cytokine with actions similar to IL-2 because of common receptor components. Although IL-15 is expressed in colonic epithelial cells and may regulate epithelial cell function, its effects on these cells are not fully defined. We explored the regulatory effects of IL-15 on IL-8 and monocyte-chemoattractant protein-1 (MCP-1) production in the colonic epithelial cell line Caco-2 as well as in freshly isolated human colonic epithelial cells. IL-15 was added to intestinal epithelial cells under various culture conditions. Levels of chemokines were determined by enzyme-linked immunosorbent assay. To determine the elements of the IL-2/IL-15R complex involved we used neutralizing antibodies specific for individual receptor chains. IL-15 down-regulates IL-8 and MCP-1 production in Caco-2 cells as well as in freshly isolated human colonic epithelial cells in a dose-dependent manner. Intestinal epithelial cells became more responsive to IL-15-induced suppression when activated with greater IL-1 doses. Strong chemokine suppression was seen when IL-15 was given prior to, simultaneous with, or after stimulatory agent. Anti-IL-2Rgamma antibodies efficiently blocked (82% inhibition) the suppression induced by IL-15, while anti-IL-2Rbeta antibodies were less effective. The involvement of beta-chain was further suggested by the finding that a mixture of both monoclonal antibodies (mAb) at a suboptimal concentration (1 microgram/ml of each mAb) produced a synergistic inhibitory effect on down-regulation of epithelial chemokine production. These results show that IL-15 can suppress IL-8 and MCP-1 secretion by intestinal epithelial cells. A microenvironment containing high concentrations of IL-15 may alter the recruitment of neutrophils to enterocytes at least partly by inhibiting IL-8 and MCP-1 production. (+info)
Propofol-induced depression of cultured rat ventricular myocytes is related to the M2-acetylcholine receptor-NO-cGMP signaling pathway.
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BACKGROUND: It is well-known that propofol sometimes causes bradycardia or asystole during anesthesia; however, the direct effect of propofol on the myocardium remains unclear. Previous reports showed the contribution of muscarinic acetylcholine receptors to propofol-induced bradycardia. Conversely, it was suggested recently that nitric oxide (NO) plays an important role in mediating the effect of vagal stimulation in the autonomic regulation of the heart. Therefore, the authors investigated the effects of propofol on spontaneous contraction and NO production in cultured rat ventricular myocytes. METHODS: The authors measured chronotropic responses of cultured rat ventricular myocytes induced by propofol stimulation with a sensor, a fiber-optic displacement measurement instrument. The authors also quantitatively analyzed NO metabolite production in cultured myocytes by measuring the levels of nitrite and nitrate in a high-performance liquid chromatography reaction system. The influence of propofol on muscarinic acetylcholine receptors of myocyte membranes was also measured with a competitive binding assay using [3H]quinuclidinyl benzilate ([3H]QNB). RESULTS: Propofol caused negative chronotropy in a dose-dependent manner. Propofol (IC50) also caused the enhancement of nitrite production in cultured myocytes. Eighty percent of the enhancement of nitrite production induced by propofol (IC50) stimulation was abolished by pretreatment with atropine, methoctramine, or N(G)-monomethyl-L-arginine acetate (L-NMMA). The negative chronotropy induced by propofol (IC50) stimulation was reduced to 40-50% by pretreatment with atropine, methoctramine, L-NMMA, or 1H[1,2,4]oxadiazolo[4,3-alpha]quanoxalin-1-one, a selective inhibitor of guanylyl cyclase. Propofol displaced [3H]QNB binding to the cell membrane of myocytes in a concentration-dependent manner. CONCLUSION: These results suggest that the negative chronotropy induced by propofol is mediated in part by M2-acetylcholine receptor activation, which involves the enhancement of NO production in cultured rat ventricular myocytes. (+info)
Antagonistic effects of phentolamine and octopamine on rhythmic motor output of crayfish thoracic ganglia.
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Spontaneous rhythmic motor output of crayfish thoracic ganglia consists of bursts of activity in antagonistic leg motor neurons (MNs), alternating with a rather slow cycle period (typically > or = 20 s). The most common pattern (77% of preparations) consists of long coxal promotor bursts, the duration of which was correlated strongly with cycle period, and relatively short remotor bursts independent of cycle period. Octopamine, at a concentration of 2-30 microM reversibly retarded this rhythm, increasing both cycle period and promotor burst duration. Higher concentrations of octopamine inhibited promotor nerve activity and abolished rhythmic bursting. Phentolamine (10-50 microM) had the opposite effect of decreasing cycle period, mainly by decreasing promotor burst duration. Whereas in the presence of octopamine promotor bursts were lengthened and became even more strongly related to cycle period, phentolamine promoted a more symmetrical rhythm with shorter promotor bursts that were less dependent on cycle period. When octopamine was applied in the presence of phentolamine, there was no significant increase in cycle period or burst duration, although high octopamine concentrations (100 microM) were still capable of inhibiting promotor nerve activity. To our knowledge, pharmacological modulation of a spontaneous locomotor rhythm by an amine antagonist (applied by itself) has not been reported previously. The results raise the testable possibility that phentolamine exerts its modulatory effects by acting as an octopamine antagonist in crayfish thoracic ganglia. (+info)
Induction of NMDA receptor-dependent long-term depression in visual cortex does not require metabotropic glutamate receptors.
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We tested the role of group I mGluRs in the induction of long-term depression (LTD) in the visual cortex, using the novel mGluR antagonist LY341495 and mice lacking mGluR5, the predominant phosphoinositide (PI)-linked mGluR in the visual cortex. We find that LY341495 is a potent blocker of glutamate-stimulated PI hydrolysis in visual cortical synaptoneurosomes, and that it effectively antagonizes the actions of the mGluR agonist 1S, 3R-aminocyclopentane-1,3-dicarboxylic acid (ACPD) on synaptic transmission in visual cortical slices. However, LY341495 has no effect on the induction of LTD by low-frequency stimulation. Furthermore, mice lacking mGluR5 show normal NMDA receptor-dependent LTD. These results indicate that group I mGluR activation is not required for the induction of NMDA receptor-dependent LTD in the visual cortex. (+info)
Corticotropin-releasing hormone receptors mediate consensus interferon-alpha YM643-induced depression-like behavior in mice.
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Depression-like behavior induced by YM643, a consensus interferon-alpha (IFN-alpha), was evaluated with the tail-suspension test in mice and compared with depression-like behavior induced by sumiferon, a natural IFN-alpha. To investigate the mechanism of IFN-alpha-induced depression-like behavior, the effects of the tricyclic antidepressant imipramine, the cyclooxygenase inhibitor indomethacin, the opioid receptor antagonist naloxone, and the selective corticotropin-releasing hormone receptor antagonist CP-154, 526 on IFN-alpha-induced depression-like behavior were evaluated. Intravenously injected YM643 (2 x 10(8)-2 x 10(9) U/kg) and sumiferon (2 x 10(6)-2 x 10(7) I.U./kg) dose-dependently increased immobility time. Repeated s.c. injection of either YM643 (6 x 10(6)-6 x 10(8) U/kg) or sumiferon (6 x 10(4)-6 x 10(6) I.U./kg) for 7 days also dose-dependently increased immobility time. After i.c.v. injection of either YM643 (2 x 10(6) U/mouse) or sumiferon (6 x 10(4) I.U./mouse), significant prolongation of immobility time also was observed. Pretreatment with imipramine (30 mg/kg s.c.) significantly reduced the YM643- or sumiferon-induced increases in immobility time. CP-154,526 (0.3-3 mg/kg s.c.) dose-dependently reduced YM643- or sumiferon-induced increases in immobility time with ID(50) values of 0.6 mg/kg against YM643 and 1.3 mg/kg against sumiferon. However, neither indomethacin (10 mg/kg s.c.) nor naloxone (3 mg/kg s.c.) had any effect on YM643- or sumiferon-induced increases in immobility time. These results suggest that IFN-alpha centrally induces depression-like behavior in mice that can be alleviated with imipramine. The results also suggest that activation of corticotropin-releasing hormone receptors is involved in IFN-alpha-induced depression-like behavior, but the prostaglandin and opioid systems do not participate in this process. (+info)
Inhibition of initiation of protein synthesis by 7-methylguanosine-5'-monophosphate.
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Translation of rabbit globin mRNA in a wheat germ protein-synthesizing system is inhibited by the nucleotide 7-methylguanosine-5'-monophosphate (m7G5'p) but not by other guanosine nucleotides without the 7-methyl group or with the phosphate in a different position. Translation of RNA of tobacco mosaic virus and poly(A) + HeLa RNA is also inhibited by m7G5'p. We show that m7G5'p prevents the association of mRNA with ribosomal subunits to form an initiation complex. We propose that m7G5'p interacts with a site on initiation factor(s) or ribosomes which is involved in mRNA recognition, presumably by binding to the 5'-terminal sequence m7G5'ppp. m7G5'p does not inhibit translation of poly(U) and RNA of satellite tobacco necrosis virus, which do not have the 5'-terminal sequence m7G5'ppp. In the case of RNA of satellite tobacco necrosis virus, some stimulation of its translation is consistently observed in the presence of m7G5'p; possible interpretations of this finding are discussed. (+info)
Reconstitution of D-glucose transport catalyzed by a protein fraction from human erythrocytes in sonicated liposomes.
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A protein fraction was obtained from human erythrocyte ghosts by solubilization with Triton X-100 or octylglucoside. Triton X-100 was removed from the protein by Bio-Beads SM-2 and octylglucoside, by diafiltration. The solubilized protein fraction catalyzed D-glucose uptake when reconstituted in sonicated liposomes. The uptake was time dependent and inhibited by mercuric ions or cytochalasin B. The results indicate that the uptake represents transport of the sugar into the liposomes rather than binding to the reconstituted liposomes. (+info)
Effects of subanaesthetic sevoflurane on ventilation. 1: Response to acute and sustained hypercapnia in humans.
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We have determined the influence of 0.1 minimum alveolar concentration (MAC) of sevoflurane on ventilation, the acute ventilatory response to a step change in end-tidal carbon dioxide and the ventilatory response to sustained hypercapnia in 10 healthy adult volunteers. Subjects undertook a preliminary 10-min period of breathing air without sevoflurane to determine their normal ventilation and natural end-tidal PCO2. This 10-min period was repeated while breathing 0.1 MAC of sevoflurane. Subjects then undertook two procedures: end-tidal PO2 was maintained at 13.3 kPa and end-tidal PCO2 at 1.3 kPa above the subject's normal value for 30 min of data collection, first with and then without 0.1 MAC of sevoflurane. A dynamic end-tidal forcing system was used to generate these gas profiles. Sevoflurane did not significantly change ventilation: 10.1 (SEM 1.0) litre min-1 without sevoflurane, 9.6 (0.9) litre min-1 with sevoflurane. The response to acute hypercapnia was also unchanged: mean carbon dioxide response slopes were 20.2 (2.7) litre min-1 kPa-1 without sevoflurane and 18.8 (2.7) litre min-1 kPa-1 with sevoflurane. Sustained hypercapnia caused a significant gradual increase in ventilation and tidal volume over time and significant gradual reduction in inspiratory and expiratory times. Sevoflurane did not affect these trends during sustained hypercapnia. These results suggest that 0.1 MAC of sevoflurane does not significantly affect the acute ventilatory response to hypercapnia and does not modify the progressive changes in ventilation and pattern of breathing that occur with sustained hypercapnia. (+info)