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R Minakuchi

Publications and source records attributed to R Minakuchi.

12 recordsLinked to original sources
PubMed1991

Characterization of the 3',5'-cyclic adenosine monophosphate-mediated regulation of IL2 production by T cells and Jurkat cells.

The effect of cyclic AMP-elevating agents on mitogen-stimulated IL2 production was examined. Prostaglandin E2 (PGE2) inhibited IL2 production by human peripheral blood T cells stimulated with PHA. In contrast, PGE2 did not inhibit PHA-stimulated IL2 production by the human leukemic T cell line. Jurkat, and often slightly enhanced IL2 production by those cells. Other cyclic adenosine monophosphate (cAMP) elevating agents (forskolin, isoproterenol, and the cAMP analogue, dibutyryl cAMP) also inhibited lectin-stimulated IL2 production by T cells, but could not inhibit IL2 production by Jurkat cells. Of the cAMP-elevating agents examined, only cholera toxin (CT) inhibited IL2 production by both Jurkat cells and peripheral blood T cells. Although phorbol myristate acetate (PMA) greatly enhanced PHA-stimulated IL2 production by Jurkat cells. CT remained markedly inhibitory. The combination of PMA and the calcium ionophore, ionomycin, also induced IL2 production by Jurkat cells, and this was similarly suppressed by CT, suggesting that a step after initial second messenger generation was inhibited. A prolonged increase in intracellular cAMP levels was induced by CT in both T cells and Jurkat cells, but the maximal level and the length of elevation achieved in T cells were much less than those observed in Jurkat cells. In contrast, PGE2 caused only a modest and transient increase in intracellular cAMP levels in Jurkat cells compared to that noted with T cells. PGE2 induced a more marked and sustained increase in cAMP levels in Jurkat cells treated with isobutylmethylxanthine (IBMX), a phosphodiesterase inhibitor. Moreover, in the presence of IBMX, PGE2 caused a marked inhibition of IL2 production by PHA-stimulated Jurkat cells. Differences in the capacity of PGE2 to induce cAMP could not be explained by disparities in the level of cAMP phosphodiesterase activity as this was comparable in Jurkat cells and in T cells. Thus, these observations indicate that IL2 production by both peripheral T cells and Jurkat cells can be modulated by cAMP-elevating agents. The data suggest that the diminished capacity of PGE2 to inhibit IL2 production by Jurkat cells reflects both a diminished capacity of PGE2 to induce increases in cAMP levels in these cells and an increase in the threshold of cAMP required to inhibit Jurkat cells.

1-Methyl-3-isobutylxanthine↗
PubMed1990

Delineation of the mechanism of inhibition of human T cell activation by PGE2.

The capacity of PGE2 to inhibit human T cell responses was examined by investigating its effect on mitogen-induced IL-2 production and proliferation of highly purified CD4+ T cells. PGE2 inhibited both PHA and anti-CD3 induced proliferation and IL-2 production by an action directly on the responding T cell. Inhibition of IL-2 production reflected decreased accumulation of mRNA for IL-2. A variety of other cAMP elevating agents exerted similar inhibitory effects. Inhibition of proliferation could be overcome by supplemental IL-2, PMA, or the anti-CD28 mAb 9.3. Although PMA and 9.3 markedly increased the amount of IL-2 produced by mitogen-stimulated T cells, the percentage inhibition of IL-2 secretion caused by PGE2 and other cAMP elevating agents remained comparable in these costimulated cultures. Rescue of T cell DNA synthesis by these agents appeared to reflect the finding that, although PGE2 markedly inhibited IL-2 production, the absolute amount of IL-2 produced was increased sufficiently to sustain mitogen-induced proliferation. As anticipated, PGE2, forskolin, and cholera toxin increased T cell cAMP levels. The quantity of cellular cAMP generated in response to PGE2, cholera toxin, and forskolin could be inhibited by PMA or 2',5'-dideoxyadenosine. Using these reagents, the inhibitory effects of PGE2 were found to reflect intracellular cAMP levels, but only within a very narrow range. The results indicate that by elevating cAMP levels, PGE2 inhibits human T cell IL-2 production at a point that is common to both the CD3 and CD28 signaling pathways.

Antigens, CD↗
PubMed1981

Widespread occurrence of calcium-activated, phospholipid-dependent protein kinase in mammalian tissues.

Ca2+-activated, phospholipid-dependent multifunctional protein kinase originally found in rat brain occurs in a variety of mammalian tissues. In most tissues the enzyme activity is comparable to that of cyclic AMP-dependent protein kinase when assayed with calf thymus H1 histone as phosphate acceptor. In some tissues such as platelets, brain, and lymphocytes the enzyme far exceeds the cyclic AMP-dependent enzyme. This species of protein kinase found in various tissues shows very similar physical, kinetic, and catalytic properties, and does not appear to show tissue and species specificities. It is conceivable that this protein kinase plays roles in transmembrane control of protein phosphorylation by a large number of extracellular messengers which induce phosphatidylinositol turnover in their target tissues.

Animals↗
PubMed1980

Inhibitory action of chlorpromazine, dibucaine, and other phospholipid-interacting drugs on calcium-activated, phospholipid-dependent protein kinase.

Ca2+-activated, phospholipid-dependent protein kinase recently found in mammalian tissues (Takai, Y., Kishimoto, A., Iwasa, Y., Kawahara, Y., Mori, T., and Nishizuka, Y. (1979) J. Biol. Chem. 254, 3692-3695) is inhibited by various phospholipid-interacting drugs such as chlorpromazine, imipramine, phentolamine, dibucaine, verapamil, and tetracaine. This effect is attributed to the inhibition of the activation process but not to the interaction with the active site of enzyme. This is supported by the fact that a catalytic fragment of this enzyme, which is obtained by limited proteolysis with Ca2+-dependent neutral protease, is fully active without without Ca2+ and phospholipid and is not susceptible to any of these drugs. Kinetic analysis suggests that these drugs cause such inhibition competitively with phospholipid. None of these drugs appears to compete with Ca2+ or to counteract the unique effect of unsaturated diacylglycerol. Unsaturated diacylglycerol has been shown previously to increase markedly the affinity of enzyme for Ca2+ as well as for phospholipid and thereby serve as an initiator for the activation of this protein kinase. Neither cyclic AMP-dependent nor cyclic GMP-dependent protein kinase is susceptible to these phospholipid-interacting drugs.

Animals↗
PubMed1980

Possible involvement of Ca2+-activated, phospholipid-dependent protein kinase in platelet activation.

Ca2+-activated, phospholipid-dependent protein kinase recently found in rat brain (Takai, Y., Kishimoto, A., Iwasa, Y., Kawahara, Y., Mori, T., & Nishizuka, Y. (1979) J. Biol. Chem. 254, 3692-3695) is present in large quantities in human platelets. The activation of this enzyme appears to be initiated by unsaturated diacylglycerol and intimately related to phosphatidylinositol hydrolysis which is induced by thrombin. The enzyme is selectively and profoundly inhibited by several phospholipid-interacting compounds such as imipramine, verapamil, and tetracaine, which concomitantly inhibit aggregation and release reaction in parallel manners. It is suggestive that this protein kinase may be involved in the transmembrane control of intracellular events eventually leading to platelet activation.

Blood Platelets↗
PubMedDate not supplied

The effect of N-(2-carboxyphenyl)-4-chloroantranilic acid disodium salt (CCA) on concanavalin A-induced superoxide anion release in human mononuclear phagocytes.

Superoxide anion (O2-), generated and released by mononuclear phagocytes (M phi), plays significant roles in tissue damage accompanying inflammatory and immunological reactions. N-(2-carboxyphenyl)-4-chloroantranilic acid disodium salt (CCA), is a newly synthesized immunomodulator for which therapeutic efficacy in the treatment of rheumatoid arthritis (RA) has been reported. In this investigation, we have examined the effect of CCA on concanavalin A (Con A)-induced O2- release in human M phi. Exposure of M phi to Con A induced a large increase of O2- release. Preincubation of M phi with CCA suppressed O2- release induced by Con A almost to a control level. On the contrary, CCA itself did not have a significant effect on basal O2- release from M phi. These results indicate that the inhibition of O2- release from activated M phi may be an important factor in the anti-inflammatory effects of this drug.

Anti-Inflammatory Agents↗