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At least 883 records · Page 49Linked to original sources
PubMed1994

Suppression of the humoral immune response by cannabinoids is partially mediated through inhibition of adenylate cyclase by a pertussis toxin-sensitive G-protein coupled mechanism.

Cannabinoid compounds, including the major psychoactive component of marihuana, delta 9-tetrahydrocannabinol (delta 9-THC), have been widely established as being inhibitory on a broad array of humoral and cell-mediated immune responses. The presence of cannabinoid receptors has been identified recently on mouse spleen cells, which possess structural and functional characteristics similar to those of the G-protein coupled cannabinoid receptor originally identified in rat brain. These findings, together with those demonstrating that delta 9-THC inhibits adenylate cyclase in splenocytes, strongly suggest that certain aspects of immune inhibition by cannabinoids may be mediated through a cannabinoid receptor-associated mechanism. The objective of the present studies was to determine whether inhibition of adenylate cyclase is relevant to mouse spleen cell immune function and, if so, whether this inhibition is mediated through a Gi-protein coupled mechanism as previously described in neuronal tissue. Spleen cell activation by the phorbol ester phorbol-12-myristate-13-acetate (PMA), plus the calcium ionophore ionomycin, produced a rapid but transient increase in cytosolic cAMP, which was inhibited completely by immunosuppressive concentrations of delta 9-THC (22 microM) and the synthetic bicyclic cannabinoid CP-55940 (5.2 microM), which produced no effect on cell viability. Inhibition by cannabinoids of lymphocyte proliferative responses to PMA plus ionomycin and sheep erythrocyte (sRBC) IgM antibody-forming cell (AFC) response, was abrogated completely by low concentrations of dibutyryl-cAMP (10-100 microM). Inhibition of the sRBC AFC response by both delta 9-THC (22 microM) and CP-55940 (5.2 microM) was also abrogated by preincubation of splenocytes for 24 hr with pertussis toxin (0.1-100 ng/mL). Pertussis toxin pretreatment of spleen cells was also found to directly abrogate cannabinoid inhibition of adenylate cyclase, as measured by forskolin-stimulated accumulation of intracellular cAMP. These results indicate that inhibition of the sRBC AFC response by cannabinoids is mediated, at least in part, by inhibition of adenylate cyclase through a pertussis toxin-sensitive Gi-protein coupled cannabinoid receptor. Additionally, these studies further support the premise that cAMP is an important mediator of lymphocyte activation.

Adenylate Cyclase Toxin↗
PubMed1995

Activation of NO:cGMP pathway by acetylcholine in bovine chromaffin cells. Possible role of Ca2+ in the down-regulation of cGMP signaling.

The production of cyclic GMP (cGMP) induced by acetylcholine and other stimuli was studied in bovine chromaffin cells. Acetylcholine increased intracellular cGMP in a transitory (peak at 2 min) and concentration-dependent manner (estimated half maximal increase, EC50 = 61 +/- 5 microM). NG-nitro-L-arginine methyl ester (NAME) inhibited such a rise in cGMP with a half maximal inhibitory concentration (IC50) of 231 +/- 55 microM. The acetylcholine-induced increase in cGMP was also inhibited by a calmodulin antagonist (calmidazolium, 30 microM) and by the absence of extracellular calcium. Other agents that strongly increased cytosolic calcium concentration ([Ca2+]i) as acetylcholine did, such as the nicotinic-agonist, 1,1-dimethyl-4-phenylpiperazinium (DMPP), high-KCl (50 mM), and ionomycin, also caused a rise in cGMP in cultured bovine chromaffin cells. Veratridine, an activator of sodium channels, produced a slowly developing calcium increase and no significant cGMP production. The muscarinic-agonist, muscarine, failed to increase cytosolic calcium, and was the weakest stimulator of cGMP production. cGMP formation, induced by sodium nitroprusside (SNP, 100 microM) and by C-type natriuretic peptide (CNP, 100 nM), was inhibited by 30-40% by increasing [Ca2+]i with ionomycin. This inhibition was abolished by calmidazolium (30 microM) and by the absence of calcium in the extracellular medium. In conclusion, bovine chromaffin cells synthesize nitric oxide (NO) to activate guanylate cyclase in response to several stimuli, which increase [Ca2+]i. Moreover, the increase in [Ca2+]i also stimulates a Ca2+/calmodulin phosphodiesterase, which could down-regulate the levels of cGMP in these cells.

Acetylcholine↗
PubMed1992

Blockade of NMDA receptor-mediated mobilization of intracellular Ca2+ prevents neurotoxicity.

NMDA receptor activation leads to elevated Ca2+ in cultured rat cortical and retinal ganglion cell neurons. If excessive, this Ca2+ response is associated with delayed neurotoxicity. We used dantrolene and ionomycin to test if the Ca2+ response to NMDA was due to mobilization of intracellular Ca2+ stores rather than merely to Ca2+ influx. In the presence of EGTA, ionomycin resulted in release and subsequent depletion of intracellular Ca2+ stores. Henceforth, despite normal extracellular Ca2+, NMDA elicited only about half of its former Ca2+ response. Similarly, when dantrolene was used to block Ca2+ release from intracellular stores, we observed > 50% smaller NMDA-evoked Ca2+ responses. These results quite surprisingly indicate that at least half the Ca2+ response to NMDA is due to release of intracellular Ca2+, a process triggered by influx of extracellular Ca2+. Dantrolene also protected neurons from NMDA receptor-mediated neurotoxicity. Release of intracellular Ca2+ may therefore be a necessary step in the cascade leading to neuronal damage induced by excessive NMDA receptor stimulation and may be amenable to pharmacological intervention.

Animals↗
PubMed1990

Regulatory role of microfilaments in the induction of T4 cell proliferation and interleukin 2 production.

The role of microfilaments in human T4 cell proliferation and lymphokine production triggered via various pathways of activation was examined by investigating the effects of cytochalasins on these responses. The data demonstrate that the effects of cytochalasins vary depending on the nature of the stimulus and on the concentration of the cytochalasin. Concentrations of cytochalasin that would be expected to bind both the low and high affinity binding sites (5-20 microM), that represent cytosolic and surface actin filaments, respectively inhibited T4 cell proliferation regardless of the stimulus. T4 cell proliferation stimulated by antigen-bearing APC or anti-CD3 was inhibited much more markedly than responses stimulated by ionomycin and PMA. In contrast, concentrations of cytochalasin expected to bind only high affinity binding sites (0.125-1 microM), represented by surface actin filaments, enhanced T4 cell proliferation and interleukin 2 production stimulated by mAb to CD2, CD3, or class I major histocompatibility complex (MHC) molecules, but not those induced by mAb to the T cell receptor, paraformaldehyde fixed, or viable antigen-bearing APC, allogeneic APC, or ionomycin and PMA. The enhancing effect of cytochalasins on responses stimulated by cross-linking class I MHC molecules was studied in detail. Enhancement of T4 cell proliferation induced in this manner required that cytochalasin B was present between 4 and 18 hr of culture, but not before or after. The data demonstrate that T cell microfilaments play a number of roles in determining the magnitude of T cell responses induced by engaging specific cell surface receptors and imply that different components of the microfilament system exert opposing intrinsic regulatory effects on T cell function.

Actin Cytoskeleton↗
PubMed1991

Uncoupling of the calcium-sensing mechanism and differentiation in squamous carcinoma cell lines.

Increases in the intracellular calcium (Cai) levels, induced either by extracellular calcium or by calcium ionophores, stimulate the terminal differentiation of normal human keratinocytes in culture (NHK). Despite extensive differences in phenotypic expression, squamous carcinoma cell lines (SCC lines) display only partial terminal differentiation even in the presence of normal extracellular calcium. Therefore, in this study, we evaluated whether the inability of SCC lines to differentiate normally is due to a defect in achieving adequate levels of Cai. Membrane-bound transglutaminase activity and involucrin levels of the various SCC lines were lower than those of NHK and correlated with their low extent of cornified envelope formation. Ionomycin, a calcium ionophore, acutely increased cornified envelope formation of NHK 60- to 70-fold, but only initiated a 1- to 5-fold increase in SCC lines. Yet resting Cai levels in and the Cai response to various agents of SCC lines were similar or higher than those of NHK. Extracellular calcium evoked a rapid, transient and a slower, sustained increase of Cai. Extracellular ATP increased Cai by a rapid release from intracellular sources. Ionomycin, on the other hand, increased Cai from both intracellular compartments and extracellular sources. Thus, these studies indicate that the abnormalities in differentiation among SCC lines do not appear to involve their calcium-sensing mechanism. An uncoupling of the Cai changes to the synthesis of the precursor molecules required for differentiation may be responsible for the defect in differentiation displayed by these SCC lines.

Adenosine Triphosphate↗
PubMed1982

Cytoplasmic free Ca2+ in human platelets: Ca2+ thresholds and Ca-independent activation for shape-change and secretion.

Cytoplasmic free [Ca2+], [Ca2+]i, was measured in human platelets using the intracellularly-trapped, fluorescent indicator quin2. Basal [Ca2+]i with the Ca2+ -ionophore ionomycin revealed apparent thresholds for shape-change, 5-HT release and aggregation of approx. 0.5 microM, 0.8 microM and 2 microM. Thrombin raised [Ca2+]i to 3 microM fast enough for the Ca2+ to have triggered the cell activation. However, thrombin released more 5-HT than ionomycin could, and in Ca2+ -free medium thrombin evoked shape-change and secretion even when [Ca2+]i remained near basal levels throughout, suggesting the existence of alternative triggers for shape-change and secretory exocytosis.

Blood Platelets↗
PubMed1983

Cytosol Mg2+ modulates Ca2+ ionophore induced secretion from rabbit neutrophils.

The influence of extracellular Mg2+ on Ca2+ ionophore (A23187 and ionomycin) induced secretion and changes in the cytosol pH of rabbit neutrophils suspended in Ca2+-free buffer has been investigated. While extracellular Ca2+ is obligatory for ionomycin induced secretion, we have defined conditions under which A23187 can induce secretion in Ca2+-free media. The different behaviour of these two Ca2+ ionophores is discussed on the basis of their different counter cation specificities.

Animals↗
PubMed1990

A novel method for measuring membrane conductance changes by a voltage-sensitive optical probe.

This study presents a method whose principles enable using a voltage-sensitive optical probe, to quantitatively measure conductivity changes elicited in membrane vesicles and cells. The procedure is based on the fact that the amplitude of the transmembrane potential difference, established across a membrane by an external electric field, is decreased when membrane conductivity is increased upon incorporation of ionophores into the membrane. The method was applied to osmotically swollen thylakoid membranes whose membrane conductivity was changed by the addition of gramicidin or ionomycin. The electric field induced stimulated luminescence from photosystem I (electrophotoluminescence-EPL) was used as a voltage-sensitive optical probe. We calculated the induced conductance changes by using a calibrated EPL vs external electric field response curve and measuring the ionophore-mediated attenuation of the EPL signal. The calculated ionophore-unmodified conductance of the thylakoid membrane yields a value of 171 +/- 56 nS/cm. The value of the membrane conductance, modified by 10 nM gramicidin was found to be 190 +/- 56 nS/cm. The modified membrane conductance and the membrane conductance changes induced by 1 microM ionomycin in the presence of CaCl2 were found to be 186 +/- 3 nS/cm and 15 +/- 3 nS/cm, respectively.

Chloroplasts↗
PubMed1996

Noradrenaline inhibition of Ca2+ channels and secretion in single patch-clamped insulinoma cells.

Noradrenaline effects on voltage-operated calcium channels and exocytosis were studied, for the first time, in single patch-clamped RINm5F insulin-secreting cells. Noradrenaline, despite small and variable inhibition of calcium currents, strongly inhibited the increase in membrane capacitance (a measure of exocytosis) stimulated by both step depolarizations and the calcium ionophore, ionomycin. Noradrenaline similarly inhibited KCl- and ionomycin-induced [3H]serotonin release from RINm5F cell populations. Noradrenaline effects were mediated by PTX-sensitive G proteins. Noradrenaline inhibitory effects on secretion are, therefore, mainly exerted downstream from Ca2+ influx.

Animals↗
PubMed1990

In vitro goldfish growth hormone responses to gonadotropin-releasing hormone: possible roles of extracellular calcium and arachidonic acid metabolism?

Two hours of incubation of primary static cultures of dispersed goldfish pituitary cells with 0.01 nM to 1 microM [Trp7,Leu8]-gonadotropin-releasing hormone (sGnRH) increased growth hormone (GH) secretion in a dose-dependent manner with an ED50 estimate of 0.13 +/- 0.04 nM. Addition of calcium ionophores, 1 to 100 microM A23187 and 5 to 100 microM ionomycin, significantly elevated GH release with ED50s of 0.84 +/- 0.38 and 4.34 +/- 1.02 microM, respectively. Replacement of normal calcium-containing media with calcium-deficient media (prepared without the addition of calcium salts) significantly depressed basal GH secretion, attenuated the A23187- and ionomycin-stimulated GH release, and completely abolished the GH response to sGnRH. Arachidonic acid (AA) at 1 to 50 microM also enhanced GH secretion with an ED50 of 4.72 +/- 1.52 microM. Coincubation with 1 and 10 microM of a lipoxygenase inhibitor, nordihydroguaiaretic acid (NDGA), 10 microM of the cyclooxygenase inhibitor, indomethacin, and 10 microM of eicosatetraynoic acid, an enzyme blocker with mixed activities on both the lipoxygenase and cyclooxygenase pathways, did not alter basal, AA-, and sGnRH-induced GH release. However, at 100 microM concentration, NDGA increased AA- and sGnRH-stimulated, as well as basal GH, responses. These results confirm the direct stimulatory action of GnRH on goldfish somatotropes and indicate the importance of extracellular calcium in mediating basal and GnRH-induced GH responses. Although AA stimulates GH secretion, its lipoxygenase and cyclooxygenase metabolites probably do not mediate sGnRH action on somatotropes.

Animals↗
PubMed1985

Vesicular demyelination induced by raised intracellular calcium.

Incubation of nerve with high concentrations of the divalent cation ionophore A23187 produces myelin vesiculation (Schlaepfer 1977). This observation has now been extended using segments of rat ventral or dorsal root incubated with high (19 microM, 10 micrograms/ml) or low (1-1.5 microM) concentrations of A23187, or another divalent ionophore, ionomycin. Low concentrations of A23187 induced no vesiculation within a 2-h period. However, subsequent incubation of these roots in fresh, ionophore-free medium for 20 h, resulted in a prominent vesicular demyelination at the Schmidt-Lanterman incisures and paranodes of many fibres. At this time (22 h) the Schwann cells associated with some demyelinating internodes appeared vital upon ultrastructural examination: the cells also excluded the nuclear dye nigrosin. High concentrations of A23187 induced a similar vesicular demyelination in affected fibres within only 15-20 min. While the Schwann cells continued to exclude nigrosin for a further 4 h, their ultrastructural appearance indicated that they were probably in the early stages of necrosis. Incubation of moribund root with the ionophore produced no myelin vesiculation. At all ionophore concentrations, the myelin vesiculation was dependent upon the presence of extracellular Ca2+, and could be modulated in severity by varying this concentration. Other divalent cations (Ba2+, Co2+, Mg2+, Mn2+, Ni2+, Sr2+) could not substitute for Ca2+. The vesiculation induced by A23187 could be entirely prevented by the addition of Zn2+ (greater than or equal to 1 microM), Ni2+ (greater than or equal to 1-10 microM), Co2+ (greater than or equal to 100 microM) or Mn2+ (greater than or equal to 100 microM) to the bathing medium. A23187 applied to only part of an isolated internode resulted in a localization of the myelin disruption to that region. Ionomycin (greater than or equal to 1 microM), an ionophore with a greater selectivity for Ca2+ than A23187, also induced a prompt Ca2+-dependent myelin vesiculation. We conclude that vesicular demyelination can be initiated in vital Schwann cells by a raised intracellular Ca2+ concentration. Such demyelination does not necessarily lead to Schwann cell death. The possible relevance of the findings to vesicular demyelinating neuropathies is discussed, and a hypothesis regarding the mechanism of demyelination is advanced.

Animals↗
PubMed1990

Effect of anti-calmodulin agents on vasopressin release in vitro to depolarization and calcium ionophore.

Calmodulin has been implicated in transducing the effects of Ca2+ on synaptic transmission and hormone release, including osmotically-stimulated vasopressin (AVP) release. If the anti-calmodulin agents block AVP release secondary to inhibition of Ca2(+)-calmodulin interactions, these drugs should inhibit AVP release to stimuli increasing Ca2+ influx via different mechanisms. Hypothalamo-neurohypophysial complexes (HNC) were exposed to ionomycin, Bay K 8644, or veratridine either alone, with any one of three distinct chemical classes of anti-calmodulin agent, or with a Ca2+ channel antagonist. All the anti-calmodulin agents impaired AVP release to ionomycin, while Ca2+ channel blockade did not. Conversely, Ca2+ channel antagonism completely blocked AVP release in response to Bay K 8644, but the anti-calmodulin agents had no effect. None of the inhibitors prevented veratridine-induced AVP release. These results are consistent with the hypothesis that the anti-calmodulin agents tested inhibit AVP release by their membrane stabilizing properties rather than by antagonizing Ca2(+)-calmodulin in HNC. Depolarization initiated by Na+ influx may stimulate Na(+)-Ca2+ exchange by a mechanism independent of slow Ca2+ channels as well.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1993

Measurement of prolactin release and cytosolic calcium in estradiol-primed lactotrophs.

We have developed a perifusion system that can measure both changes of cytosolic free calcium concentration [Ca2+]i and prolactin release simultaneously from cultured lactotrophs. This model incorporated a commonly-used perifusion system to a spectrofluorometer. Indo-1 loaded cells were injected into Sephadex G-150 matrix in the cuvette at a site where the emitting light of the fluorometer projects. During perifusion periods, the perifusate was collected in a fraction collector, while optical density of the emitting light at 405 nm was recorded. The [Ca2+]i was calculated based on an ionomycin and Mn2+ quenching technique. As expected, TRH (1 mumol/l) stimulated prolactin release from cultured lactotrophs in this system. We further observed that prolactin releases as induced by TRH and ionomycin were not proportional with changes of the [Ca2+]i, suggesting that changes of [Ca2+]i is not the sole final pathway of intracellular transduction systems for prolactin release.

Animals↗
PubMed1987

Age-related changes of the function of T cell subsets: predominant defect of the proliferative response in CD8 positive T cell subset in aged persons.

The proportion of CD8 positive cells in the peripheral blood AET-rosette forming T cells from aged persons was significantly reduced than that from young persons. The difference in the proportion between aged and young groups became more significant after proliferative response to a mitogen phytohemagglutinin (PHA) or a specific antigen tuberculin active peptide (TAP). The purified macrophage-deprived T cells (Twp), CD4 (T4) positive cells or CD8 positive cells were prepared from aged or young persons. These cell preparations lost proliferative response to PHA or TAP but showed marked proliferative response to the combined stimulation to 1 microM of ionomycin and 1 nM of phorbol-12-myristate-13-acetate (PMA) at usual culture cell density (2.5 X 10(5)/ml). Proliferative responses of these cell preparations to the combined stimulation were significantly reduced in the aged than those in the young and the magnitude of the difference in the proliferative responses between aged and young groups was more pronounced in CD8 positive cell population than in CD4 positive cell population. Although the cell preparations were relatively independent of exogenous IL-2 for the proliferative response to the combined stimulation of ionomycin and PMA at usual culture cell density, they needed exogenous IL-2 for sustained proliferation at lower culture cell density (5 X 10(3)/ml). These IL-2-dependent proliferative responses to the combined stimulation in the aged were significantly lower than those in the young and again the difference in the proliferative magnitude between aged and young groups was greater in CD8 positive population. The mechanism(s) of age-related change of the proportion and proliferative ability of T subsets were discussed.

Adult↗
PubMed1988

Human platelet activation by bacterial phospholipase C: mechanism of inhibition by flurazepam.

We have shown earlier that phospholipase C (PLC) from Clostridium perfringens causes platelet activation possibly by inducing turnover of phosphoinositides and phosphorylation of a 47,000 Dalton protein (P47). Moreover, only 15 microM and 11 microM flurazepam inhibits PLC-induced platelet aggregation and serotonin secretion by 50% respectively. This study was conducted to better understand the mechanism of platelet activation by PLC and its inhibition by flurazepam. Incubation of (14C)-arachidonic acid labelled platelets with PLC produced diacylglycerol in a time- and concentration-dependent manner. Flurazepam did not inhibit diacylglycerol production by PLC. Paranitrophenolphosphorylcholine and prostaglandin E1 inhibited diacylglycerol production by 75% and 20% respectively. In a platelet-free system PLC hydrolyzed 14C-choline-phosphatidylcholine (14C-PC) in a time- and calcium ions-dependent manner. Flurazepam had no effect on PLC-induced hydrolysis of 14C-PC. Platelet cytosolic fraction (PCF), containing phosphatidylinositol-specific PLC (PI-PLC), hydrolyzed (3H-inositol)-phosphatidylinositol (3H-PI) in a platelet-free system. Flurazepam did not inhibit hydrolysis of 3H-PI by PCF. Phospholipase C caused phosphorylation of P47 in 32P-labelled platelets. Flurazepam did not block phosphorylation of P47 in the first three minutes and had very little inhibitory effect by five minutes. However, flurazepam completely blocked phosphorylation of P47 by seven minutes. Platelet aggregation induced by ionomycin, a calcium ionophore, was completely inhibited by 100 microM flurazepam whereas platelet aggregation induced by 12-O-Tetradecanoylphorbol-13-acetate (TPA), which mimics the action of diacylglycerol, was partially inhibited by 300 microM flurazepam. These findings suggest that PLC induced platelet activation depends, at least in part, on diacylglycerol production and phosphorylation of P47. These data also suggest that flurazepam does not inhibit PLC-induced platelet activation by inhibiting: (a) the production of diacylglycerol from phosphatidylcholine; and (b) the action of PI-PLC on phosphatidylinositol. The ability of flurazepam to inhibit ionomycin-induced platelet aggregation indicates that flurazepam is able to block platelet activation by inhibiting the increase in free cytosolic calcium ions in platelets or by inhibiting a step subsequent to the rise in intraplatelet calcium ions.

Alprostadil↗
PubMed1993

Actions of interleukin-2 on chorio-decidual prostaglandin biosynthesis.

The onset of preterm labor requires increased intrauterine prostaglandin production. Intrauterine infections are frequently associated with preterm labor and increased cytokine production. The cytokine interleukin-2 (IL-2) is a potent T-cell growth factor necessary for effective cell-mediated immunity. In this study we evaluated the effect IL-2 has on prostaglandin E2 (PGE2) biosynthesis by human chorion and decidual cells. IL-2 alone significantly stimulated decidual and chorion PGE2 production. IL-2 enhanced the stimulatory actions of interleukin-1 (IL-1), epidermal growth factor (EGF), ionomycin, and phorbol 12-myristate 13-acetate (PMA) on PGE2 production by decidual cells. Similarly, IL-2 enhanced the stimulatory actions of EGF and PMA, but not IL-1 or ionomycin, on PGE2 production by chorion cells. These data suggest that IL-2 could potentially participate in the mechanisms of preterm labor in association with intrauterine infection.

Cells, Cultured↗
PubMed1996

Cyclosporin A inhibits prostaglandin E2 production by fetal amnion cells in response to various stimuli.

Use of cyclosporin A as part of an immunosuppressive regimen in pregnant transplant patients is not uncommon. Although successful pregnancies have been reported with the use of various immunosuppressive agents including cyclosporin A, the concern for fetal outcome still remains. Our purpose was to evaluate the effects of immunosuppressive cyclosporin A on prostaglandin E2 (PGE2) production by human fetal amnion. Amnion cells were isolated from term placentae obtained at elective cesarean section before the onset of labor. Cells were grown to confluence and then incubated for 16 hours with cyclosporin A (1-1000 ng/ml) in the presence and absence of interleukin 1 beta (IL-1 beta, 1 ng/ml), phorbol 12-myristate 13-acetate (PMA, 10(-7) M) and ionomycin (0.5 microM). PGE2 was measured by radioimmunoassay and cellular protein determined. IL-1 beta, PMA and ionomycin all stimulated amnion cell PGE2 production as expected. However, these stimulatory actions were attenuated by at least 50% when cells were co-incubated with cyclosporin A (1000 ng/ml). Concentrations of cyclosporin A tested included the therapeutic range (250-1000 ng/ml). Our results indicate that cyclosporin A does not stimulate amnion cell PGE2 production and is probably unrelated to preterm labor and delivery in allograft recipients.

Amnion↗
PubMedDate not supplied

Regulation of chorion laeve prostaglandin E2 production by epidermal growth factor, protein kinase C activation and calcium.

The effects of epidermal growth factor (EGF), phorbol 12-myristate 13-acetate (PMA), A23187, and ionomycin on prostaglandin production by chorion laeve cells in culture for 3 days and 10 days were tested. Experiments were conducted at day 3 because at this time the cultures became confluent and again at day 10 because changes have been observed in the biochemical properties of these cells with time in culture. At 3 days of culture the cells did not respond to EGF but at 10 days EGF (10 ng/ml) induced a significant increase in prostaglandin E2 production. PMA (10(-9) to 10(-6) M) induced a significant increase in PGE2 production at both times in culture. The calcium ionophores, A23187 and ionomycin, were less effective in eliciting a response at either time in culture. Only A23187 (1 microM) induced a significant increase in PGE2 production at day 10 of culture. These data suggest that the presence of functional EGF receptors may increase with time in culture. Furthermore, activation of the protein kinase C pathway in the chorion laeve stimulates prostaglandin biosynthesis. On the other hand, chorion laeve cell prostaglandin biosynthesis is not responsive to increases in intracellular calcium induced by mobile ion carriers such as the ionophores used in this study.

Calcimycin↗