PubMed Health⌕ Search

Biomedical subjects

O Thastrup

Publications and source records attributed to O Thastrup.

At least 37 records · Page 2Linked to original sources
PubMed1991

Stimulatory effect of thapsigargin, a non-TPA-type tumor promoter, on arachidonic acid metabolism in the murine keratinocyte line HEL30 and on epidermal cell proliferation in vivo as compared to the effects of phorbol ester TPA.

The effect of thapsigargin (Tg), a non-12-O-tetradecanoylphorbol-13-acetate (TPA) type skin tumor promoter, on arachidonic acid and prostaglandin E2 (PGE2) formation in HEL30 keratinocytes and on epidermal DNA synthesis in vitro and in vivo (mouse skin) was investigated and compared with that of the phorbol ester TPA. On a molar basis Tg was 30-fold more potent in inducing the arachidonic acid/PGE2 release than TPA. Applied together, the two agents showed a strong synergistic action. The response critically depended on the presence of Ca2+ in the extracellular medium. While the TPA-induced release was mediated by protein kinase C (PKC) the Tg-induced release was not. In contrast to TPA (1 microM), which is a stimulator of HEL30 DNA synthesis, Tg (0.1-1 microM) inhibited DNA labeling in vitro due to a pronounced cytotoxic effect. TPA did not exhibit such an effect. In vivo both agents were practically equipotent in inducing epidermal DNA synthesis and hyperplasia with TPA having an approximately 10-fold higher irritating potential than Tg. It is concluded that the hyperplasiogenic and tumor-promoting effect of Tg in vivo is due to cytotoxicity causing cell death and regenerative hyperproliferation. Thus, Tg-induced skin tumor promotion seems to resemble tumor promotion by mechanical skin wounding, whereas TPA evokes a more specific, i.e. PKC-mediated response. Since despite these mechanistic differences both agents induce an immediate release of arachidonic acid/PGE2 in keratinocytes, this response may be considered to provide an in vitro parameter for irritancy and tumor promotion.

Animals↗
PubMed1991

Role of inositol (1,4,5)trisphosphate in epidermal growth factor-induced Ca2+ signaling in A431 cells.

The effects of epidermal growth factor on Ca2+ signaling in A431 cells were investigated. Epidermal growth factor induced a transient Ca2+ signal in the absence of external Ca2+ and a sustained response in the presence of extracellular Ca2+, indicating an ability to mobilize intracellular Ca2+ as well as the ability to increase Ca2+ entry from the extracellular space. The Ca(2+)-ATPase inhibitor thapsigargin also activated Ca2+ entry, and neither epidermal growth factor nor the guanine nucleotide-dependent protein-linked receptor agonist bradykinin activated additional Ca2+ entry over that due to thapsigargin. In nominally Ca(2+)-free medium, the addition of bradykinin to A431 cells rapidly but transiently increased inositol 1,4,5-trisphosphate and, in parallel fashion, transiently increased cytosolic Ca2+. Unexpectedly, under these experimental conditions, epidermal growth factor elicited a small but significant Ca2+ signal after the addition of bradykinin. Experiments were designed to determine whether the Ca2+ response to epidermal growth factor after bradykinin results from mobilization of Ca2+ by an inositol 1,4,5-trisphosphate-independent mechanism. Epidermal growth factor stimulated additional inositol 1,4,5-trisphosphate formation in bradykinin-treated cells. Furthermore, the Ca2+ signals elicited by both bradykinin and epidermal growth factor were blocked in cells microinjected with the inositol 1,4,5-trisphosphate receptor antagonist heparin, whereas the intracellular Ca(2+)-ATPase inhibitor thapsigargin still mobilized Ca2+. Finally, histamine, a less efficacious guanine nucleotide-dependent protein-linked receptor agonist, as well as photolyzed, microinjected, caged inositol 1,4,5-trisphosphate, also mobilized Ca2+ after bradykinin. The results of this study show (i) that epidermal growth factor activates intracellular Ca2+ release as well as Ca2+ entry, the latter most likely resulting from an indirect effect due to the depletion of intracellular Ca2+ pools, (ii) that the actions of epidermal growth factor on Ca2+ homeostasis can be fully accounted for by inositol 1,4,5-trisphosphate formation, and (iii) that the ability of A431 cells to produce Ca2+ signals when epidermal growth factor is applied after bradykinin can be explained by the rapid and complete desensitization of the bradykinin stimulated phospholipase C activity.

Bradykinin↗
PubMed1990

Inositol trisphosphate and thapsigargin discriminate endoplasmic reticulum stores of calcium in rat brain.

ATP dependent Ca2+ accumulation into oxalate-loaded rat brain microsomes is potently inhibited by thapsigargin with an IC50 of 2 nM and maximal inhibition at 10 nM. Approximately 15% of the total A23187-releasable microsomal calcium store is insensitive to thapsigargin concentrations up to 100 microM. Inositol-1,4,5-trisphosphate (IP3) maximally inhibits 40% of the net Ca2+ accumulation by whole brain microsomes. Its effects are non-additive with thapsigargin suggesting that the IP3-sensitive Ca2+ pool is a subset of the thapsigargin sensitive Ca2+ pool. Marked regional differences occur in Ca2+ transport rates and sensitivity to both thapsigargin and IP3.

Animals↗
PubMed1990

Thapsigargin, but not caffeine, blocks the ability of thyrotropin-releasing hormone to release Ca2+ from an intracellular store in GH4C1 pituitary cells.

Thapsigargin stimulates an increase of cytosolic free Ca2+ concentration [( Ca2+]c) in, and 45Ca2+ efflux from, a clone of GH4C1 pituitary cells. This increase in [Ca2+]c was followed by a lower sustained elevation of [Ca2+]c, which required the presence of extracellular Ca2+, and was not inhibited by a Ca2(+)-channel blocker, nimodipine. Thapsigargin had no effect on inositol phosphate generation. We used thyrotropin-releasing hormone (TRH) to mobilize Ca2+ from an InsP3-sensitive store. Pretreatment with thapsigargin blocked the ability of TRH to cause a transient increase in both [Ca2+]c and 45Ca2+ efflux. The block of TRH-induced Ca2+ mobilization was not caused by a block at the receptor level, because TRH stimulation of InsP3 was not affected by thapsigargin. Rundown of the TRH-releasable store by Ca2(+)-induced Ca2+ release does not appear to account for the action of thapsigargin on the TRH-induced spike in [Ca2+]c, because BAY K 8644, which causes a sustained rise in [Ca2+]c, did not block Ca2+ release caused by TRH. In addition, caffeine, which releases Ca2+ from intracellular stores in other cell types, caused an increase in [Ca2+]c in GH4C1 cells, but had no effect on a subsequent spike in [Ca2+]c induced by TRH or thapsigargin. TRH caused a substantial decrease in the amount of intracellular Ca2+ released by thapsigargin. We conclude that in GH4C1 cells thapsigargin actively discharges an InsP3-releasable pool of Ca2+ and that this mechanism alone causes the block of the TRH-induced increase in [Ca2+]c.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1990

Y1 receptors for neuropeptide Y are coupled to mobilization of intracellular calcium and inhibition of adenylate cyclase.

Two types of binding sites have previously been described for neuropeptide Y (NPY), called Y1 and Y2 receptors. The intracellular events following Y1 receptor activation was studied in the human neuroblastoma cell line SK-N-MC. Both NPY and the specific Y1 receptor ligand, [Leu31,Pro34]-NPY, caused a rapid and transient increase in the concentration of free calcium in the cytoplasm as measured by the fluorescent probe, Fura-2. The effect of both peptides was independent of extracellular calcium as addition of EGTA or manganese neither changed the size nor the shape of the calcium response. The calcium response to NPY was abolished by pretreatment with thapsigargin, which can selectively deplete a calcium store in the endoplasmic reticulum. Y1 receptor stimulation, by both NPY and [Leu31,Pro34]NPY, also inhibited the forskolin-stimulated cAMP production with an EC50 of 3.5 nM. There was a close relation between the receptor binding and the cellular effects as half-maximal displacement of [125I-Tyr36]monoiodoNPY from the receptor was obtained with 2.1 nM NPY. The Y2-specific ligand NPY(16-36)peptide had no effect on either intracellular calcium or cAMP levels in the SK-N-MC cells. It is concluded that Y1 receptor stimulation is associated with both mobilization of intracellular calcium and inhibition of adenylate cyclase activity.

Adenylyl Cyclase Inhibitors↗
PubMed1990

Calcium efflux across the plasma membrane of rat parotid acinar cells is unaffected by receptor activation or by the microsomal calcium ATPase inhibitor, thapsigargin.

The rate of Ca2+ extrusion across the plasma membrane of rat parotid acinar cells was determined by measuring the decay of the intracellular calcium concentration, [Ca2+]i, following the addition of EGTA to agonist stimulated cells. In the presence of extracellular Ca2+, the muscarinic cholinergic receptor agonist, methacholine, rapidly increased [Ca2+]i (peaking within 5 s), which then decreased to a higher steady state level. This elevated steady state level was dependent on extracellular Ca2+ concentration. Likewise, thapsigargin, a non-phorbol ester tumor promoter that does not increase inositol phosphates, gradually increased [Ca2+]i, peaking within 1 min and then declining to a new elevated plateau level which was also dependent on extracellular Ca2+. [Ca2+]i, elevated by methacholine or thapsigargin, was rapidly decreased by the addition of EGTA by a process the kinetics of which depended on the value of [Ca2+]i before the addition of EGTA. That is, [Ca2+]i increased as a function of the extracellular Ca2+ concentration and also the apparent half-time for Ca2+ extrusion following the addition of EGTA to cells was increased as the [Ca2+]i increased. This presumably reflects the saturable nature of the Ca2+ extrusion mechanism. The steady state [Ca2+]i in cells stimulated with methacholine or thapsigargin in nominally Ca2+ free medium was similar to the steady state [Ca2+]i in unstimulated cells in normal, Ca2(+)-containing medium. Under these similar [Ca2+]i conditions, stimulated and unstimulated cells showed a similar time course of decay upon addition of EGTA. In addition, neither methacholine nor phorbol myristate acetate decreased the sustained elevation of [Ca2+]i induced by ionomycin.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

[Leu31, Pro34]neuropeptide Y: a specific Y1 receptor agonist.

Two types of binding sites have previously been described for 36-amino acid neuropeptide Y (NPY), called Y1 and Y2 receptors. Y2 receptors can bind long C-terminal fragments of NPY-e.g., NPY-(13-36)-peptide. In contrast, Y1 receptors have until now only been characterized as NPY receptors that do not bind such fragments. In the present study an NPY analog is presented, [Leu31, Pro34]NPY, which in a series of human neuroblastoma cell lines and on rat PC-12 cells can displace radiolabeled NPY only from cells that express Y1 receptors and not from those expressing Y2 receptors. The radiolabeled analog, [125I-Tyr36] monoiodo-[Leu31, Pro34]NPY, also binds specifically only to cells with Y1 receptors. The binding of this analog to Y1 receptors on human neuroblastoma cells is associated with a transient increase in cytoplasmic free calcium concentrations similar to the response observed with NPY. [Leu31, Pro34]NPY is also active in vivo as it is even more potent than NPY in increasing blood pressure in anesthetized rats. It is concluded that [Leu31, Pro34]NPY is a specific Y1 receptor agonist and that the analog or variants of it can be useful in delineating the physiological importance of Y1 receptors.

Amino Acid Sequence↗
PubMed1990

Thapsigargin, a tumor promoter, discharges intracellular Ca2+ stores by specific inhibition of the endoplasmic reticulum Ca2(+)-ATPase.

Thapsigargin, a tumor-promoting sesquiterpene lactone, discharges intracellular Ca2+ in rat hepatocytes, as it does in many vertebrate cell types. It appears to act intracellularly, as incubation of isolated rat liver microsomes with thapsigargin induces a rapid, dose-dependent release of stored Ca2+. The thapsigargin-releasable pool of microsomal Ca2+ includes the pools sensitive to inositol 1,4,5-trisphosphate and GTP. Thapsigargin pretreatment of microsomes blocks subsequent loading with 45Ca2+, suggesting that its target is the ATP-dependent Ca2+ pump of endoplasmic reticulum. This hypothesis is strongly supported by the demonstration that thapsigargin causes a rapid inhibition of the Ca2(+)-activated ATPase activity of rat liver microsomes, with an identical dose dependence to that seen in whole cell or isolated microsome Ca2+ discharge. The inhibition of the endoplasmic reticulum isoform of the Ca2(+)-ATPase is highly selective, as thapsigargin has little or no effect on the Ca2(+)-ATPases of hepatocyte or erythrocyte plasma membrane or of cardiac or skeletal muscle sarcoplasmic reticulum. These results suggest that thapsigargin increases the concentration of cytosolic free Ca2+ in sensitive cells by an acute and highly specific arrest of the endoplasmic reticulum Ca2+ pump, followed by a rapid Ca2+ leak from at least two pharmacologically distinct Ca2+ stores. The implications of this mechanism of action for the application of thapsigargin in the analysis of Ca2+ homeostasis and possible forms of Ca2+ control are discussed.

Animals↗
PubMed1990

Effects of MeCh, thapsigargin, and La3+ on plasmalemmal and intracellular Ca2+ transport in lacrimal acinar cells.

The Ca2(+)-mobilizing actions of the muscarinic receptor agonist, methacholine (MeCh), and the microsomal Ca2+ pump inhibitor, thapsigargin, were investigated in lacrimal acinar cells. As previously shown for parotid cells (J. Biol. Chem. 264: 12266-12271, 1989), thapsigargin activates both internal Ca2+ release and Ca2+ entry from the extracellular space without increasing cellular inositol phosphates. The inorganic Ca2+ antagonist La3+ inhibited MeCh- or thapsigargin-activated Ca2+ entry. However, when added before MeCh or thapsigargin, La3+ inhibited the extrusion of Ca2+ at the plasma membrane. This phenomenon was exploited in protocols designed to investigate the pathways for filling agonist-sensitive Ca2+ stores in lacrimal cells. The results show that, in contrast to previous suggestions that external Ca2+ is required to replenish agonist-regulated Ca2+ stores, the inhibition of Ca2+ extrusion permits recycling of Ca2+ released by MeCh back into an MeCh- and thapsigargin-sensitive pool. Thus, although extracellular Ca2+ is the major source for refilling the intracellular Ca2+ stores under physiological conditions, the pathway by which this Ca2+ enters the pool need not be a direct one. These results are consistent with the recently revised capacitative model for the refilling of intracellular Ca2+ stores through Ca2+ influx subsequent to Ca2+ depletion, according to which refilling of intracellular Ca2+ stores occurs via a cytoplasmic route rather than a direct channel between intracellular Ca2+ stores and the extracellular space.

Animals↗
PubMed1989

Activation of calcium entry by the tumor promoter thapsigargin in parotid acinar cells. Evidence that an intracellular calcium pool and not an inositol phosphate regulates calcium fluxes at the plasma membrane.

The depletion of an inositol 1, 4,5-trisphosphate-sensitive intracellular Ca2+ pool has been proposed to be the signal for Ca2+ entry in agonist-activated cells. Consistent with this idea, thapsigargin, which releases intracellular Ca2+ without inositol phosphate formation, has been reported to activate Ca2+ entry in certain cells. We now report the effects of thapsigargin on Ca2+ entry in parotid acinar cells. In fura-2-loaded parotid acinar cells, thapsigargin caused a sustained elevation of [Ca2+], but did not increase inositol phosphate formation. In the absence of extracellular Ca2+, the increase in [Ca2+], was transient, suggesting that thapsigargin activates both the release of Ca2+ from intracellular stores and the entry of Ca2+ from the extracellular space. In the absence of extracellular Ca2+, pretreatment with methacholine, an agonist believed to mobilize Ca2+ through the production of inositol 1,4,5-trisphosphate, inhibited but did not completely block the response to thapsigargin; likewise, pretreatment with thapsigargin inhibited the response to methacholine. In permeabilized cells, thapsigargin gradually released Ca2+, whereas inositol 1,4,5-trisphosphate caused a rapid and transient discharge of Ca2+. The simultaneous addition of thapsigargin with inositol 1,4,5-trisphosphate evoked a maximum Ca2+ release similar to that for inositol 1,4,5-trisphosphate alone, but the reuptake seen with inositol 1,4,5-trisphosphate alone was abolished. In intact cells, methacholine and thapsigargin together produced a greater initial release of Ca2+ than either alone, but they were not additive in the sustained phase of Ca2+ mobilization. These results demonstrate that the mechanisms for activation of Ca2+ entry by thapsigargin and methacholine are the same and are consistent with the idea that entry is initiated by the depletion of the intracellular inositol 1,4,5-trisphosphate-sensitive Ca2+ pool. The results also indicate that, in contrast to previously proposed models, Ca2+ entry into agonist-activated cells occurs directly across the plasma membrane to the cytoplasm rather than through a cycle of uptake and release by the intracellular Ca2+ pool.

Animals↗
PubMed1989

Stimulation of AIDS lymphocytes with calcium ionophore (A23187) and phorbol ester (PMA): studies of cytoplasmic free Ca, IL-2 receptor expression, IL-2 production, and proliferation.

We have studied whether the decreased lymphocyte proliferative responses of AIDS lymphocytes to stimulation by mitogens and antigens may be overcome when challenged with a combination of calcium ionophore A23187 and phorbol ester PMA. Comparison of the proliferative response of lymphocytes from nine patients with AIDS with the response of lymphocytes from nine control subjects showed that the response of AIDS lymphocytes was severely decreased when stimulated with PHA and no further response could be achieved by stimulation with A23187/PMA. On the other hand, no significant difference between the PHA-induced rise of cytoplasmic free calcium concentration ([Ca2+]1) in normal and AIDS lymphocytes was observed. The percentage of cells expressing IL-2 receptors (CD25) was also normal both after addition of PHA and after addition of A23187/PMA and the expression was normal on both CD4 and CD8 cells. The production of IL-2 in normal lymphocytes stimulated with A23187/PMA was 33 times higher than that after stimulation with PHA. In AIDS lymphocytes the production of IL-2 induced by all activators was severely decreased compared to control subjects, although the production of IL-2 after stimulation with A23187/PMA was higher than that in control lymphocytes after stimulation with PHA. The present study shows that a direct activation of protein kinase C combined with mobilization of cytoplasmic calcium does not overcome the lymphocyte proliferative deficiency of AIDS lymphocytes.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Ca2+ transients and Mn2+ entry in human neutrophils induced by thapsigargin.

Human neutrophils, preloaded with the fluorescent probe, Fura-2, were exposed to Ca2+-releasing agents. The monitored traces of fluorescence were transformed by computer to cytosolic Ca2+ concentration ([ Ca2+]i). Due to quenching of Fura-2, the addition of Mn2+ enabled us to compute the cytosolic concentration of total manganese ([Mn]i). The agents used were the novel Ca2+-mobilizing agent, thapsigargin (Tg), the chemotactic peptide, formyl-methionyl-leucyl-phenylalanine (FMLP), and the divalent cation ionophore, A23187. The agents caused transient rises of [Ca2+]i and monotonous rises of [Mn]i, suggesting influx but no efflux of Mn2+. The rise time of [Ca2+]i and the time constants and magnitude of the apparent Mn2+ influx were strongly dependent on the sequence of addition of the agonist and Ca2+. Contrary to FMLP, Tg needed several minutes to exert its full effect on the rise of [Ca2+]i and on the influx of Mn2+, the latter being dependent on two phases, activation and partial inactivation. Pretreatment with phorbol 12-myristate 13-acetate (PMA) inhibited the responses of Tg, FMLP and A23187. For comparison, human red blood cells were tested. Contrary to A23187, Tg did not induce Ca2+ uptake in ATP-depleted red cells but increased the Ca2+ pump flux in intact red cells by 10%. The experimental data and computer simulations of the granulocyte data suggest that time-dependent changes of both passive Ca2+ flux into the cytosol and Ca2+ flux of the plasma membrane pump are involved in the transient [Ca2+]i response.

Benzofurans↗
PubMed1989

How do inositol phosphates regulate calcium signaling?

Activation of a variety of cell surface receptors results in the phospholipase C-catalyzed hydrolysis of the minor plasma membrane phospholipid phosphatidylinositol 4,5-bisphosphate, with concomitant formation of inositol 1,4,5-trisphosphate and diacylglycerol. There is strong evidence that inositol 1,4,5-trisphosphate stimulates Ca2+ release from intracellular stores. The Ca2+-releasing actions of inositol 1,4,5-trisphosphate are terminated by its metabolism through two distinct pathways. Inositol 1,4,5-trisphosphate is dephosphorylated by a 5-phosphatase to inositol 1,4-bisphosphate; alternatively, inositol 1,4,5-trisphosphate can also be phosphorylated to inositol 1,3,4,5-tetrakisphosphate by a 3-kinase. Although the mechanism of Ca2+ mobilization is understood, the precise mechanisms involved in Ca2+ entry are not known; the proposal that inositol 1,4,5-trisphosphate secondarily elicits Ca2+ entry by emptying an intracellular Ca2+ pool is considered.

Animals↗
PubMed1989

Immunodeficiency after allogeneic bone marrow transplantation in man. Effect of phorbol ester (phorbol myristate acetate) and calcium ionophore (A23187) in vitro.

This study was undertaken to clarify the mechanism behind the severely decreased lymphocyte proliferative response upon stimulation with mitogens and antigens seen after allogeneic bone marrow transplantation (BMT) in man. We investigated eight BMT patients and eight controls and found that the proliferative response of patient cells was reduced both when the cells were stimulated with phytohaemagglutinin (PHA) and when they were stimulated with a combination of phorbol myristate acetate (PMA), which is an activator of protein kinase C (PKC), and the calcium ionophore A23187, which irreversibly opens for calcium transport into the cell (median relative responses were 41 and 37%, respectively). However, the PHA-induced increase in the concentration of intracellular free calcium in post-BMT cells was not significantly different from the values found in control cells and the expression of interleukin 2 (IL-2) receptors (CD25) was only slightly decreased. However, the production of IL-2 was severely decreased in patient cells after stimulation with A23187/PMA (median 3541 units), although it was higher than in PHA-stimulated control cells (median 354 units). These results show that a direct activation of PKC by PMA combined with an increase in intracellular free calcium by A23187 cannot overcome the lymphocyte proliferation deficiency in cells from patients after allogeneic BMT. The data suggests that the defect is affecting the diacylglycerol pathway considerably more than the inositol triphosphate pathway.

Adolescent↗
PubMed1989

Thapsigargin, a new calcium-dependent epithelial anion secretagogue.

1. Thapsigargin, a sesquiterpene lactone, was shown to cause electrogenic anion secretion in monolayers of human colonic epithelial cells, an effect which was crucially dependent upon calcium and did not involve eicosanoid formation. 2. To measure the secretory effect calcium needed to be present in the external bathing solution. By means of Fura-2 fluorescence measurements thapsigargin was shown to raise Cai by around 250 nM when the bathing solution contained calcium. In the nominal absence of external calcium thapsigargin raised Cai by only 60 nM, but from a lower basal value. This was insufficient to cause secretion. 3. Effects of other calcium-dependent secretagogues (e.g. lysylbradykinin) were inhibited in the presence of thapsigargin, whereas kinin responses were potentiated if the peptide was added following a stimulus which increases cyclic AMP. 4. From the data given here and the known behaviour of colonic epithelia it is concluded that thapsigargin increases Cai by a non-ionophoric mechanism by release from internal stores. Calcium-stimulated calcium influx then follows resulting in the opening of basolateral K channels, increasing the electrochemical gradient for chloride efflux, or alternatively by activating anion channels in the apical membrane. It is concluded that thapsigargin is a potentially important tool for examining epithelial mechanisms.

Adenocarcinoma↗
PubMed1988

Effect of thapsigargin on cytoplasmic Ca2+ and proliferation of human lymphocytes in relation to AIDS.

The tumor-promoting sesquiterpene lactone, thapsigargin, induced a dose-dependent increase of the cytoplasmic Ca2+ concentration ([ Ca2+]i) in human lymphocytes from a resting level between 100 and 150 nM up to about 1 microM. Half-maximum response was found at about 1 nM of thapsigargin, full response at 100 nM. The effect of thapsigargin on [Ca2+]i exceeded that of phytohaemagglutinin (PHA) which raised [Ca2+]i to maximum 300 nM. In combination with phorbol 12-myristate 13-acetate (PMA), thapsigargin stimulated the proliferation of normal lymphocytes to the same extent as did PHA, whereas the thapsigargin/PMA treatment could not restore the defective proliferation of AIDS lymphocytes in spite of the increased [Ca2+]i. Thapsigargin or PMA added separately had no stimulatory effects on cell proliferation. The thapsigargin/PMA treatment caused an increase in the interleukin-2 (IL-2) production of the lymphocytes, which was much higher than that caused by the PHA treatment, even in AIDS lymphocytes. Moreover, the thapsigargin/PMA treatment stimulated the expression of the IL-2 receptors on both normal and AIDS lymphocytes, similar to the effect of PHA. It is concluded that thapsigargin exerts its effects on lymphocyte proliferation by increasing [Ca2+]i, and that the general defect of AIDS lymphocytes, rather than being ascribed to the initiating signal systems, is associated with later events related to DNA synthesis and proliferation.

Acquired Immunodeficiency Syndrome↗