Phorbol myristate acetate: a mitogen selective for a T-lymphocyte subpopulation.

Touraine, Jean‐Louis; Hadden, John W.; Touraine, F.; Hadden, Elba M.; Estensen, Richard D.; Ra, Good

doi:10.1084/jem.145.2.460

Cited by 165 publications

(48 citation statements)

References 14 publications

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“…Protein kinase C is thought to account for all or most of the biological events that occur after treatment of cells with PMA (45). In previous studies that used primary cultures of unfractionated PBL, PMA was reported to be a T-cell mitogen with a potency approximately one-third that of the lectin PHA (58). After treatment of purified CD28+ cells with PMA only, thymidine incorporation was only slightly above the baseline ( Table 1), indicating that PMA is a comitogen for T cells, and that "accessory" cells (monocytes) are required for PMA to cause T-cell proliferation (10).…”

Section: Resultsmentioning

confidence: 99%

T-cell proliferation involving the CD28 pathway is associated with cyclosporine-resistant interleukin 2 gene expression.

June¹,

Ledbetter²,

Gillespie³

et al. 1987

Mol. Cell. Biol.

464

278

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CD28 is a homodimeric glycoprotein expressed on the surface of a major subset of human T cells that has recently been identified as a member of the immunoglobulin supergene family. The binding of monoclonal antibodies to the CD28 antigen on purified T cells does not result in proliferation; however, previous studies have shown that the combination of CD28 stimulation and protein kinase C activation by phorbol myristate acetate (PMA) results in T-cell proliferation that is independent of both accessory cells and activation of the T-cell receptor-CD3 complex. In the present study, effects of stimulation by anti-CD28 on cell cycle progression and on the interleukin 2 (IL-2) and IL-2 receptor system have been investigated on primary cultures of purified peripheral-blood CD28+ T cells. There was no measurable effect on cell size or on DNA synthesis after stimulation of resting (GO) cells by CD28 alone. After 3 h of activation of T cells by PMA alone, a slight (8%) increase in cell volume occurred that did not progress to DNA synthesis. In contrast, T-cell stimulation by CD28 in combination with PMA resulted in a progressive increase in cell volume in --100% of cells at 12 to 14 h after stimulation. Northern blot (RNA blot) analysis revealed that CD28 stimulation alone failed to cause expression of the alpha chain of the IL-2 receptor or of IL-2 mRNA, and in accord with previous studies, stimulation by PMA alone resulted in the accumulation of IL-2 receptor transcripts but no detectable IL-2 mRNA. In contrast, T-cell stimulation by the combination of CD28 and PMA resulted in the appearance of IL-2 transcripts and enhanced expression of IL-2 receptor mRNA. Functional studies revealed that the proliferation induced by CD28 and PMA stimulation was entirely resistant to cyclosporine, in contrast to T-cell activation induced by the CD3-T-cell receptor complex. Cyclosporine was found not to affect the accumulation of IL-2 mRNA after CD28 plus PMA stimulation, although there was no detectable IL-2 mRNA after stimulation by CD3 in the presence of the drug. Furthermore, stimulation by CD28 in combination with immobilized CD3 antibodies caused a striking enhancement of IL-2 mRNA expression that was, in part, resistant to the effects of cyclosporine. These studies indicate that the CD28 molecule synergizes with protein kinase C activation to induce IL-2 gene expression and demonstrate that stimulation by the CD28 pathway can cause vigorous T-cell proliferation even in the presence of cyclosporine and that cyclosporine does not prevent transcription of 16-2 mRNA, as has been suggested previously. Moreover, these findings suggest that a potential role for the CD28 molecule in vivo may be to augment IL-2 production after stimulation of the CD3-T-cell receptor molecular complex and thereby to amplify an antigen-specific immune response. Finally, these results provide further evidence that the CD28 molecule triggers T-cell proliferation in a manner that differs biochemically from CD3-T-cell receptor-induced proliferation.The binding ...

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Section: Resultsmentioning

confidence: 99%

T-cell proliferation involving the CD28 pathway is associated with cyclosporine-resistant interleukin 2 gene expression.

June¹,

Ledbetter²,

Gillespie³

et al. 1987

Mol. Cell. Biol.

464

278

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“…Thus, PD tumor promoters increase killing by activated macrophages and by polymorphonuclear leukocytes through the generation of reactive forms of oxygen (26)(27)(28). PD tumor promoters are also mitogenic for a subpopulation of human T lymphocytes (29), but the activity of these cells in host defense is not known. Because Media.…”

Section: Introductionmentioning

confidence: 99%

Natural killing of tumor cells by human peripheral blood cells. Suppression of killing in vitro by tumor-promoting phorbol diesters.

Seaman¹,

Gindhart²,

Blackman³

et al. 1981

J. Clin. Invest.

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A B S T R A C T Tumor-promoting phorbol diesters were shown to suppress natural killing in vitro by human peripheral blood mononuclear cells. The inhibitory effect of different phorbol diesters and their analogues correlated with their potency as tumor promoters, the most effective agent being 12-0-tetradecanoylphorbol-13-acetate (TPA). Both peripheral blood cells and targets specifically bound TPA, and natural killing could be inhibited by pretreatment of either cell population with TPA, though this was less effective than direct addition of TPA to the assay. Cells that had been pretreated with TPA released TPA and metabolites of TPA during subsequent incubation in fresh medium. This release of TPA was evidently responsible for the inhibition of natural killing by pretreated target cells; in experiments where labeled and unlabeled target cells were mixed, pretreatment of unlabeled targets with TPA inhibited killing of labeled targets. Suppression of natural killing by TPA was greatly reduced when adherent cells were removed from the peripheral blood cells, suggesting that monocytes mediate suppression. Inhibition of natural killing by TPA provides a model for examining the regulation of natural killing. Suppression of natural killing by phorbol diesters may contribute to their activity as tumor promoters.

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“…TPA enhances the mitogenic effect of plant lectins on various animal lymphocytes (for review, Mastro, 1983) and is mitogenic by itself for human T cells in the presence of (greater than approximately 0 5 %) monocytes (Touraine, Hadden, Touraine, Hadden, Estensen & Good, 1977; Koretzky, Daniele & Nowell, 1982). We reasoned that the effect of TPA on bulk populations of human lymphocytes might be more easily interpreted than those arising from the plant lectins, which interact with many cell surface molecules.…”

Section: Introductionmentioning

confidence: 99%

Voltage‐gated potassium conductance in human T lymphocytes stimulated with phorbol ester.

Deutsch¹,

Krause²,

Lee³

1986

The Journal of Physiology

146

111

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SUMMARY1. The whole-cell patch-clamp method was used to study the voltage-gated K+ conductance of human peripheral blood T lymphocytes.2. After entry into whole-cell recording mode, there are time-dependent changes in some properties of the conductance. Over the first 10-30 min, the threshold for activation shifts about 10 mV more negative, and the rates of activation and inactivation increase. Inactivation is less strongly voltage dependent than activation or deactivation.3. Lymphocytes were stimulated to proliferate in culture with the tumour promoter 12-O-tetradecanoylphorbol-13-acetate (TPA).4. No changes in K+ conductance were observed in the first few hours of TPA stimulation. 5. At 24 h after mitogen addition, TPA-treated cells were found to have 17-fold greater average voltage-gated K+ conductance than unstimulated control cells.6. At 48 h, TPA-stimulated cells had the same average K+ conductance as at 24 h, even though the cells were now much increased in size, as measured by cell capacitance.7. DNA synthesis by cultures stimulated with TPA, phytohaemagglutinin or succinyl concanavalin A was depressed by the addition of 0-1 mM-quinine at any point in the culture period. In the first 20 h after mitogen addition, DNA synthesis was more effectively inhibited by quinine than if the drug were added later. Cell proliferation was equally sensitive to quinine regardless of mitogen.

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Phorbol myristate acetate: a mitogen selective for a T-lymphocyte subpopulation.

Cited by 165 publications

References 14 publications

T-cell proliferation involving the CD28 pathway is associated with cyclosporine-resistant interleukin 2 gene expression.

T-cell proliferation involving the CD28 pathway is associated with cyclosporine-resistant interleukin 2 gene expression.

Natural killing of tumor cells by human peripheral blood cells. Suppression of killing in vitro by tumor-promoting phorbol diesters.

Voltage‐gated potassium conductance in human T lymphocytes stimulated with phorbol ester.

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