Induction of Interleukin 2 Messenger RNA Inhibited by Cyclosporin A

Elliott, JF; Lin, Yuan; Mizel, S.B.; Bleackley, R. Chris; Harnish, DG; Paetkau, Verner

doi:10.1126/science.6334364

Cited by 388 publications

(101 citation statements)

References 14 publications

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“…We argue that the step inhibited by immunophilin ligands in these two cell types is part of a general Ca2l-dependent signaling mechanism. Indeed, in addition to the findings described above, the actions of these immunosuppressive agents in both cell types show several similarities: (i) CsA inhibits TCR-mediated exocytosis in cytolytic T cells, without affecting TCR-mediated PI hydrolysis (22); (ii) CsA and FK506 inhibit IgE receptor-mediated activation of the nuclear factor AP-1 (T.H., J. Segars, and R.J.H., unpublished results), which is reminiscent of their effects in T cells (23,24); (iii) CsA inhibits cytokine transcription in both mast cells and T cells (25)(26)(27)(28)(29).…”

Section: Discussionmentioning

confidence: 99%

Immunophilin ligands demonstrate common features of signal transduction leading to exocytosis or transcription.

Hultsch

Albers²,

Schreiber³

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

110

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Investigations of the actions and interactions of the immunophilin ligands FK506, cyclosporin A (CsA), rapamycin, and 506BD suggest that complexes of FK506 with an FK506-binding protein or of CsA with a cyclophilin (CsAbinding protein) inhibit the T-cell receptor-mediated signal transduction that results in the transcription of interleukin 2. Now we report an identical spectrum of activities of FK506, CsA, rapamycin, and 506BD on IgE receptor-mediated signal transduction that results in exocytosis of secretory granules from the rat basophilic leukemia cell line RBL-2113, a mast cell model. Both FK506 and CsA inhibit receptor-mediated exocytosis (CsA IC50 = 200 nM; FK506 IC5s = 2 nM) without affecting early receptor-associated events (hydrolysis of phosphatidylinositol, synthesis and release of eicosanoids, uptake of Ca21). In contrast, rapamycin and 506BD, which share common structural elements with FK506, by themselves have no effect on IgE receptor-mediated exocytosis. Both compounds, however, prevent inhibition by FK506 but not by CsA. Affinity chromatography with FKS06, CsA, and rapamycin matrices indicates that the same set of immunophilins present in RBL-2113 cells have been found in Jurkat T cells and calf thymus; however, the relative amounts ofthese proteins differ in the two cell types. These results suggest the existence of a common step in cytoplasmic signaling in T cells and mast cells that may be part of a general signaling mechanism. Despite significant progress in our understanding of the events at the plasma membrane involved in receptormediated activation, little is known of the mechanisms of signal transduction through the cytoplasm. The immunosuppressive agents FK506, cyclosporin A (CsA), and rapamycin inhibit cytoplasmic signaling events in T cells (1-5), probably through the formation of complexes with cytoplasmic receptors termed immunophilins (1,2,4). The rat basophilic leukemia cell line RBL-2H3, a tumor analog of a mucosal mast cell that has been used to study the biochemical events of mast cell activation (6-8), was used to investigate the effects of FK506, rapamycin, and 506BD on IgE receptormediated exocytosis. These cells contain both CsA-sensitive (9) and FK506-sensitive (T.H. and R.J.H., unpublished results) rotamases. To date, every known immunophilin is a rotamase (i.e., a peptidyl-prolyl cis-trans isomerase).Here we show that the same interactions of these immunosuppressive agents that take place in the human T-cell line Jurkat are operative in a rat mast cell line. IgE receptormediated exocytosis from these cells is inhibited by concentrations of CsA (10) (1, 2, 4, 11, 12), inhibit the actions of FK506, but not CsA, in both mast cell and T-cell lines. However, rapamycin and 506BD by themselves have no effect on the TCR-mediated pathway or IgE receptor-mediated pathway. A preliminary characterization ofthe immunophilins in this mast cell line by affinity chromatography indicates that all of the proteins observed from Jurkat cells are present in RBL-2H3 cells, although ...

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Section: Discussionmentioning

confidence: 99%

Immunophilin ligands demonstrate common features of signal transduction leading to exocytosis or transcription.

Hultsch

Albers²,

Schreiber³

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

110

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“…Still, although the cellular and molecular mechanisms that induce this cytokine are well understood (52), the processes that temper IL-2 production during acute inflammatory responses remain obscure. Various pharmacological agents, including cyclosporine A and FK506 (53,54), can inhibit IL-2 production, and several host-derived factors have been shown to mediate this effect. Two examples are the inhibitory receptor CTLA-4 and the regulatory cytokine TGF-␤; the former can suppress IL-2 production by preventing CD28-dependent costimulation, and the latter by activating Smad3, a transcription factor that binds the IL-2 gene promoter and hinders transcription (55,56).…”

Section: Cellular Factors That Limit Th Cell Il-2 Productionmentioning

confidence: 99%

IL-27 Limits IL-2 Production during Th1 Differentiation

Villarino

Stumhofer

Saris

et al. 2006

The Journal of Immunology

200

155

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Although the ability of IL-27 to promote T cell responses is well documented, the anti-inflammatory properties of this cytokine remain poorly understood. The current work demonstrates that during infection with Toxoplasma gondii, IL-27R-deficient mice generate aberrant IL-2 responses that are associated with the development of a lethal inflammatory disease. Because in vivo depletion of IL-2 prolongs the survival of infected IL-27R−/− mice, these data suggest that IL-27 curbs the development of immunopathology by limiting parasite-induced IL-2 production. Consistent with this hypothesis, IL-27R−/− CD4+ T cells produce more IL-2 than wild-type counterparts during in vitro differentiation, and when rIL-27 is introduced, it can suppress the expression of IL-2 mRNA and protein by the latter group. Additionally, these studies reveal that, like IL-27, IL-12 can inhibit IL-2 production, and although each employs distinct mechanisms, they can synergize to enhance the effect. In contrast, this property is not shared by closely related cytokines IL-6 and IL-23. Thus, while traditionally viewed as proinflammatory agents, the present findings establish that IL-27 and IL-12 cooperate to limit the availability of IL-2, a potent T cell growth and survival factor. Moreover, because the current studies demonstrate that both can induce expression of suppressor of cytokine signaling 3, a protein that tempers cytokine receptor signaling, they also suggest that IL-27 and IL-12 share additionally inhibitory properties.

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“…The immunosuppressants eyclosporin A (CsA) and FK506 inhibit T-cell activation via a common pathway by preventing the transcriptional activation of the interleukin-2 gene [1][2][3][4][5], These drugs bind to distinct intracellular receptors, CsA to cyclophilin (CyP) [6,7] and FK506 to FK506-binding protein [8,9]. Recently, the Caa+/ealmodulin (CaM)-dependent protein phosphatuse calcineurin (CN) was implicated as the common proximal target of these drug receptor complexes [10], Several studies have since supported this by demonstrating that both CsA-Cyp and FKS06-FKBP complexes inhibit calcineurin in vitro [10][11][12][13], and that overexpression of calcineurin in the T-cell line Jurkat resulted in an increased resistance to these drugs [14,15].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of calcineurin by cyclosporin A‐cyclophilin requires calcineurin B

et al. 1992

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The interaction of the immunosuppressive complex cyclosporin A‐cyclophilin (CsA‐CyP) with the Ca2+/calmodulin‐dependent protein phosphatase calcineurin is investigated using a recombinant form of the A subunit of calcineurin (rCNA). Only in the presence of purified calcineurin B (CNB) does rCNA show the response of native calcineurin, i.e. 50% inhibition of rCNA phosphatase activity at 6 nM human cyclophilin B and 0.6 μM human cyclophilin A using [32P]casein as substrate, yet stimulation of activity with p‐nitrophenyl phosphate as substrate. This study demonstrates that the B subunit is necessary to confer sensitivity of calcineurin to CsA‐CyP.

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Induction of Interleukin 2 Messenger RNA Inhibited by Cyclosporin A

Cited by 388 publications

References 14 publications

Immunophilin ligands demonstrate common features of signal transduction leading to exocytosis or transcription.

Immunophilin ligands demonstrate common features of signal transduction leading to exocytosis or transcription.

IL-27 Limits IL-2 Production during Th1 Differentiation

Inhibition of calcineurin by cyclosporin A‐cyclophilin requires calcineurin B

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