Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P14784 (IL-2 receptor)
 3,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

FK506 is a recently introduced immunosuppressive agent synthesised by the microorganism Streptomyces tskubaensis. It has been found to be more potent than Cyclosporin A in inhibiting T cell activation. We investigated its effects on the expression of membrane bound as well as soluble interleukin-2 receptors on human lymphocytes. The membrane-bound IL-2 receptor expression was inhibited by FK506 in resting lymphocytes at a concentration of 1 pmol/l. At 10 nmol/l no further inhibition was seen. In activated lymphocytes FK506 exerted no inhibitory effect on the IL-2 receptor expression. The release of soluble IL-2 receptor showed a pronounced decline in the concentration interval between 10 pmol/l and 0.1 nmol/l. Above a concentration of 10 nmol/l, no further decrease was seen. In activated lymphocytes the expression of soluble IL-2 receptors was unaffected by FK506 incubated up to 72 h. Pretreatment of the lymphocytes with the compound did not further depress the expression of the membrane-bound or the soluble receptor. Our results also indicate that the expression of the membrane-bound receptor is more sensitive to the drug than the soluble form of the receptor.
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PMID:The immunosuppressive agent FK506 inhibits in vitro expression of membrane-bound and soluble interleukin-2 receptors on resting but not on activated human lymphocytes. 172 Apr 17

The high affinity form of the human IL-2 receptor (IL-2R) has two known components, the IL-2R alpha (p55) and the IL-2R beta chain (p75). We have previously shown that recombinant IL-2 (rIL-2) could induce the expression of the alpha-chain (p55) on T cells and thymocytes, and increase this expression following suboptimal activation with concanavalin A (Con A) in combination with IL-2. An increase in the accumulation of IL-2R alpha-specific mRNA induced by rIL-2 in T cells and thymocytes had also been documented. We report here that the expression of IL-2R beta on the cell surface can be demonstrated on human thymocytes by the binding of Mik beta1, a MoAb directed against an epitope of the beta-chain. The IL-2R beta chain is constitutively expressed on freshly isolated thymocytes; this expression can be increased in thymocytes activated with Con A in combination with IL-2 or tetradecanoylphorbol 13-acetate (TPA). Blocking the formation of high affinity receptors with a MoAb directed against the alpha-chain of the receptor results in an increase in the display of IL-2R beta as evidenced by binding of MoAb Mik beta1. The accumulation of IL-2R-beta-specific mRNA is observed in freshly isolated thymocytes and it is increased in thymocytes cultured with rIL-2 alone, with Con A, and further enhanced by the addition of rIL-2 in combination with Con A or with TPA. Cyclosporine (CsA), which inhibits the accumulation of lymphokine-specific mRNA of thymocytes, does not inhibit the induction of the accumulation of IL-2R beta-specific mRNA. This is analogous to its effect on the expression of the alpha-chain (p55), and the accumulation of alpha-chain-specific mRNA.
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PMID:Regulation of IL-2 beta receptor expression and beta-chain mRNA by human thymocytes. 173 30

Cyclosporine has dramatically improved the success rates for all forms of organ transplantation. However, its use is complicated by the frequent occurrence of hypertension and reversible nephrotoxicity. The iatrogenic hypertension induced by cyclosporine resembles a low-renin, salt-sensitive form of essential hypertension, which is often controlled with salt restriction and therapies counteracting renal salt acquisition, e.g., diuretics and calcium channel blockers (CCBs). CCBs may also counteract the direct vasoconstrictive effects of cyclosporine, as well as the effects of other vasoconstrictors, such as endothelin or thromboxane, that may be stimulated by cyclosporine. Additionally, CCBs may potentiate the immunosuppression of cyclosporine, yet minimize nephrotoxicity. We demonstrated that the in vitro combination of verapamil and cyclosporine had an additive inhibitory effect on the activation and function of human peripheral blood mononuclear cells in several assays of the afferent and efferent limbs of immunologic responses. This additive immunosuppression was not likely to have been related to these drugs' effects on interleukin-2 (IL-2) circuitry, since no additive inhibition of IL-2 production or IL-2 responsiveness was found. There was some additive inhibition of IL-2 receptor expression at the higher concentrations of verapamil and cyclosporine that were tested. Although the combination of verapamil and cyclosporine additively inhibited mitogen-induced 45Ca uptake, the inhibitory effect of cyclosporine appears to be due to an inhibition of lymphocyte activation rather than direct inhibition of calcium flux through the slow calcium channel, suggesting that the two drugs do not have additive effects in depressing the transmembrane flux of calcium. More recently, we have demonstrated that the inactive enantiomer of verapamil, which does not block the slow calcium channel, has identical immunosuppressive capabilities as the active enantiomer. Thus, the antiproliferative effect of verapamil is probably slow-calcium-channel independent and may represent the ability of the drug to interfere with muscarinic, alpha 1-adrenergic, or even opiate receptors on lymphocytes or to block lymphocyte potassium channels. An even better possibility is that verapamil may diminish necessary precursor molecule uptake into lymphocytes, since both the inactive and active isomeric forms of verapamil are capable of diminishing thymidine, uridine, and leucine incorporation into stimulated lymphocytes--necessary for DNA, RNA, and protein synthesis, respectively. These in vitro observations may have clinical applicability, as early studies demonstrate reduced rejection rates of cyclosporine-treated transplant patients receiving CCBs. Consequently, CCBs are important medications to be considered for use in cyclosporine-treated organ transplant recipients.
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PMID:Therapeutic benefits of calcium channel blockers in cyclosporine-treated organ transplant recipients: blood pressure control and immunosuppression. 203 18

Blast formation and mitotic activation of G0-arrested mouse thymocytes were triggered by the addition of concanavalin A plus interleukin 2 (IL-2) to the culture medium. When added alone, Con A induces within 6 hr a complex reprogramming ("priming") that comprises the activation of the IL-2 receptor gene. The primed thymocytes are competent to interact with IL-2 and to respond to its growth-promoting effect, which corresponds to blast formation and mitotic activation. Cyclosporin A, an immunosuppressive cyclic peptide of fungal origin, prevents in T lymphocytes the activation of a set(s) of genes encoding lymphokines and the IL-2 receptor but does not affect their expression once they have been activated. The biomedical implications of these observations are discussed.
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PMID:Cyclosporin A prevents induction of the interleukin 2 receptor gene in cultured murine thymocytes. 242 33

The effect of in vitro administration of Cyclosporin A (CsA) during mitogen, antigen and alloantigen activation of human T-lymphocytes on high affinity interleukin-2 (IL-2) receptor expression and -turnover and IL-2 production was investigated. The presence of CsA reduced 3H-thymidine incorporation and binding of radiolabelled human recombinant (ala125) IL-2 to high-affinity receptors in a dose-dependent fashion, although a pronounced inter- and intra-individual variation in sensitivity to CsA mediated immunosuppression was observed. Maximum inhibition was obtained when antigen and CsA were added to culture medium simultaneously. Preincubation with CsA did not influence the response. Although the number of IL-2 receptors was reduced, the turnover of the remaining high affinity IL-2 receptors on CsA treated cells was unaffected. Thus, binding, internalization and degradation were qualitatively unaltered by CsA administration. Finally, T cell activation in the presence of CsA reduced radioimmuno detectable IL-2 in cell culture supernatants to about 20%. CsA, added during antigen activation, reduced the number of Tac antigen presenting cells, but anti-Tac was unable to detect variations in the expression of high affinity IL-2 receptors. The present data indicate that CsA mediates immunosuppression by affecting early events during T-cell activation, and that variations in high affinity IL-2 receptor expression and IL-2 production are secondary to this affection.
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PMID:Cyclosporin A mediated immunosuppression in vitro: effect on high affinity interleukin-2 receptor expression and -turnover. 278 98

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 (G0) 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 approximately 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.
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PMID:T-cell proliferation involving the CD28 pathway is associated with cyclosporine-resistant interleukin 2 gene expression. 283 Apr 95

Cyclosporine (CsA) is a novel immunosuppressive agent currently used clinically, to prevent rejection of solid organ allografts and to prevent graft-vs.-host disease. Early studies in a variety of animal models exhibited transplantation tolerance after limited treatment with this unique agent. The apparent specific immunological unresponsiveness induced by CsA is thought to be maintained by antigen-specific suppressor T lymphocytes. Studies attempting to dissect the mechanism of action of this unique agent suggested that CsA selectively affected different T lymphocyte populations. Cyclosporine was very effective at inhibiting the production of interleukin-2 (IL-2), a soluble lymphokine known to amplify cytotoxic T cell responses and was also capable of preventing IL-2 receptor expression on the precursor cytotoxic T lymphocyte. In contrast, to the effect on T helper cells and on the precursor cytotoxic T lymphocyte, studies in vitro and in vivo demonstrated that CsA had a sparing effect on suppressor T cell induction. More recent studies have indicated that CsA allows for the amplification of suppressor T lymphocytes independent of interleukin-2 indicating that other cellular and/or soluble factors are important for potentiation of suppressor T lymphocyte activity. However, the molecular action of CsA at the cellular level still remains unresolved. Thus, CsA is not only a useful drug in clinical transplantation but it has become increasingly important as an immunologic probe allowing the dissection of complex cellular interactions involved in the immune response.
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PMID:Cyclosporine and the immune response: basic aspects. 294 35

The effects of cyclosporine on T cell activation induced by monoclonal anti-CD3 antibodies, 12-O-tetradecanoyl phorbol-13-myristate acetate (TPA), or human recombinant interleukin 2 (IL-2) were investigated. Cyclosporine inhibited anti-CD3-mediated expression of IL-2 receptors and IL-2 factor production by peripheral blood mononuclear cells (PBM). Cyclosporine did not inhibit when TPA rather than anti-CD3 was used to activate the PBM. Effects of cyclosporine on the activation of memory T cells were also dependent on the stimulus used to activate memory T cells. Cyclosporine inhibited alloantigen associated memory T cell activation, but not when IL-2 provided the necessary triggering signal to memory T cells. IL-2-mediated memory T cell activation was inhibitable with monoclonal antibodies directed at the IL-2 receptor or at the IL-2 factor. Collectively, these findings indicate that the inhibitory activity of cyclosporine is dependent on the activating signals provided to T cells. Moreover, antibodies directed at the IL-2 system together with cyclosporine might prove to be more potent immunosuppressants than either agent alone.
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PMID:Inhibitory activity of cyclosporine is dependent on the activating signal(s) provided to T cells. 296 Jul 93

Cyclosporine in combination with other chemical or biological immunosuppressive modalities has been useful in clinical and experimental organ transplantation. In these studies, the efficacy of adjunctive subtherapeutic doses of CsA given to immunologically enhanced heart graft recipients or to animals treated with an anti-IL-2 receptor monoclonal antibody (ART18) are described. Individually, the treatment entities are only partially effective. In rats undergoing active and passive enhancement alone, heart allograft survival was increased to 25 +/- 12 days in two-thirds, indefinitely in one-third. After ART18 treatment, grafts survive 21 +/- 1 days. Grafts are accepted permanently in animals receiving full-dose CsA (15 mg/kg X 7), but are rejected acutely (c. 7 days) when subtherapeutic doses (1.5 mg/kg X 7) are used. However, when subtherapeutic doses of CsA are given in combination with immunological enhancement or with interleukin-2-receptor-targeted therapy, graft survival increases dramatically, with permanent or markedly prolonged engraftment occurring in all instances. In the early phases of host unresponsiveness, both enhancement and IL-2R-targeted therapy, graft survival increases dramatically, with permanent or markedly prolonged engraftment occurring in all instances. In the early phases of host unresponsiveness, both enhancement and IL-2R-targeted therapy spare selectively T cells with suppressor activity in vivo; in enhanced animals, the W3/25+ subset is responsible for prolonged graft survival, the OX8+ fraction is responsible in ART18-treated animals and in CsA-treated animals. Both subpopulations show suppressor activity in the later stages of combination treatment. IL-3 production is increased significantly in these states of unresponsiveness, an observation also noted during maintenance CsA treatment; this seems to correlate with suppressor activity. Immunoperoxidase studies of the graft infiltrates emphasize the synergistic effects of combination treatments. Thus, subtherapeutic doses of CsA plus biologic host manipulations produce greatly increased graft survival by affecting selectively different host immune mechanisms.
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PMID:Synergy between subtherapeutic doses of cyclosporine and immunobiological manipulations in rat heart graft recipients. 297 Jan 37

The in vivo administration of the immunosuppressive drug, Cyclosporin A (CSA), has allowed us to define IL-2 dependent and IL-2 independent pathways of T cell activation in vivo. Thus, CSA inhibited T cell activation and the production of IL-2 mRNA in the draining lymph node (LN) population following footpad injection of anti-CD3 mAb. In contrast, even though CSA completely inhibited the induction of IL-2 mRNA in the draining LN following the injection of allogeneic cells, T cell activation proceeded normally. In the present study, we have analyzed the effects of CSA on the T cell activation induced in vivo by T. cruzi. BALB/c and C57BL/6 mice were injected subcutaneously in the footpad with irradiated, cultured T. cruzi trypomastigotes (CMTs, clone sylvio-X10/4). CSA was delivered to the mice via an osmotic pump, Alzet 2001 at a concentration of 35mg/Kg/day. The injection of CMTs resulted in a dose dependent activation of the draining LN population including an increase in the number of cells, an increase in cell size, induction of expression of the IL-2 receptor and other T cell activation antigens (Ly-6, CD28), induction of responsiveness to IL-2, and a vigorous proliferative response when the freshly explanted node was cultured for 18 h in vitro in the presence of 3H-TdR. CSA markedly inhibited all of these parameters of T cell activation. Thus, the early T cell activation response observed after injection of irradiated T. cruzi CMTs appears to be mediated by an IL-2 dependent, CSA sensitive T cell activation pathway.
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PMID:Comparative aspects of T cell activation in vivo following stimulation with anti-CD3 MAB, allogeneic cells and Trypanosoma cruzi. 307 79


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