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)

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

The effect of a single intravenous dose of calcium channel blocking agent verapamil (VER) on immune parameters in humans remains uncertain. In this study the effects of VER on lymphocyte subpopulations, interleukin 1 (IL-1) and 2 (IL-2) production in vitro, autologous mixed lymphocyte reaction (AMLR), IL-2 receptor expression (Tac positive cells) and natural killer (NK) cell activity were assessed. The investigations were undertaken on 12 hospitalized men, aged 19-23 years, with small abdominal complaints. None of them had active duodenal ulcer disease, while in the remaining no signs of organic disease were found. VER was given intravenously in a dose of 0.15 mg/kg and examinations were performed on peripheral blood mononuclear cells (PBL) drawn before and 30 and 150 min following VER injection. The single VER dose induced a significant, but transient increase in T, T helper, T suppressor lymphocytes and monocytes, and decrease in IL-1 and IL-2 generation as well as diminished Tac antigen expression. These data provide evidence that calcium channel blockers may transiently disturb immunoregulation.
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PMID:Effect of a single intravenous dose of verapamil on some immune parameters in duodenal ulcer patients. 326 13

The calcium channel blockers, verapamil and diltiazem, inhibit phytohemagglutinin (PHA)-induced mitogenesis at concentrations that block the T lymphocyte K channel currents. K channel blockers also inhibit the allogeneic mixed lymphocyte response in a dose-dependent manner with the same potency sequence as for block of K currents. K channel blockers inhibit PHA-stimulated mitogenesis only if added during the first 20-30 h after PHA addition, but not later, indicating a requirement for functional K channels during this period. We investigated the effect of K channel blockers on various aspects of protein synthesis for two reasons: first, protein synthesis appears to be necessary for the events leading to DNA synthesis, and second, the increase in the protein synthetic rate commences during the first 24-48 h after PHA addition. PHA-induced total protein synthesis was reduced to the level in unstimulated T lymphocytes by K channel blockers in a dose-dependent manner with the same potency sequence as for the block of K currents and inhibition of [3H]thymidine incorporation. Two-dimensional gel electrophoresis demonstrated that although the synthesis of the majority of proteins was reduced by K channel blockers to the level in unstimulated T cells, some proteins continued to be synthesized at an enhanced rate compared with resting cells. Two proteins, S and T, detected by two-dimensional gel electrophoresis in unstimulated T lymphocytes, appeared to be reduced in intensity in gels of PHA-treated T lymphocytes, in contrast to the increased synthesis of the remaining proteins. 4-Aminopyridine (4-AP), at concentrations that inhibit protein synthesis, prevented the apparent PHA-induced reduction of proteins S and T. These proteins may play a role in maintaining the T lymphocyte in a resting state and may be related to the translation inhibitory factors reported to be present at a higher specific activity in quiescent T lymphocytes than in PHA-activated T cells. The expression of the IL-2 receptor (Tac) during T lymphocyte activation was not altered by K channel blockers, whereas the production of interleukin 2 (IL-2) was reduced to the level in unstimulated T lymphocytes. Exogenous IL-2 partially relieved the inhibition of mitogenesis by low, but not by high, concentrations of 4-AP. These experiments clarify the role of K channels in T lymphocyte activation and suggest that functional K channels are required either for protein synthesis or for events leading to protein synthesis.
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PMID:Voltage-gated potassium channels are required for human T lymphocyte activation. 608 61

To evaluate the role of interleukin-2 (IL-2) in the inhibition of the proliferation of human peripheral blood mononuclear cells (PBMC) by calcium channel blockade, the effect of nifedipine, which blocks the L-type calcium channel on the proliferation, the IL-2 expression and the IL-2 production in human PBMC, was compared with the effect of mibefradil, which blocks both L- and T-type calcium channels with a more selective blockade of T-type channels. The rate of [3H]-thymidine incorporation into control and concanavalin A-induced PBMC in the presence or absence of the calcium channel blockers nifedipine or mibefradil (1, 10 or 50 microM) was assayed in the cells cultured for 3 days. The cellular cytotoxicity and the cell number in growing cultures was also determined in nifedipine- or mibefradil-treated control or stimulated cells. Restoration of the proliferative response in nifedipine- or mibefradil-treated cells was investigated by addition of exogenous IL-2. IL-2 receptor expression in the cells was monitored using antiactivated T-cell antigen (Tac) antibody, and the IL-2 production in the cell supernatants of the cultures was determined by an enzyme amplified sensitive immunoassay. Nifedipine and mibefradil concentration-dependently reduced the cell number and [3H]-thymidine incorporation or the do novo DNA synthesis in control and concanavalin A-stimulated human PBMC. The proliferative response of nifedipine- or mibefradil-treated cells was restored by addition of exogenous IL-2. The normal expression of IL-2 receptors was preserved while the IL-2 production was blocked in the presence of nifedipine or mibefradil.
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PMID:Inhibition of proliferation of human peripheral blood mononuclear cells by calcium antagonists. Role of interleukin-2. 1079 Dec 90