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 purpose of these investigations was to compare the immunosuppressive mechanism of cyclosporine (CsA) with those of lipid-soluble local anesthetics and calmodulin antagonists. Chlorpromazine (CPZ) and pentobarbital (PB) both inhibit lymphocyte activation by attenuating sodium and potassium ion potentials. CPZ and N-(6-aminohexyl)-5-chloro-1-naphthalene sulfonamide (W-7) can also block calcium-dependent activation processes by inhibition of calmodulin and protein kinase C. All four compounds were found to suppress human and murine lymphoproliferation to both alloantigen or mitogen in a dose-dependent and saturable manner. Exogenous interleukin-2 (IL-2) restored mitogenic responsiveness to cultures suppressed using W-7 and CsA, but not to lymphocytes suppressed with either CPZ or PB. Cytofluorographic analysis revealed that the degree of suppression in drug-treated lymphocytes was significantly correlated with the surface expression of receptors for transferrin and interleukin-2. Inhibition of IL-2 activation by PB was demonstrated to result from a blockade of the mitogenic growth factor signal using the IL-2-dependent cell line HT-2. Thus, the mechanism of action of cyclosporine can be differentiated from those of anesthetic immunosuppressants at the level of responsiveness to interleukin-2. The data support the hypothesis that cyclosporine may be an antagonist of calmodulin that selectively blocks early events in T lymphocyte activation leading to IL-2 synthesis, but does not inhibit the expression or function of the IL-2 receptor.
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PMID:Comparison of the immunosuppressive effects of cyclosporine, lipid-soluble anesthetics, and calmodulin antagonists. Response to exogenous interleukin 2. 309 93