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Recombinant interleukin-2 acts like a class I antiarrhythmic drug on human cardiac sodium channels
T Proebstle1, M Mitrovics, M Schneider
1Abteilung für Allgemeine Physiologie der Universität Ulm, Germany.
Insights
Human recombinant interleukin-2 (rIL-2) blocks cardiac sodium channels, similar to Class I antiarrhythmic drugs. This action may explain high-dose rIL-2
Area of Science:
- Cardiology
- Molecular Pharmacology
- Immunology
Background:
- Interleukin-2 (IL-2) is a cytokine used in cancer therapy.
- High-dose IL-2 can cause cardiac side effects.
- The direct effects of IL-2 on cardiac ion channels are not well understood.
Purpose of the Study:
- To investigate the effects of human recombinant interleukin-2 (rIL-2) on sodium currents in isolated human cardiocytes.
- To determine the mechanism of rIL-2's action on cardiac sodium channels.
- To compare the effects of rIL-2 with recombinant tumor necrosis factor alpha (rTNF-alpha).
Main Methods:
- Whole-cell patch-clamp recording technique to measure sodium currents in human cardiocytes.
- Application of varying concentrations of rIL-2.
- Analysis of current-voltage relationships, inactivation curves, and recovery from block.
- Use of anti-IL-2 antibodies to elucidate the mechanism of action.
Main Results:
- rIL-2 reversibly blocked sodium currents in a concentration-dependent manner (50% block at 500 U/ml).
- rIL-2 shifted the steady-state inactivation curve in the negative direction by 15 mV.
- Block was use-dependent at stimulation frequencies >4 Hz.
- rIL-2's effects were abolished by polyclonal anti-IL-2 antibodies but not by anti-IL-2 receptor antibodies.
- rTNF-alpha did not affect sodium currents.
Conclusions:
- rIL-2 acts on human cardiac sodium channels similarly to Class I antiarrhythmic drugs.
- The observed effects are mediated by IL-2 binding to its receptor.
- These findings may explain the proarrhythmic side effects associated with high-dose intravenous rIL-2 therapy.
Abstract:
Human recombinant interleukin-2 (rIL-2) was bath-applied to isolated human cardiocytes while sodium currents were triggered and registered using the whole-cell recording technique. In the presence of the cytokine the sodium currents were reversibly blocked, 50% peak current reduction occurring at a concentration of 500 U/ml. The current-voltage relationship was not affected, but the steady-state inactivation curve was not affected, but the steady-state inactivation curve was shifted in the negative direction by 15 mV. When 35% of the sodium current was blocked the time constant of recovery from block at -135 mV was in the range of 63 +/- 27 ms. Use dependence was observed only at stimulation frequencies above 4 Hz. Addition of a polyclonal anti-IL-2 antibody to the extracellular solution prevented all of the above effects, while incubation of the cells with a function-blocking monoclonal anti-IL-2 receptor antibody had no influence on the described rIL-2 action. In contrast to rIL-2, recombinant tumor necrosis factor alpha (rTNF-alpha) did not affect the sodium currents. It is concluded that rIL-2 acts like a class I antiarrhythmic drug on human cardiac sodium channels. This might explain some of its proarrhythmic side effects when given intravenously in high doses.