Inhibition of human mast cell proliferation and survival by tamoxifen in association with ion channel modulation

Abstract

Background Human lung mast cells (HLMCs) and the human mast cell line HMC-1 express a strongly outwardly rectifying Cl − current characteristic of that carried by the voltage-dependent Cl − channel ClC-5. A similar but distinct current has been implicated in the control of cell proliferation in astrocytes. Objective In this study, we have examined the effects of the Cl − channel blocker tamoxifen on ion channel activity and cell proliferation in both HMC-1 and HLMCs. Methods We used the whole-cell patch-clamp technique to characterize macroscopic ion currents in mast cells before and after addition of tamoxifen. HMC-1 proliferation was assessed by incorporation of tritiated thymidine, HLMC proliferation was determined by counting cells in long-term culture, and cell viability was assessed by annexin V binding and propidium iodide uptake. Results In HMC-1, tamoxifen reduced the outward Cl − current at +130 mV by 73% ± 9% at a concentration of 3 μmol/L and simultaneously opened a novel inwardly rectifying nonselective cation current with a mean inward current of 153 ± 18 pA at −130 mV. Tamoxifen produced a dose-dependent inhibition of HMC-1 proliferation (90.3% ± 4.0% inhibition at 30 μmol/L) without altering cell viability. Tamoxifen inhibited the outward ClC-5-like current in HLMCs, did not open an inward current, and produced a dose-dependent inhibition of HLMC proliferation in long-term culture. Conclusion Tamoxifen inhibits HMC proliferation, possibly through ion channel modulation. This suggests that tamoxifen might be useful in the treatment of mast-cell-mediated diseases, including mastocytosis, asthma, and pulmonary fibrosis.