Interleukin-4 activates large-conductance, calcium-activated potassium (BKCa) channels in human airway smooth muscle cells.
Large-conductance, calcium-activated potassium (BK(Ca)) channels are regulated by voltage and near-membrane calcium concentrations and are determinants of membrane potential and excitability in airway smooth muscle cells. Since the T helper-2 (Th2) cytokine, interleukin (IL)-4, is an important mediator of airway inflammation, we investigated whether IL-4 rapidly regulated BK(Ca) activity in normal airway smooth muscle cells. On-cell voltage clamp recordings were made on subconfluent, cultured human bronchial smooth muscle cells (HBSMC). Interleukin-4 (50 ng ml(-1)), IL-13 (50 ng ml(-1)) or histamine (10 microm) was added to the bath during the recordings. Immunofluorescence studies with selective antibodies against the alpha and beta1 subunits of BK(Ca) were also performed. Both approaches demonstrated that HBSMC membranes contained large-conductance channels (>200 pS) with both calcium and voltage sensitivity, all of which is characteristic of the BK(Ca) channel. Histamine caused a rapid increase in channel activity, as expected. A new finding was that perfusion with IL-4 stimulated rapid, large increases in BK(Ca) channel activity (77.2 +/- 63.3-fold increase, P < 0.05, n = 18). This large potentiation depended on the presence of external calcium. In contrast, IL-13 (50 ng ml(-1)) had little effect on BK(Ca) channel activity, but inhibited the effect of IL-4. Thus, HBSMC contain functional BK(Ca) channels whose activity is rapidly potentiated by the cytokine, IL-4, but not by IL-13. These findings are consistent with a model in which IL-4 rapidly increases near-membrane calcium concentrations to regulate BK(Ca) activity.
Martin
Gilles
G
Department of Medicine, LRB 319, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA.
O'Connell
Robert J
RJ
Pietrzykowski
Andrzej Z
AZ
Treistman
Steven N
SN
Ethier
Michael F
MF
Madison
J Mark
JM
D001980:Bronchi / Q000166:cytology / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D006632:Histamine / Q000502:physiology; D006801:Humans; D018793:Interleukin-13 / Q000502:physiology; D015847:Interleukin-4 / Q000502:physiology*; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000502:physiology*; D008564:Membrane Potentials; D009130:Muscle, Smooth / Q000166:cytology / Q000502:physiology*; D018408:Patch-Clamp Techniques
D018793:Interleukin-13; D051036:Large-Conductance Calcium-Activated Potassium Channels; D015847:Interleukin-4; D006632:Histamine; D002118:Calcium