Rapid anti-secretory effects of glucocorticoids in human airway epithelium.
Glucocorticoids are anti-inflammatory molecules classically described as acting through a genomic pathway. Similar to many steroid hormones, glucocorticoids also induce rapid non-genomic responses. The present paper provides a general overview of the rapid non-genomic effects of glucocorticoids in airway and will be mainly focused on a retrospective of the authors work on rapid effects of glucocorticoids in airway epithelial cell transport. Using fluorescence microscopy, short circuit current measurements in human bronchial epithelial (16HBE14o(-)) cells, we reported rapid non-genomic effects of dexamethasone on cell signalling and ion transport. Dexamethasone (1 nM) rapidly stimulated Na(+)/H(+) exchanger activity and pH(i) regulation in 16HBE14o(-) cells. Dexamethasone also produced a rapid decrease of intracellular [Ca(2+)](i) to a new steady state concentration and inhibited the large and transient [Ca(2+)](i) increase induced by apical adenosine tri-phosphate (ATP). Dexamethasone also reduced by 1/3 the Ca(2+)-dependent Cl(-) secretion induced by apical ATP. The rapid effects of dexamethasone on intracellular pH and Ca(2+) were not affected by inhibitors of transcription, cycloheximide or by the classical glucocorticoid and mineralocorticoid receptors antagonists, RU486 and spironolactone, respectively. The rapid responses to glucocorticoid were reduced by the inhibitors of adenylated cyclase, cAMP-dependent protein kinase (PKA) and mitogen-activated protein kinase (ERK1/2). Our results demonstrate, that dexamethasone at low concentrations, rapidly regulates intracellular pH, Ca(2+) and PKA activity and inhibits Cl(-) secretion in human bronchial epithelial cells via a non-genomic mechanism which neither involve the classical glucocorticoid nor mineralocorticoid receptor.
Urbach
V
V
INSERM U454, Centre Hospitalier Universitaire Arnaud de Villeneuve, Montpellier, France. urbach@montp.inserm.fr
Verriere
V
V
Grumbach
Y
Y
Bousquet
J
J
Harvey
B J
BJ
D002118:Calcium / Q000037:antagonists & inhibitors / Q000502:physiology; D003907:Dexamethasone / Q000494:pharmacology; D005938:Glucocorticoids / Q000502:physiology*; D006801:Humans; D007424:Intracellular Fluid / Q000187:drug effects / Q000378:metabolism; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D005938:Glucocorticoids; D003907:Dexamethasone; D002118:Calcium