Progesterone inhibits chloride transport in human intestinal epithelial cells

Abstract

Several pieces of evidence suggest that female sex hormones may play a role in the regulation of electrolyte transport. We therefore hypothesized that female sex hormones might impair regulated transcellular chloride transport in human intestinal epithelial cells. The T84 cell line was used for electrophysiological studies. Changes in transepithelial resistance and short-circuit current (Isc) were measured via a dual voltage/current clamp in epithelial monolayers. Short-circuit current is equivalent to chloride secretion in T84 cells. Forskolin and 8-Br-cyclic adenosine monophosphate (cAMP) were used to activate cAMP-dependent Cl? transport. Ca2+-dependent secretion was stimulated by the receptor-mediated Ca2+ agonist carbachol. Acute exposure (30 minutes) to either progesterone or estradiol did not affect monolayer viability as reflected by transepithelial resistance. Moreover, the secretory response to both cAMP and Ca2+ agonists remained unaffected. In contrast, long-term exposure (24 hours) to physiological concentrations of progesterone (100 nM), but not estradiol, dose-dependently reduced the peak Isc induced by the cAMP-agonist forskolin from 125 +/- 2.7 mA. cm(2) in the control group to 96 +/- 2.5 mA. cm(2) in monolayers exposed to progesterone (n = 6 for each group; p <0.001). When the cAMP-analogue 8-Br-cAMP was used, the same behavior was observed (peak Isc = 112 +/- 1.6 mA. cm(2) vs 88 +/- 1.7 mA. cm(2) for control vs. progesterone-treated monolayers; n = 6 for each group; p <0.001). Taken together, our results suggest that progesterone but not estradiol inhibits cAMP-stimulated Cl- secretion in intestinal epithelial cells at a site distal to cyclic nucleotide generation.

Genistein Stimulates Jejunum Chloride Secretion via an Akt-Mediated Pathway in Intact Female Mice

“…E2 effects have also been linked to non-genomic inhibition of female rat colonic Cl − secretion mediated via Ca 2+ and PKC activation [ 38 ], likely mediated via inhibition of basolateral K Ca and/or CFTR channel activity. In addition, progesterone and estradiol have been shown to inhibit CFTR-mediated ion transport in PANC-1 pancreatic epithelial cells [ 39 ], and in T84 intestinal cells [ 40 ]. Anti-secretory responses to estrogen may be characteristic of whole body salt and water retention during specific parts (specifically during high estrogen states) of the menstrual cycle, for instance right before ovulation in pre-menopausal women [ 41 ].…”

The Role of Ion Transporters in the Pathophysiology of Infectious Diarrhea

“… 95 Thiazolidione, pyrimido-pyrrolo-quinoxalinedione (PPQ)/benzopyrimido-pyrrolo-oxazinedione, and glycine hydrides are CFTR inhibitors that currently are being explored in this context. 96 , 97 Similarly, although it has not reportedly been used in infectious diarrhea in human beings, the antisecretory agent crofelemer is approved for the treatment of human immunodeficiency virus–induced diarrhea and appears to act by inhibiting chloride secretion via CFTR and CLCA. 98 It also is being evaluated for the treatment of diarrhea occurring in the setting of cancer chemotherapy.…”

Intestinal Barrier Function and the Brain-Gut Axis

“…In contrast, estrogen receptor-β is mainly expressed in epithelial cells and is the most abundant estrogen receptor in the colon [181]. Both progesterone and estradiol have been shown to reduce chloride secretion in intestinal epithelial cells [182,183], whereas estradiol has also been found to reinforce epithelial permeability [184], and to up-regulate JAM-A and occludin expression [185].…”