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Hydrogen peroxide inhibits Ca 2+ ‐dependent chloride secretion across colonic epithelial cells via distinct kinase signaling pathways and ion transport proteins
Author(s) -
Chappell Alfred E.,
Bunz Michael,
Smoll Eric,
Dong Hui,
Lytle Christian,
Barrett Kim E.,
McCole Declan F.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.07-099697
Subject(s) - signal transduction , kinase , chemistry , secretion , cotransporter , microbiology and biotechnology , mapk/erk pathway , ion transporter , biochemistry , biology , sodium , organic chemistry , membrane
Reactive oxygen species (ROS) are key mediators in a number of inflammatory conditions, including inflammatory bowel disease (IBD). ROS, including hydrogen peroxide (H 2 O 2 ), modulate intesti nal epithelial ion transport and are believed to contrib ute to IBD‐associated diarrhea. Intestinal crypt fluid secretion, driven by electrogenic Cl − secretion, hy drates and sterilizes the crypt, thus reducing bacterial adherence. Here, we show that pathophysiological con centrations of H 2 O 2 inhibit Ca 2+ ‐dependent Cl − secretion across T 84 colonic epithelial cells by elevating cytosolic Ca 2+ , which contributes to activation of two distinct signaling pathways. One involves recruitment of the Ca 2+ ‐responsive kinases, Src and Pyk‐2, as well as extracellular signal‐regulated kinase (ERK). A separate pathway recruits p38 MAP kinase and phosphoinositide 3‐kinase (PI3‐K) signaling. The ion transport response to Ca 2+ ‐dependent stimuli is mediated in part by K + efflux through basolateral K + channels and Cl − uptake by the Na + ‐K + ‐2Cl − cotransporter, NKCC1. We dem onstrate that H 2 O 2 inhibits Ca 2+ ‐dependent basolateral K + efflux and also inhibits NKCC1 activity indepen dently of inhibitory effects on apical Cl − conductance. Thus, we have demonstrated that H 2 O 2 inhibits Ca 2+ ‐ dependent Cl − secretion through multiple negative regulatory signaling pathways and inhibition of specific ion transporters. These findings increase our under standing of mechanisms by which inflammation dis turbs intestinal epithelial function and contributes to intestinal pathophysiology.— Chappell, A. E., Bunz, M., Smoll, E., Dong, H., Lytle, C., Barrett, K. E., McCole, D. F. Hydrogen peroxide inhibits Ca2+‐dependent chlo ride secretion across colonic epithelial cells via distinct kinase signaling pathways and ion transport proteins. FASEB J. 22, 2023—2036 (2008)