UNIGE document Scientific Article
previous document  unige:3875  next document
add to browser collection
Title

Inhibition of basal p38 or JNK activity enhances epithelial barrier function through differential modulation of claudin expression

Authors
Published in American Journal of Physiology. Cell Physiology. 2009, vol. 297, no. 3, p. C775-87
Abstract Tight junctions (TJs) form a barrier to the paracellular diffusion of ions and solutes across epithelia. Although transmembrane proteins of the claudin family have emerged as critical determinants of TJ permeability, little is known about the signaling pathways that control their expression. The aim of this study was to assess the role of three mitogen-activated protein kinases (MAPKs), i.e., extracellular signal-regulated kinase-1/2 (ERK1/2), c-Jun NH(2)-terminal kinases (JNKs), and p38 kinases, in the regulation of epithelial barrier function and claudin expression in mammary epithelial cells. Addition of either PD169316 (a p38 inhibitor) or SP600125 (a JNK inhibitor) induced formation of domes (a phenomenon dependent on TJ barrier function) and enhanced transepithelial electrical resistance, whereas U0126 (an inhibitor of the ERK1/2 activators MEK1/MEK2) had no significant effect. Similar results were obtained using mechanistically unrelated p38 or JNK inhibitors. PD169316 increased the expression of claudin-4 and -8, whereas SP600125 increased claudin-4 and -9 and downregulated claudin-8. Silencing of p38alpha by isoform-specific small interfering RNAs increased claudin-4 and -8 mRNAs, whereas silencing of p38beta only increased claudin-4 mRNA. Silencing of either JNK1 or JNK2 increased claudin-9 mRNA expression while decreasing claudin-8 mRNA. Moreover, selective silencing of JNK2 increased claudin-4 and -7 mRNAs. Finally, both PD169316 and SP600125 inhibited the paracellular diffusion of Na(+) and Cl(-) across epithelial monolayers. Collectively, these results provide evidence that inhibition of either p38 or JNK enhances epithelial barrier function by selectively modulating claudin expression, implying that the basal activity of these MAPKs exerts a tonic effect on TJ ionic permeability.
Keywords AnimalsAnthracenes/pharmacologyButadienes/pharmacologyCell LineDogsEpithelium/physiologyFemaleImidazoles/pharmacologyMAP Kinase Kinase 4/antagonists & inhibitors/metabolismMammary Glands, Animal/cytologyMembrane Proteins/genetics/metabolismMiceNitriles/pharmacologyP38 Mitogen-Activated Protein Kinases/antagonists & inhibitors/metabolism
Identifiers
PMID: 19605737
Full text
Article (Author postprint) (1.9 MB) - document accessible for UNIGE members only Limited access to UNIGE
Supplemental data - I (138 Kb) - public document Free access
Supplemental data - II (123 Kb) - public document Free access
Supplemental data - III (24 Kb) - public document Free access
Other version: http://ajpcell.physiology.org/cgi/content/full/297/3/C775
Structures
Research groups Groupe Eric Féraille (néphrologie) (29)
Etudes et traitement de l'hépatite C et B (554)
Citation
(ISO format)
CARROZZINO, Fabio et al. Inhibition of basal p38 or JNK activity enhances epithelial barrier function through differential modulation of claudin expression. In: American Journal of Physiology. Cell Physiology, 2009, vol. 297, n° 3, p. C775-87. https://archive-ouverte.unige.ch/unige:3875

254 hits

325 downloads

Update

Deposited on : 2009-10-22

Export document
Format :
Citation style :