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GROWTH, DIFFERENTIATION, AND APOPTOSIS

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

¹Department of Cell Physiology and Metabolism, ²Department of Pathology and Immunology, Division of Clinical Pathology, and ³Service de Néphrologie, Fondation pour Recherches Médicales, Faculty of Medicine, University of Geneva, Geneva, Switzerland

Submitted 24 February 2009 ; accepted in final form 13 July 2009

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 NH₂-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 p38 by isoform-specific small interfering RNAs increased claudin-4 and -8 mRNAs, whereas silencing of p38β 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.

mitogen-activated protein kinases; domes; transepithelial electrical resistance; tight junction; mammary epithelial cells; c-Jun NH₂-terminal kinase