ABSTRACT
Epithelial and endothelial tight junctions (TJs) act as a physical barrier against the diff usion of material between adjacent cells. Cell-cell barrier failure is associated with the loss of cellular diff erentiation and increased antigen exposure. Th ese events play an important role in the pathogenesis of a number of diseases, including infl ammatory bowel diseases, asthma, cystic fi brosis, and cancer. At the molecular level, the TJ barrier can be attributed to a complex array of proteins, including claudins, a diverse family of transmembrane proteins that form ion and size-selective aqueous pores. Th e stability of claudin-based junctions is maintained by an array of protein scaff olds, with linkages to the intercellular actin network. Recent studies have determined the detrimental eff ects of proinfl ammatory cytokines on TJ-dependent barrier properties. Proinfl ammatory cytokines, such as interferon gamma and tumor necrosis factor alpha, and interleukins, remodel TJs through the regulation of both claudin and TJ scaff old proteins. Additionally, proinfl ammatory cytokines regulate actin cytoskeletal dynamics, through the myosin light chain intercellular signaling cascade, resulting in structural and functional changes in TJs. Conversely, anti-infl ammatory cytokines such as IL-10 and transforming growth factor beta attenuate pro-infl ammatory stimuli. While it remains unclear whether TJ dysfunction is causative or symptomatic of detrimental infl ammatory stimuli, investigations into the molecular mechanisms involved have increased our understanding of TJ regulation. Th is chapter will review recent advances in our understanding of the mechanisms of cytokine modulation of TJ structure and barrier function.
