60 Wbroblasts), increased Ca2+-independent adhesion was observed, indicating that when interacting with ZO-1, occludin mediates adhesive functions (Van Itallie and Anderson 1997). Addition of neutralizing peptides of the peptide sequence of the second extracellular loop elicited competitive interference with cell–cell-adhesion in a dose dependent manner, implicating that this loop directly par- ticipates in adhesive interaction (Wong and Gumbiner 1997). Relating epithelial malignancy to the loss of cell–cell- adhesion, it was demonstrated that overexpression of onco- genic Raf 1 in rat salivary gland epithelial cells (Pa4–Raf1) disrupts TJs and induces an oncogenic phenotype by down- regulating the expression of occludin (Wang et al. 2005). Raf1-mediated transformation of Pa4–Raf1 cells was sub- sequently shown to induce transcriptional downregulation of occludin and forced re-expression of occludin rescued the polarized phenotype of epithelial cells (Wang et al. 2007). Interestingly, forced expression of an occludin mutant lacking the second extracellular loop did not rescue the epithelial phenotype in vitro nor did it prevent tumor growth in vivo. These results demonstrate that the TJ pro- tein occludin has a potent inhibitory eVect on the Raf1- mediated tumorigenesis, and the second loop of occludin appears to be required for suppression of Raf1-induced tumor growth, potentially by mediating cell–cell-adhesion Table 1 Modulation of TJ barrier function in human disease Histochem Cell Biol (2008) 130:55–70 as presented above contributing to contact inhibition of cell division. TJs and human disease Modulation of barrier function by cytokines Many cytokines have been shown to inXuence epithelial and endothelial TJ function and the actin cytoskeleton both in vivo and in vitro. To name the most prominent, the inter- leukins IL-0, IL-1, IL-3, IL-4, as well as tumor necrosis factor alpha (TNF ) and interferon gamma (IFN ) could be demonstrated to inXuence TJ barrier function in epithelia and endothelia (Ahdieh et al. 2001; Oshima et al. 2001; Youakim and Ahdieh 1999). This review will emphasise the inXuence of a few selected cytokines on TJ structure/ function and its adjoining actin cytoskeleton in diseases like inXammatory bowel disease and inXammatory disease of the CNS (Table 1). InXammatory bowel disease: Crohn’s disease Crohn’s disease ranks among the chronic inXammatory bowel diseases (IBD) with diarrhoea as a leading symptom. This is chieXy attributed to epithelial barrier dysfunction, ClassiWcation Cancer Breast cancer: invasive ductal cancer Prostate cancer: prostatic adenocarcinomas Thyroid neoplasma, follicular adenoma Gastroesophageal reXux disease: Barrett’s esophagus (dysplasia) Lung cancer: Basaloid squamous carcinoma InXammation InXammatory bowel disease: Morbus Crohn Collagenous collitis Multiple sclerosis Hereditary diseases Hereditäry deafness Familial hypomagnesemia cystic Wbrosis Vision loss Diabetic eye disease: diabetic retinopathy Viral infection Reoviral infection (hydrocephalus, encephalitis) Bacterial toxins Clostridium perfringens enterotoxin 123 Tight junction protein aVected Reference Claudin-1, ZO-1 Claudins-1, -3, -4 and claudin-7 Occludin and claudin-1, -4 and -7 Claudin-18 Ultrastructural junctional dediVerentiation Claudins-2,-3, -5, and -8, ZO-1 Occludin, claudin-2 and -4 Occludin, claudin-5 Claudin-14 Claudin-16 Occludin, claudin-1, -4, JAM, ZO-1 Occludin, ZO-1 JAM-1 Claudin-3 and -4 Itoh and Bissell (2003), detailed here Sheehan et al. (2007) Tzelepi et al. (2007) Jovov et al. (2007) Gilcrease and Guzman-Paz (1998) Zeissig et al. (2007), detailed here Burgel et al. (2002) Förster et al. (2007), detailed here Ben-Yosef et al. (2003), detailed here Simon et al. (1999), detailed here Coyne et al. (2002) Felinski and Antonetti (2005), detailed here Forrest et al. (2003) McClane (2001), detailed here