Hochschulschrift:
Dissertation, Berlin, Freie Universität Berlin, 2021
Anmerkungen:
Beschreibung:
Campylobacter concisus impaired colonic epithelial sodium channel (ENaC) function with the transcriptional downregulation of regulatory ENaC subunits (-β and -γ). The activation of intracellular mitogen-activated protein kinase (MAPK) enzyme extracellular signal-regulated kinase (ERK) by C. concisus is ascertained as an intracellular cell signaling pathway in inducing ENaC dysfunction. The transcriptional upregulation of interleukin (IL)-32 plays a pivotal role in C. concisus-induced ENaC dysfunction as the bioinformatics prediction from ingenuity pathway analysis (IPA) identified IL-32 as a potential activator of the ERK signaling pathway. The increase in expression of tight junction (TJ) protein claudin-8 following steroid stimulation prevents paracellular back-leakage of sodium (Na+) ions absorbed by ENaC in colonic epithelium. Claudin-8 protein expression was decreased along with the subcellular redistribution off the tight junction (TJ) domain by C. concisus infection in the colonic epithelial cells stimulated by steroids. Therefore, claudin-8 disruption in the colonic epithelium is another cellular pathomechanism of C. concisus in the context of Na+-malabsorptive diarrhea. The epithelial barrier dysfunction induced by C. concisus was more pronounced under the influence of immune response in the co-culture model of colonic epithelial cells and macrophages. The macrophage activation by C. concisus in the co-culture setup was accompanied by an increase in the release of proinflammatory cytokines, tumor necrosis factor (TNF)-α, IL-1β and IL-6. Concomitantly, the expression of TJ proteins occludin and tricellulin was decreased along with the subcellular redistribution of these proteins from the TJ domains. Moreover, C. concisus infection increased the flux of fluorescein (332 Da) in the monoculture and co-culture cell monolayers. In contrast, the flux of the macromolecule fluorescein isothiocyanate (FITC)-dextran (4 kDa) was increased only in the co-culture monolayers after infection. Furthermore, C. concisus ...