Induction of lncRNA U90926 provides feedback regulation to TNF-alpha-induced cellular responses in intestinal epithelial cells

TNF-α is an important pro-inflammatory cytokine with pleiotropic functions in regulating intestinal homeostasis and disease pathogenesis but the TNF-α signaling requires precise control to prevent the development of deleterious excessive or chronic inflammation. U90926 is long non-coding RNA that is highly induced in macrophages and dendritic cells by Toll-like receptor activation and is protective during endotoxic shock. We previously observed that U90926 is induced in murine intestinal epithelial cells following infection by a zoonotic apicomplexan parasite Cryptosporidium. Here, we report that U90926 is induced in murine intestinal epithelial cells in response to TNF-α stimulation. Knockdown of U90926 resulted in an enhanced transcription of many TNF-α-stimulated genes in intestinal epithelial cells through modulation of G9a-mediated chromatin remodeling mechanisms, implying an inhibitory effect on the cellular response to TNF-α by U90926. Moreover, U90926 can modulate TNF-α-stimulated autophagy and LPS-tolerance in intestinal epithelial cells. Therefore, U90926 is induced in murine intestinal epithelial cells following TNF-α stimulation and induction of U90926 can suppress TNF-α-stimulated gene transcription and inflammatory cellular response in intestinal epithelial cells. Our findings suggest a mechanism by lncRNA U9926 for the feedback regulation of TNF-α-stimulated gene transcription and inflammatory cellular response in intestinal epithelial cells.