Resumen de The role of ripk1 in tnf-induced cell death in intestinal epithelial cells
Inflammatory bowel diseases (IBD) are chronic inflammatory processes that affect the gastrointestinal tract. IBD is characterized by an intestinal inflammation and epithelial cell injury leading to a poor psychosocial wellbeing and increased the risk for cancer. IBD pathogenesis is multifactorial, involving genetic predisposition, epithelial barrier defects, dysregulated immune responses, and environmental factors. The current gold standard therapy is TNF blockade, a key proinflammatory cytokine. TNF activates the NF-κB pathway inducing an anti-apoptotic cell response and it plays an important role in the regulation of the intestinal homeostasis.
However, in certain situations, TNF can also trigger cell death through different signaling cascades, a typical feature seen in IBD. This work shows how apoptotic IEC areas in IBD human samples co-localize with NF-κB activation and A20 upregulation. Furthermore, using animal models as well as in vitro studies, we show how NF-κB activation and A20 upregulation are required events to trigger TNFdependent cell death in intestinal epithelial cells. We also show how other cytokines that are usually upregulated in IBD interact with TNF to induce cell death.
Specifically, lymphotoxin β receptor activation synergizes with TNF to trigger apoptosis. We have proven that intestinal epithelial cells undergo apoptotsis downstream of TNFR in a RIPK1 dependent manner, and that kinase inhibition of RIPK1 prevents cell death. Chronic NF-κB induces apoptosis downstream of TNF in a ROS dependent manner and A20 requires its linear ubiquitin binding domain, zinc finger seven, to enhance the formation of complex IIb or ripoptosome after TNF stimulation. Overall these results help to further understand the pathogenesis of IBD and suggests RIPK1 as a possible target for new drugs to treat IBD.
