Newfound role for noncanonical NF-κB signaling in Inflammatory Bowel Disease: Gene expression levels serve as a proxy for predicting anti-TNF therapy responsiveness

Abstract

Abstract The canonical arm of NF-κB signaling is well studied in Inflammatory Bowel Disease (IBD) while its noncanonical counterpart has yet to be fully defined. The activation of the noncanonical pathway initiates the nuclear transcription of chemokines associated with chronic inflammation and other diverse immunological processes. Infliximab is an effective anti-TNF treatment that reduces inflammation in IBD, yet a significant percentage of patients are unresponsive or lose responsiveness. Here, we show that noncanonical NF-κB signaling has more relevant implications on IBD and its expression levels correlate to infliximab responsiveness. Our study evaluated noncanonical NF-κB signaling in 27 IBD patient and 9 non-IBD control patient tissue biopsies. Data from these studies were analyzed using bioinformatics to predict its influence on cellular pathways. Genes related to the noncanonical NF-κB pathway were significantly upregulated in IBD lesions compared to healthy tissue. IBD patients that positively respond to infliximab had significantly decreased expression levels compared to nonresponsive patients. These results suggest infliximab, when effective, decreases noncanonical signaling to lessen inflammation. Through targeting in part, the noncanonical NF-κB pathway has prominent emerging roles in IBD pathobiology and is an indicator for improving drug efficacy.