Noncanonical NF-κB signaling is elevated in inflammatory bowel disease patients and may be associated with therapeutic response

Abstract

Abstract The canonical NF-κB signaling pathway is well characterized in the context of inflammatory bowel disease (IBD). However, noncanonical NF-κB signaling has not been evaluated. This pathway is key for the production of specific chemokines with diverse immunological effects in the gut. To evaluate this pathway, biopsy specimens from control patients and patients with IBD (CD and UC) were collected and pathways associated with inflammation were assessed via custom RT-PCR arrays. These expression data were compared to lesion status, IBD subtype (CD or UC), and treatment. Our analysis revealed significant up-regulation of several key genes associated with noncanonical NF-κB signaling in lesion tissue from IBD patients compared to controls and non-lesion areas. Interestingly, CD patients displayed increased noncanonical signaling compared to both control and UC patients in over 20 genes directly involved in the noncanonical pathway. Treatment with the anti-TNF biologic infliximab resulted in down-regulation of these and other noncanonical NF-κB signaling molecules in CD patients. Subsequent bioinformatics analysis of CD patients revealed that elevation of chemokines associated with noncanonical NF-κB signaling are indicators of infliximab responsiveness, with patients refractory to infliximab showing significantly elevated levels of gene expression. Together, these data indicate that noncanonical NF-κB signaling is elevated in IBD patients and may have links to therapeutic response.