Genetic and environmental factors, including the commensal microbiota, have a crucial role in the development of inflammatory bowel disease. Aberrant activation of the transcription factor NF-kappa B is associated with chronic intestinal inflammation in mice and humans. Recently, an emerging family of innate lymphoid cells (ILCs) has been identified at mucosal sites contributing to the maintenance of gut homeostasis and intestinal immunopathology. Here, we show that the NF-kappa B protein c-Rel regulates the inflammatory potential of colonic IFN-gamma(+)Thy1(+) ILCs to induce anti-CD40-mediated colitis in rag1(-/-) mice. Stimulation of dendritic cells (DCs) with anti-CD40 or CD40L led to translocation of c-Rel into the nucleus resulting in induction of expression of interleukin-12 (IL-12) and IL-23, key regulators of innate cell-induced colitis. While c-Rel deficiency completely abrogated anti-CD40-induced colitis, adoptively transferred wild-type DCs were able to induce pronounced colonic inflammation in rag1(-/-) rel(-/-) mice. In summary, these results suggest that the expression of c-Rel in DCs is essential for initiating anti-CD40-mediated intestinal pathogenesis.