Together, these data demonstrate that loss of hematopoietic C/EBPα renders greater susceptibility to TNBS-induced colitis; IL-12 is the primary target in the MDP/NOD2-C/EBPα regulatory axis; MDP requires C/EBPα to selectively inhibit IL-12 production and to resist TNBS-induced pathogenesis. The gene discussed is CEBPA; the disease is colitis.