NF-κB Is Required Within the Innate Immune System to Inhibit Microflora-Induced Colitis and Expression of IL-12 p40

Abstract

We have previously presented evidence demonstrating that mice deficient in NF-κB subunits are susceptible to colitis induced by the pathogenic enterohepatic Helicobacter species, H. hepaticus. However, it has not been determined whether NF-κB is required within inhibitory lymphocyte populations, within cells of the innate immune system, or both, to suppress inflammation. To examine these issues, we have performed a series of adoptive transfer experiments using recombination-activating gene (Rag)-2−/− or p50−/−p65+/−Rag-2−/− mice as hosts for wild-type (WT) and p50−/−p65+/− lymphocyte populations. We have shown that although the ability of H. hepaticus to induce colitis in Rag-2−/− mice is inhibited by the presence of either WT or p50−/−p65+/− splenocytes, these splenocyte populations are unable to suppress H. hepaticus-induced colitis in p50−/−p65+/−Rag-2−/− mice. Colitis in these animals is characterized by increased expression of inflammatory cytokines including IL-12 p40, and depletion of IL-12 p40 from p50−/−p65+/− mice ameliorates H. hepaticus-induced disease. Consistent with a primary defect in the regulation of IL-12 expression, H. hepaticus induced markedly higher levels of IL-12 p40 in p50−/−p65+/− macrophages than in WT macrophages. These results suggest that inhibition of H. hepaticus-induced IL-12 p40 expression by NF-κB subunits is critical to preventing colonic inflammation in response to inflammatory microflora.