NF-kappaB Is Required Within the Innate Immune System to Inhibit Microflora-Induced Colitis and Expression of IL-12P40~1

摘要

We have previously presented evidence demonstrating that mice deficient in NF-kappaB subunits are susceptible to colitis induced by the pathogenic enterohepatic Hclicobacter species, H. hepaticus. However, it has not been determined whether NF-kappaB is required within inhibitory lymphocyte populations, within cells of the innate immune system, of 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-12p40, and depletion of IL-12p40 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-12p40 in p50~-/-p65~+/-macrophages than in WT macrophages. These results suggest that inhibition of H. hepaticus-induced IL-12p40 expression by NF-kappaB subunits is critical to preventing colonic inflammation in response to inflammatory microflora.