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B Is Required Within the Innate Immune System to Inhibit Microflora-Induced Colitis and Expression of IL-12 p401
* Immunology Research Division, Department of Pathology, Brigham and Women’s Hospital, Boston, MA 02115;
Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139; and
Division of Emergency Medicine, Children’s Hospital, Boston, MA 02115
We have previously presented evidence demonstrating that mice deficient in NF-
B subunits are susceptible to colitis induced by the pathogenic enterohepatic Helicobacter species, H. hepaticus. However, it has not been determined whether NF-B 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-B subunits is critical to preventing colonic inflammation in response to inflammatory microflora.
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