title: NF-kappa B 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-kappaB subunits are susceptible to colitis induced by the pathogenic enterohepatic Helicobacter 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, 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-kappaB subunits is critical to preventing colonic inflammation in response to inflammatory microflora.
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Michal F
authors.initials: MF
authors.lastname: Tomczak
authors.forename: Susan E
authors.initials: SE
authors.lastname: Erdman
authors.forename: Theofilos
authors.initials: T
authors.lastname: Poutahidis
authors.forename: Arlin B
authors.initials: AB
authors.lastname: Rogers
authors.forename: Hilda
authors.initials: H
authors.lastname: Holcombe
authors.forename: Benjamin
authors.initials: B
authors.lastname: Plank
authors.forename: James G
authors.initials: JG
authors.lastname: Fox
authors.forename: Bruce H
authors.initials: BH
authors.lastname: Horwitz
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D003092:Colitis / Q000235:genetics / Q000276:immunology / Q000382:microbiology* / Q000517:prevention & control*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D016998:Helicobacter / Q000276:immunology*; D007106:Immune Sera / Q000008:administration & dosage; D007113:Immunity, Innate / Q000235:genetics; D007274:Injections, Intraperitoneal; D018664:Interleukin-12 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000276:immunology; D053762:Interleukin-12 Subunit p40; D007413:Intestinal Mucosa / Q000276:immunology* / Q000382:microbiology* / Q000473:pathology; D016131:Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology*; D021122:Protein Subunits / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000276:immunology; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000637:transplantation; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
chemical_list: D004268:DNA-Binding Proteins; D007106:Immune Sera; D053762:Interleukin-12 Subunit p40; D016328:NF-kappa B; D021122:Protein Subunits; C499308:Rag2 protein, mouse; C064655:V(D)J recombination activating protein 2; D018664:Interleukin-12