Abstract
Inflammatory bowel disease is a chronic inflammatory response of the gastrointestinal tract mediated in part by an aberrant response to intestinal microflora. Expression of IL-23 subunits p40 and p19 within cells of the innate immune system plays a central role in the development of lower bowel inflammation in response inflammatory challenge. The NF-kappaB subunit c-Rel can regulate expression of IL-12/23 subunits suggesting that it could have a critical role in mediating the development of chronic inflammation within the lower bowel. In this study, we have analyzed the role of c-Rel within the innate immune system in the development of lower bowel inflammation, in two well-studied models of murine colitis. We have found that the absence of c-Rel significantly impaired the ability of Helicobacter hepaticus to induce colitis upon infection of RAG-2-deficient mice, and ameliorated the ability of CD4(+)CD45RB(high) T cells to induce disease upon adoptive transfer into RAG-deficient mice. The absence of c-Rel interfered with the expression of IL-12/23 subunits both in cultured primary macrophages and within the colon. Thus, c-Rel plays a critical role in regulating the innate inflammatory response to microflora within the lower bowel, likely through its ability to modulate expression of IL-12/23 family members.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Chronic Disease
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Colitis / immunology*
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Colitis / metabolism*
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Colitis / microbiology
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Cyclin-Dependent Kinase Inhibitor p19 / biosynthesis
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Cytokines / biosynthesis
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Cytokines / deficiency
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Cytokines / physiology
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Helicobacter Infections / genetics
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Helicobacter Infections / immunology
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Helicobacter Infections / microbiology
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Helicobacter hepaticus / immunology
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Immunity, Innate* / genetics
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Inflammation Mediators / metabolism
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Inflammation Mediators / physiology
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Interleukin-10 / biosynthesis
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Interleukin-10 / deficiency
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Interleukin-12 / biosynthesis
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Interleukin-12 / deficiency
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Interleukin-23 / biosynthesis
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Interleukin-23 / deficiency
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Mice
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Mice, Knockout
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Multigene Family / immunology
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Proto-Oncogene Proteins c-rel / deficiency
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Proto-Oncogene Proteins c-rel / genetics
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Proto-Oncogene Proteins c-rel / physiology*
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Receptors, G-Protein-Coupled / biosynthesis
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T-Lymphocyte Subsets / immunology*
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Up-Regulation / genetics
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Up-Regulation / immunology
Substances
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Cdkn2d protein, mouse
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Cyclin-Dependent Kinase Inhibitor p19
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Cytokines
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DNA-Binding Proteins
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Inflammation Mediators
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Interleukin-23
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Lancl1 protein, mouse
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Proto-Oncogene Proteins c-rel
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Rag2 protein, mouse
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Receptors, G-Protein-Coupled
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Interleukin-10
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Interleukin-12