c-Rel is essential for the development of innate and T cell-induced colitis.
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.
Immunology Research Division, Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
Yanyan
Y
Wang
Barry H
BH
Rickman
Theofilos
T
Poutahidis
Katherine
K
Schlieper
Erin A
EA
Jackson
Susan E
SE
Erdman
James G
JG
Fox
Bruce H
BH
Horwitz
D000818:Animals; D002908:Chronic Disease; D003092:Colitis / Q000276:immunology* / Q000378:metabolism* / Q000382:microbiology; D050764:Cyclin-Dependent Kinase Inhibitor p19 / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D016481:Helicobacter Infections / Q000235:genetics / Q000276:immunology / Q000382:microbiology; D044923:Helicobacter hepaticus / Q000276:immunology; D007113:Immunity, Innate / Q000235:genetics; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology; D016753:Interleukin-10 / Q000096:biosynthesis / Q000172:deficiency; D018664:Interleukin-12 / Q000096:biosynthesis / Q000172:deficiency; D053759:Interleukin-23 / Q000096:biosynthesis / Q000172:deficiency; D051379:Mice; D018345:Mice, Knockout; D005810:Multigene Family / Q000276:immunology; D020569:Proto-Oncogene Proteins c-rel / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000096:biosynthesis; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
C493975:Cdkn2d protein, mouse; D050764:Cyclin-Dependent Kinase Inhibitor p19; D016207:Cytokines; D004268:DNA-Binding Proteins; D018836:Inflammation Mediators; D053759:Interleukin-23; C485882:Lancl1 protein, mouse; D020569:Proto-Oncogene Proteins c-rel; C499308:Rag2 protein, mouse; D043562:Receptors, G-Protein-Coupled; D016753:Interleukin-10; D018664:Interleukin-12