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c-Rel Is Essential for the Development of Innate and T Cell-Induced Colitis¹

Yanyan Wang^*, Barry H. Rickman, Theofilos Poutahidis^,, Katherine Schlieper, Erin A. Jackson, Susan E. Erdman, James G. Fox and Bruce H. Horwitz^2,*,

^* 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; Laboratory of Pathology, Faculty of Veterinary Medicine, Aristotle University, Thessaloniki, Greece; and Division of Emergency Medicine, Children’s Hospital, Boston, MA 02115

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-B 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant NIH AI52267 (to B.H.H. and S.E.E.), Crohn’s and Colitis Foundation of America and the William and Shelby Modell Family Foundation Senior Research Grant (to B.H.H.), NIH CA108854 (to S.E.E.), and NIH CA67529 (to J.G.F.).

² Address correspondence and reprint requests to Dr. Bruce H. Horwitz, Department of Pathology, Brigham and Women’s Hospital, HNRB 630E, 77 Avenue Louis Pasteur, Boston, MA 02115. E-mail address: bhorwitz{at}rics.bwh.harvard.edu

³ Abbreviations used in this paper: Hh, Helicobacter hepaticus; BMDM, bone marrow-derived macrophages; RPA, RNase protection analyses; MLN, mesenteric lymph node; WT, wild type.