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Inhibition of Helicobacter hepaticus-Induced Colitis by IL-10 Requires the p50/p105 Subunit of NF-B¹

Michal F. Tomczak^*, Susan E. Erdman, Anne Davidson, Yan Yan Wang^*, Prashant R. Nambiar, Arlin B. Rogers, Barry Rickman, David Luchetti, 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; Department of Medicine and Microbiology, Columbia University Medical Center, New York, NY 10032; and Division of Emergency Medicine, Children’s Hospital, Boston, MA 02115

Defects within the innate immune system sensitize NF-B-deficient (p50^–/–; p65^+/–) mice to Helicobacter hepaticus (Hh)-induced colitis. Because IL-10 plays a central role in the inhibition of Hh-induced colitis, we hypothesized that the ability of IL-10 to inhibit the innate inflammatory response to Hh may be compromised in NF-B-deficient mice. To test this hypothesis, we evaluated the ability of an IL-10-Ig fusion protein with IL-10-like properties to inhibit Hh-induced colitis in RAG-2^–/– (RAG) and p50^–/–; p65^+/–; RAG-2^–/– (3X/RAG) mice. As expected, IL-10-Ig efficiently inhibited the development of colitis in RAG mice. In contrast, the ability of IL-10-Ig to inhibit colitis was compromised in 3X/RAG mice. The defect in response to IL-10-Ig appeared to be primarily the result of the absence of the p50/p105 subunit, because the ability of IL-10-Ig to inhibit colitis was also compromised in p50^–/–; RAG-2^–/– (p50/RAG) mice. Radiation chimeras demonstrated that the presence of p50/p105 within hemopoietic cells of the innate immune system was necessary for efficient inhibition of colitis by IL-10-Ig. Consistent with a defect in the suppressive effects of IL-10 in the absence of p50/p105, we found that the ability of IL-10 to control LPS-induced expression of IL-12 p40 was significantly compromised in macrophages lacking p50/p105. These results suggest that the absence of the p50/p105 subunit of NF-B within hemopoietic cells of the innate immune system interferes with the ability of IL-10 to suppress inflammatory gene expression and Hh-induced colitis.

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 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.), National Institutes of Health Grant CA67529 (to J.G.F.), and a Crohn’s and Colitis Foundation of America Research Fellowship Grant (to M.F.T.).

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

³ Abbreviations used in this paper: IBD, inflammatory bowel disease; BMDM, bone marrow-derived macrophage; Hh, Helicobacter hepaticus; IP-10, IFN--inducible protein 10; RPA, RNase protection analysis; WT, wild type.

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