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Infection and Immunity, July 2001, p. 4232-4241, Vol. 69, No. 7
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.7.4232-4241.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Helicobacter hepaticus-Induced Colitis in Interleukin-10-Deficient Mice: Cytokine Requirements for the Induction and Maintenance of Intestinal Inflammation

Marika C. Kullberg,1,* Antonio Gigliotti Rothfuchs,1,dagger Dragana Jankovic,1 Patricia Caspar,1 Thomas A. Wynn,1,2 Peter L. Gorelick,3 Allen W. Cheever,4 and Alan Sher1

Immunobiology Section1 and Schistosomiasis Immunology and Pathology Unit,2 Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland 20892-0425; Animal Health Diagnostic Laboratory, Laboratory Animal Sciences Program, National Cancer Institute-Frederick Cancer Research and Development Center, Science Applications International Corporation, Frederick, Maryland 21702-12013; and The Biomedical Research Institute, Rockville, Maryland 208524

Received 6 February 2001/Returned for modification 15 March 2001/Accepted 9 April 2001

We have previously shown that specific-pathogen-free interleukin-10 (IL-10)-deficient (IL-10 KO) mice reconstituted with Helicobacter hepaticus develop severe colitis associated with a Th1-type cytokine response. In the present study, we formally demonstrate that IL-12 is crucial for disease induction, because mice deficient for both IL-10 and IL-12 p40 show no intestinal pathology following H. hepaticus infection. By using monoclonal antibodies (MAbs) to IL-12, gamma interferon (IFN-gamma ), and tumor necrosis factor alpha (TNF-alpha ), we have further analyzed the role of these cytokines in the maintenance of the Th1 response and inflammation in IL-10 KO mice with established H. hepaticus-induced colitis. Treatment of infected colitic IL-10 KO mice with anti-IL-12 p40 resulted in markedly reduced intestinal inflammation, colonic IFN-gamma , TNF-alpha , and inducible nitric oxide synthase (iNOS) mRNA levels, and H. hepaticus-specific IFN-gamma secretion by mesenteric lymph node (MLN) cells compared to the findings in control MAb-treated mice. Moreover, the diminished pathology was associated with decreased numbers of colonic CD3+ T cells and significantly reduced frequencies of Helicobacter-reactive CD4+ Th1 cells in MLN. In contrast, anti-IFN-gamma and/or anti-TNF-alpha had no effect on intestinal inflammation in IL-10 KO mice with established colitis. Using IL-10/IFN-gamma double-deficient mice, we further show that IFN-gamma is not required for the development of colitis follwing H. hepaticus infection. MLN cells from infected IL-10/IFN-gamma KO animals secreted elevated amounts of IL-12 and TNF-alpha following bacterial antigen stimulation, indicating alternative pathways of disease induction. Taken together, our results demonstrate a crucial role for IL-12 in both inducing and sustaining intestinal inflammation through recruitment and maintenance of a pool of pathogenic Th1 cells.

* Corresponding author. Mailing address: Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 4, Room 126, 4 Center Dr., Bethesda, MD 20892-0425. Phone: (301) 496-8218. Fax: (301) 402-0890. E-mail: mkullberg{at}niaid.nih.gov.

dagger Present address: Microbiology and Tumorbiology Center, Karolinska Institutet, SE-171 77 Stockholm, Sweden.

Infection and Immunity, July 2001, p. 4232-4241, Vol. 69, No. 7
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.7.4232-4241.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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