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Infection and Immunity, July 2001, p. 4232-4241, Vol. 69, No. 7
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-
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

), and tumor
necrosis factor alpha (TNF-
), 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-
, TNF-
, and inducible nitric oxide synthase (iNOS) mRNA
levels, and H. hepaticus-specific IFN-
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-
and/or anti-TNF-
had no effect on
intestinal inflammation in IL-10 KO mice with established colitis.
Using IL-10/IFN-
double-deficient mice, we further show that IFN-
is not required for the development of colitis follwing H.
hepaticus infection. MLN cells from infected IL-10/IFN-
KO animals secreted elevated amounts of IL-12 and TNF-
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.
Present address: Microbiology and Tumorbiology Center, Karolinska
Institutet, SE-171 77 Stockholm, Sweden.
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