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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,
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-
), 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.
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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