Helicobacter hepaticus triggers colitis in specific-pathogen-free interleukin-10 (IL-10)-deficient mice through an IL-12- and gamma interferon-dependent mechanism.
Mice rendered deficient in interleukin-10 (IL-10) by gene targeting (IL-10(-/-) mice) develop chronic enterocolitis resembling human inflammatory bowel disease (IBD) when maintained in conventional animal facilities. However, they display a minimal and delayed intestinal inflammatory response when reared under specific-pathogen-free (SPF) conditions, suggesting the involvement of a microbial component in pathogenesis. We show here that experimental infection with a single bacterial agent, Helicobacter hepaticus, induces chronic colitis in SPF-reared IL-10(-/-) mice and that the disease is accompanied by a type 1 cytokine response (gamma interferon [IFN-gamma], tumor necrosis factor alpha, and nitric oxide) detected by restimulation of spleen and mesenteric lymph node cells with a soluble H. hepaticus antigen (Ag) preparation. In contrast, wild-type (WT) animals infected with the same bacteria did not develop disease and produced IL-10 as the dominant cytokine in response to Helicobacter Ag. Strong H. hepaticus-reactive antibody responses as measured by Ag-specific total immunoglobulin G (IgG), IgG1, IgG2a, IgG2b, IgG3, and IgA were observed in both WT and IL-10(-/-) mice. In vivo neutralization of IFN-gamma or IL-12 resulted in a significant reduction of intestinal inflammation in H. hepaticus-infected IL-10(-/-) mice, suggesting an important role for these cytokines in the development of colitis in the model. Taken together, these microbial reconstitution experiments formally establish that a defined bacterial agent can serve as the immunological target in the development of large bowel inflammation in IL-10(-/-) mice and argue that in nonimmunocompromised hosts IL-10 stimulated in response to intestinal flora is important in preventing IBD.
Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-0425, USA. MKULLBERG@atlas.niaid.nih.gov
M C
MC
Kullberg
J M
JM
Ward
P L
PL
Gorelick
P
P
Caspar
S
S
Hieny
A
A
Cheever
D
D
Jankovic
A
A
Sher
D000818:Animals; D000942:Antigens, Bacterial / Q000096:biosynthesis; D003092:Colitis / Q000209:etiology* / Q000276:immunology / Q000382:microbiology*; D003433:Crosses, Genetic; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D016998:Helicobacter / Q000472:pathogenicity*; D016481:Helicobacter Infections / Q000276:immunology / Q000473:pathology; D007249:Inflammation / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000276:immunology*; D016753:Interleukin-10 / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013047:Specific Pathogen-Free Organisms / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology
D000942:Antigens, Bacterial; D016207:Cytokines; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma