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.
Kullberg
M C
MC
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
Ward
J M
JM
Gorelick
P L
PL
Caspar
P
P
Hieny
S
S
Cheever
A
A
Jankovic
D
D
Sher
A
A
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