Both IL-12 and IL-18 contribute to small intestinal Th1-type immunopathology following oral infection with Toxoplasma gondii, but IL-12 is dominant over IL-18 in parasite control.
Oral infection of C57BL/6 mice with Toxoplasma gondii results in small intestinal Th1-type immunopathology mediated by local production of IFN-gamma, TNF-alpha, and NO. To analyze whether the proinflammatory cytokines IL-12 and IL-18 play a role in the induction of immunopathology, IL-12p35/p40(-/-) and IL-18(-/-) mice were orally infected with T. gondii. Wild-type mice developed massive necrosis in their small intestines and died 7-10 days post infection. Even though IL-12p35/40(-/-) mice did not develop the necrosis they all died between day 9 and 11 after infection. In contrast, 50% of IL-18(-/-) mice died during the acute phase of infection. Compared to wild-type mice, IL-12p35/p40(-/-) but not IL-18(-/-) mice showed significantly higher parasite numbers in their small intestines and significantly higher numbers of parasite-associated inflammatory foci in their livers. IFN-gamma production was similar in infected wild-type and IL-18(-/-) mice but significantly decreased in IL-12p35/p40(-/-) mice. Treatment of mice with anti-IL-12- or anti-IL-18 antibodies after infection prevented the development of intestinal necrosis. These results reveal that both IL-12 and IL-18 play an important role in the development of intestinal immunopathology following oral infection with T. gondii. However, IL-12 is dominant over IL-18 in the host defense against parasite replication. Therefore, neutralization of IL-18 (rather than TNF-alpha, IL-12, and IFN-gamma) may be a safe strategy for the treatment of Th1-associated diseases.
Vossenkämper
Anna
A
Abteilung für Medizinische Mikrobiologie und Infektionsimmunologie, Institut für Infektionsmedizin, Charité Universitätsmedizin Berlin, Berlin, Germany.
Struck
Daniela
D
Alvarado-Esquivel
Cosme
C
Went
Tobias
T
Takeda
Kioyshi
K
Akira
Shizuo
S
Pfeffer
Klaus
K
Alber
Gottfried
G
Lochner
Matthias
M
Förster
Irmgard
I
Liesenfeld
Oliver
O
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D001921:Brain / Q000469:parasitology / Q000473:pathology; D005260:Female; D006651:Histocytochemistry; D007371:Interferon-gamma / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology*; D053765:Interleukin-12 Subunit p35; D053762:Interleukin-12 Subunit p40; D020382:Interleukin-18 / Q000276:immunology*; D007421:Intestine, Small / Q000276:immunology* / Q000469:parasitology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000276:immunology; D021122:Protein Subunits / Q000276:immunology*; D013047:Specific Pathogen-Free Organisms; D013154:Spleen / Q000469:parasitology / Q000473:pathology; D014122:Toxoplasma / Q000276:immunology*; D014123:Toxoplasmosis / Q000276:immunology* / Q000469:parasitology / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
D000911:Antibodies, Monoclonal; D053765:Interleukin-12 Subunit p35; D053762:Interleukin-12 Subunit p40; D020382:Interleukin-18; D021122:Protein Subunits; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D009569:Nitric Oxide; D007371:Interferon-gamma