In the absence of endogenous IL-10, mice acutely infected with Toxoplasma gondii succumb to a lethal immune response dependent on CD4+ T cells and accompanied by overproduction of IL-12, IFN-gamma and TNF-alpha.
To examine the function of IL-10 synthesis during early infection with the intracellular protozoan Toxoplasma gondii, IL-10 knockout (KO) mice were inoculated with an avirulent parasite strain (ME-49). In contrast to control littermates that displayed 100% survival, the IL-10-deficient animals succumbed within the first 2 wk of the infection, with no evidence of enhanced parasite proliferation. The mortality in the IL-10 KO mice was associated with enhanced liver pathology characterized by increased cellular infiltration and intense necrosis. Levels of IL-12 and IFN-gamma in sera of infected IL-10-deficient animals were four- to sixfold higher than those in sera from control mice, as were mRNA levels for IFN-gamma, IL-1 beta, TNF-alpha, and IL-12 in lung tissue. Similarly, macrophages from IL-10 KO mice activated in vitro or in vivo with T. gondii produced higher levels of TNF-alpha and IL-12 than macrophages from control animals. Moreover, spleen cells from IL-10 KO mice infected with T. gondii secreted more IFN-gamma than splenocytes from nondeficient animals. In vitro depletion experiments indicated that CD4+ lymphocytes are the major source of the latter cytokine in the spleen cell populations, and in vivo depletion with anti-CD4 Abs protected the IL-10 KO mice from parasite-induced mortality. Together the data suggest that endogenous IL-10 synthesis plays an important role in vivo in down-regulating monokine and IFN-gamma responses to acute intracellular infection, thereby preventing host immunopathology.
Gazzinelli
R T
RT
Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA.
Wysocka
M
M
Hieny
S
S
Scharton-Kersten
T
T
Cheever
A
A
Kühn
R
R
Müller
W
W
Trinchieri
G
G
Sher
A
A
D000208:Acute Disease; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000172:deficiency* / Q000235:genetics; D018664:Interleukin-12 / Q000096:biosynthesis; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D014122:Toxoplasma / Q000276:immunology*; D014124:Toxoplasmosis, Animal / Q000276:immunology* / Q000401:mortality; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D015854:Up-Regulation / Q000276:immunology
D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma