IL-10-independent STAT3 activation by Toxoplasma gondii mediates suppression of IL-12 and TNF-alpha in host macrophages.
Infection of mouse macrophages by Toxoplasma gondii renders the cells resistant to proinflammatory effects of LPS triggering. In this study, we show that cell invasion is accompanied by rapid and sustained activation of host STAT3. Activation of STAT3 did not occur with soluble T. gondii extracts or heat-killed tachyzoites, demonstrating a requirement for live parasites. Parasite-induced STAT3 phosphorylation and suppression of LPS-triggered TNF-alpha and IL-12 was intact in IL-10-deficient macrophages, ruling out a role for this anti-inflammatory cytokine in the suppressive effects of T. gondii. Most importantly, Toxoplasma could not effectively suppress LPS-triggered TNF-alpha and IL-12 synthesis in STAT3-deficient macrophages. These results demonstrate that T. gondii exploits host STAT3 to prevent LPS-triggered IL-12 and TNF-alpha production, revealing for the first time a molecular mechanism underlying the parasite's suppressive effect on macrophage proinflammatory cytokine production.
Butcher
Barbara A
BA
Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA. bab26@cornell.edu
Kim
Leesun
L
Panopoulos
Athanasia D
AD
Watowich
Stephanie S
SS
Murray
Peter J
PJ
Denkers
Eric Y
EY
D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005260:Female; D066298:In Vitro Techniques; D016753:Interleukin-10 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018664:Interleukin-12 / Q000378:metabolism*; D015850:Interleukin-6 / Q000172:deficiency / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000469:parasitology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D050796:STAT3 Transcription Factor; D014122:Toxoplasma / Q000276:immunology* / Q000472:pathogenicity*; D014124:Toxoplasmosis, Animal / Q000276:immunology; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D016207:Cytokines; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D008070:Lipopolysaccharides; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D018664:Interleukin-12