Toxoplasma gondii tachyzoites inhibit proinflammatory cytokine induction in infected macrophages by preventing nuclear translocation of the transcription factor NF-kappa B.
Control of microbial infection requires regulated induction of NF-kappaB-dependent proinflammatory cytokines such as IL-12 and TNF-alpha. Activation of this important transcription factor is driven by phosphorylation-dependent degradation of the inhibitory IkappaB molecule, an event which enables NF-kappaB translocation from the cytoplasm to the nucleus. In this study, we show that intracellular infection of macrophages with the protozoan parasite Toxoplasma gondii induces rapid IkappaB phosphorylation and degradation. Nevertheless, NF-kappaB failed to translocate to the nucleus, enabling the parasite to invade cells without triggering proinflammatory cytokine induction. Infected cells subsequently subjected to LPS triggering were severely crippled in IL-12 and TNF-alpha production, a result of tachyzoite-induced blockade of NF-kappaB nuclear translocation. Our results are the first to demonstrate the ability of an intracellular protozoan to actively interfere with the NF-kappaB activation pathway in macrophages, an activity that may enable parasite survival within the host.
Butcher
B A
BA
Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA.
Kim
L
L
Johnson
P F
PF
Denkers
E Y
EY
D021581:Active Transport, Cell Nucleus / Q000276:immunology; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000276:immunology / Q000378:metabolism* / Q000469:parasitology; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D020672:I-kappa B Proteins; D007249:Inflammation / Q000276:immunology / Q000469:parasitology / Q000517:prevention & control; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010766:Phosphorylation; D014122:Toxoplasma / Q000254:growth & development* / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D025801:Ubiquitin / Q000378:metabolism
D016207:Cytokines; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D014409:Tumor Necrosis Factor-alpha; D025801:Ubiquitin; D000072000:NF-KappaB Inhibitor alpha; D018664:Interleukin-12; D020928:Mitogen-Activated Protein Kinases