TRAF6-dependent mitogen-activated protein kinase activation differentially regulates the production of interleukin-12 by macrophages in response to Toxoplasma gondii.
The production of interleukin-12 (IL-12) is critical to the development of innate and adaptive immune responses required for the control of intracellular pathogens. Many microbial products signal through Toll-like receptors (TLR) and activate NF-kappaB family members that are required for the production of IL-12. Recent studies suggest that components of the TLR pathway are required for the production of IL-12 in response to the parasite Toxoplasma gondii; however, the production of IL-12 in response to this parasite is independent of NF-kappaB activation. The adaptor molecule TRAF6 is involved in TLR signaling pathways and associates with serine/threonine kinases involved in the activation of both NF-kappaB and mitogen-activated protein kinase (MAPK). To elucidate the intracellular signaling pathways involved in the production of IL-12 in response to soluble toxoplasma antigen (STAg), wild-type and TRAF6(-/-) mice were inoculated with STAg, and the production of IL-12(p40) was determined. TRAF6(-/-) mice failed to produce IL-12(p40) in response to STAg, and TRAF6(-/-) macrophages stimulated with STAg also failed to produce IL-12(p40). Studies using Western blot analysis of wild-type and TRAF6(-/-) macrophages revealed that stimulation with STAg resulted in the rapid TRAF6-dependent phosphorylation of p38 and extracellular signal-related kinase, which differentially regulated the production of IL-12(p40). The studies presented here demonstrate for the first time that the production of IL-12(p40) in response to toxoplasma is dependent upon TRAF6 and p38 MAPK.
Mason
Nicola J
NJ
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Fiore
Jim
J
Kobayashi
Takashi
T
Masek
Katherine S
KS
Choi
Yongwon
Y
Hunter
Christopher A
CA
D000818:Animals; D000953:Antigens, Protozoan / Q000276:immunology; D002478:Cells, Cultured; D004789:Enzyme Activation; D017353:Gene Deletion; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000276:immunology; D008264:Macrophages / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D048029:TNF Receptor-Associated Factor 6; D014122:Toxoplasma / Q000276:immunology* / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases
D000953:Antigens, Protozoan; D011506:Proteins; D048029:TNF Receptor-Associated Factor 6; D018664:Interleukin-12; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases