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* Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853;
Department of Medical Microbiology and Immunology, University of Aarhus, Aarhus, Denmark; and
Department of Immunology and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520
The intracellular protozoan Toxoplasma gondii triggers rapid MAPK activation in mouse macrophages (M
). We used synthetic inhibitors and dominant-negative M mutants to demonstrate that T. gondii triggers IL-12 production in dependence upon p38 MAPK. Chemical inhibition of stress-activated protein kinase/JNK showed that this MAPK was also required for parasite-triggered IL-12 production. Examination of upstream MAPK kinases (MKK) 3, 4, and 6 that function as p38 MAPK activating kinases revealed that parasite infection activates only MKK3. Nevertheless, in MKK3–/– M, p38 MAPK activation was near normal and IL-12 production was unaffected. Recently, MKK-independent p38
MAPK activation via autophosphorylation was described. Autophosphorylation depends upon p38 MAPK association with adaptor protein, TGF-
-activated protein kinase 1-binding protein-1. We observed TGF--activated protein kinase 1-binding protein-1-p38 MAPK association that closely paralleled p38 MAPK phosphorylation during Toxoplasma infection of M. Furthermore, a synthetic p38 catalytic-site inhibitor blocked tachyzoite-induced p38 MAPK phosphorylation. These data are the first to demonstrate p38 MAPK autophosphorylation triggered by intracellular infection.
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