p38 MAPK autophosphorylation drives macrophage IL-12 production during intracellular infection.

The intracellular protozoan Toxoplasma gondii triggers rapid MAPK activation in mouse macrophages (Mφ). We used synthetic inhibitors and dominant-negative Mφ 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 −/− Mφ, p38 MAPK activation was near normal and IL-12 production was unaffected. Recently, MKK-independent p38α MAPK activation via autophosphorylation was described. Autophosphorylation depends upon p38α MAPK association with adaptor protein, TGF-β-activated protein kinase 1-binding protein-1. We observed TGF-β-activated protein kinase 1-binding protein-1-p38α MAPK association that closely paralleled p38 MAPK phosphorylation during Toxoplasma infection of Mφ. Furthermore, a synthetic p38 catalytic-site inhibitor blocked tachyzoite-induced p38α MAPK phosphorylation. These data are the first to demonstrate p38 MAPK autophosphorylation triggered by intracellular infection.