title: p38 MAPK autophosphorylation drives macrophage IL-12 production during intracellular infection.
abstract: The intracellular protozoan Toxoplasma gondii triggers rapid MAPK activation in mouse macrophages (Mphi). We used synthetic inhibitors and dominant-negative Mphi 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(-/-) Mphi, p38 MAPK activation was near normal and IL-12 production was unaffected. Recently, MKK-independent p38alpha MAPK activation via autophosphorylation was described. Autophosphorylation depends upon p38alpha MAPK association with adaptor protein, TGF-beta-activated protein kinase 1-binding protein-1. We observed TGF-beta-activated protein kinase 1-binding protein-1-p38alpha MAPK association that closely paralleled p38 MAPK phosphorylation during Toxoplasma infection of Mphi. Furthermore, a synthetic p38 catalytic-site inhibitor blocked tachyzoite-induced p38alpha MAPK phosphorylation. These data are the first to demonstrate p38 MAPK autophosphorylation triggered by intracellular infection.
authors.affiliation: Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853-6401, USA.
authors.forename: Leesun
authors.initials: L
authors.lastname: Kim
authors.forename: Laura
authors.initials: L
authors.lastname: Del Rio
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Butcher
authors.forename: Trine H
authors.initials: TH
authors.lastname: Mogensen
authors.forename: Søren R
authors.initials: SR
authors.lastname: Paludan
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.forename: Eric Y
authors.initials: EY
authors.lastname: Denkers
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D001854:Bone Marrow Cells; D005260:Female; D007239:Infections / Q000201:enzymology / Q000209:etiology*; D018664:Interleukin-12 / Q000096:biosynthesis*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism / Q000469:parasitology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D010766:Phosphorylation; D014122:Toxoplasma / Q000472:pathogenicity; D014123:Toxoplasmosis / Q000201:enzymology / Q000209:etiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C486300:TAB1 protein, human; D018664:Interleukin-12; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases