Abstract
We show in this study that Toxoplasma gondii infection induces rapid activation of p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase 1/2, and stress-activated protein kinase/c-Jun N-terminal kinase MAPK, followed promptly by their deactivation in mouse macrophages. Nevertheless, when infected cells were subsequently subjected to LPS triggering, MAPK activation was severely defective, in particular in the case of p38 MAPK, which is required for LPS-triggered TNF-alpha and IL-12 production. Similar effects occurred during endotoxin tolerance, but the phenomena were distinct. LPS pretriggering failed to activate the major p38 MAPK kinase, MAPK kinase 3/6. Toxoplasma infection, in contrast, resulted in sustained activation of this kinase. Furthermore, endotoxin pre-exposure blocked IkappaBalpha degradation upon subsequent LPS triggering, but this was not the case for Toxoplasma preinfection. Endotoxin-mediated down-regulation of the LPS receptor, Toll-like receptor 4, has been suggested as one possible mechanism contributing to tolerance, and we found in this study that LPS down-modulated Toll-like receptor 4 expression. In contrast, Toxoplasma infection induced up-regulation of this pattern recognition receptor. Our results show that T. gondii blocks LPS-triggered cytokine production in part through MAPK inactivation, and that this occurs through pathways distinct from endotoxin-induced tolerance.
Publication types
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Animals
-
Calcium-Calmodulin-Dependent Protein Kinases / metabolism
-
Cells, Cultured
-
Down-Regulation / immunology
-
Enzyme Activation / immunology
-
Female
-
I-kappa B Proteins / metabolism
-
Immune Tolerance*
-
Interleukin-12 / antagonists & inhibitors
-
Interleukin-12 / biosynthesis
-
Interleukin-12 Subunit p40
-
Kinetics
-
Lipopolysaccharides / antagonists & inhibitors
-
Lipopolysaccharides / pharmacology*
-
MAP Kinase Kinase 3
-
MAP Kinase Kinase 6
-
MAP Kinase Signaling System / immunology
-
Macrophages / enzymology*
-
Macrophages / immunology*
-
Macrophages / parasitology
-
Membrane Glycoproteins / antagonists & inhibitors
-
Membrane Glycoproteins / biosynthesis
-
Mice
-
Mice, Inbred C57BL
-
Mitogen-Activated Protein Kinase Kinases / metabolism
-
Mitogen-Activated Protein Kinases / antagonists & inhibitors*
-
Mitogen-Activated Protein Kinases / metabolism*
-
Mitogen-Activated Protein Kinases / physiology
-
NF-KappaB Inhibitor alpha
-
Phosphorylation
-
Protein Subunits / antagonists & inhibitors
-
Protein Subunits / biosynthesis
-
Protein-Tyrosine Kinases / metabolism
-
Receptors, Cell Surface / antagonists & inhibitors
-
Receptors, Cell Surface / biosynthesis
-
Time Factors
-
Toll-Like Receptors
-
Toxoplasma / immunology*
-
Tumor Necrosis Factor-alpha / antagonists & inhibitors
-
Tumor Necrosis Factor-alpha / biosynthesis
-
Up-Regulation / immunology
-
p38 Mitogen-Activated Protein Kinases
Substances
-
I-kappa B Proteins
-
Interleukin-12 Subunit p40
-
Lipopolysaccharides
-
Membrane Glycoproteins
-
Nfkbia protein, mouse
-
Protein Subunits
-
Receptors, Cell Surface
-
Toll-Like Receptors
-
Tumor Necrosis Factor-alpha
-
NF-KappaB Inhibitor alpha
-
Interleukin-12
-
Protein-Tyrosine Kinases
-
Calcium-Calmodulin-Dependent Protein Kinases
-
Mitogen-Activated Protein Kinases
-
p38 Mitogen-Activated Protein Kinases
-
MAP Kinase Kinase 3
-
MAP Kinase Kinase 6
-
Map2k3 protein, mouse
-
Map2k6 protein, mouse
-
Mitogen-Activated Protein Kinase Kinases