Cytosolic Peroxiredoxin Attenuates the Activation of JNK and p38 but Potentiates That of ERK in HeLa Cells Stimulated with Tumor Necrosis Factor-α

Tumor necrosis factor-α (TNF-α) induces the activation of all three types of mitogen-activated protein kinase (MAPK): c-Jun NH ₂-terminal kinase (JNK), p38, and extracellular signal-regulated kinase (ERK). This cytokine also induces the production of several types of reactive oxygen species, including H₂O₂. With the use both of HeLa cells expressing wild-type or dominant negative forms of the cytosolic peroxidase peroxiredoxin II and of mouse embryonic fibroblasts deficient in this protein, we evaluated the roles of H₂O₂ in the activation of MAPKs by TNF-α. In vitro kinase assays as well as immunoblot analysis with antibodies specific for activated MAPKs indicated that H₂O₂ produced in response to TNF-α potentiates the activation of JNK and p38 induced by this cytokine but inhibits that of ERK. Our results also suggest that cytosolic peroxiredoxins are important regulators of TNF signaling pathways.