Requirement of mitogen-activated protein kinase kinase 3 (MKK3) for tumor necrosis factor-induced cytokine expression

The p38 mitogen-activated protein kinase is activated by treatment of cells with cytokines and by exposure to environmental stress. The effects of the se stimuli on p38 MAP kinase are mediated by the MAP kinase kinases (MKKs) MKK3, MKK4, and MKK6, We have examined the function of the p38 MAP kinase s ignaling pathway by investigating the effect of targeted disruption of the Mkk3 gene. Here we report that Mkk3 gene disruption caused a selective defe ct in the response of fibroblasts to the proinflammatory cytokine tumor nec rosis factor, including reduced p38 MAP kinase activation and cytokine expr ession. These data demonstrate that the MKK3 protein kinase is a critical c omponent of a tumor necrosis factor-stimulated signaling pathway that cause s increased expression of inflammatory cytokines.