The protein kinase PKR is required for p38 MAPK activation and the innate immune response to bacterial endotoxin

Protein kinase RNA-regulated (PKR) is an established component of innate an tiviral immunity. Recently, PKR has been shown to be essential for signal t ransduction in other situations of cellular stress. The relationship betwee n PKR and the stress-activated protein kinases (SAPKs), such as p38 mitogen -activated protein kinase (MAPK), is not clear. Using embryonic fibroblasts from PKR wild-type and null mice, we established a requirement for PKR in the activation of SAPKs by double-stranded RNA, lipopolysaccharide (LPS) an d proinflammatory cytokines, This does not reflect a global failure to acti vate SAPKs in the PKR-null background as these kinases are activated normal ly by anisomycin and other physicochemical stress. Activation of p38 MAPK w as restored in immortalized PKR-null cells by reconstitution with human PKR . We also show that LPS induction of interleukin-6 and interleukin-12 mRNA is defective in PKR-null cells, and that production of these cytokines is i mpaired in PKR-null mice challenged with LPS, Our findings indicate, for th e first time, that PKR is required for p38 MAPK signaling and plays a poten tially important role in the innate response against bacterial endotoxin.