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      PKR regulates TLR2/TLR4-dependent signaling in murine alveolar macrophages.

      American journal of respiratory cell and molecular biology
      2-Aminopurine, pharmacology, Animals, Antimetabolites, Bacteria, immunology, Cell Wall, Cells, Cultured, Enzyme Activation, drug effects, Female, Gene Deletion, Immunity, Innate, physiology, Interleukin-6, biosynthesis, genetics, JNK Mitogen-Activated Protein Kinases, metabolism, Ligands, Lipopeptides, Lipopolysaccharides, Lung, MAP Kinase Kinase 4, MAP Kinase Signaling System, Macrophages, Alveolar, Male, Mice, Mice, Inbred BALB C, Mice, Knockout, Peptides, Phosphorylation, Toll-Like Receptor 2, agonists, Toll-Like Receptor 4, Transcription Factor RelA, Tumor Necrosis Factor-alpha, eIF-2 Kinase, p38 Mitogen-Activated Protein Kinases

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          Abstract

          The double-stranded RNA (dsRNA)-activated serine/threonine kinase R (PKR) is well characterized as an essential component of the innate antiviral response. Recently, PKR has been implicated in Toll-like receptor (TLR) signal transduction in response to bacterial cell wall components. Its contribution to pulmonary immunity, however, has not yet been elucidated. In this report we investigated whether PKR is involved in TLR2/TLR4-mediated immune responses of primary alveolar macrophages (AM). We found that both TLR2 (Pam3CSK4) and TLR4 (LPS) ligands induced rapid phosphorylation of PKR. Moreover, this activation was strictly dependent on the functionality of the respective TLR. Pharmacologic inhibition of PKR activity using 2-aminopurine (2-AP) and PKR gene deletion was found to reduce the TLR2/TLR4-induced activation of the JNK signaling pathway (MKK4/JNK/c-Jun), but did not affect p38 and extracellular signal-regulated kinase 1/2 activation. Moreover, inhibition of PKR phosphorylation severely impaired TNF-alpha and IL-6 production by AM in response to LPS and Pam3CSK4. In addition, we found that PKR phosphorylation plays a major role in LPS- but not Pam3CSK4-induced activation of the p65 subunit of NF-kappaB. Collectively, these results indicate that functional PKR is critically involved in inflammatory responses of primary AM to gram-positive as well as gram-negative bacterial cell wall components.

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