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PKR Regulates TLR2/TLR4-Dependent Signaling in Murine Alveolar Macrophages

¹ University of Giessen Lung Center, Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine and Infectious Diseases, Justus-Liebig-University, Giessen, Germany

Correspondence and requests for reprints should be addressed to Maciej Cabanski, University of Giessen Lung Center, Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine and Infectious Diseases, Justus-Liebig-University, Klinikstrasse 36, Giessen 35392, Germany. E-mail: maciej.cabanski{at}uglc.de

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- 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-B. 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.

Key Words: PKR • 2-aminopurine • alveolar macrophages • LPS • Pam3CSK4

CLINICAL RELEVANCE Our results demonstrate that serine/threonine kinase R (PKR) is involved in the control of Toll-like receptor (TLR)2/TLR4-mediated inflammatory response of alveolar macrophages to bacterial pathogen-associated molecular patterns. This suggests that PKR may also contribute to host defense mechanisms in vivo against bacterial infections.