Protein Kinase R Regulates Double-Stranded RNA Induction of TNF-α But Not IL-1β mRNA in Human Epithelial Cells

Abstract

Epithelial cells represent the initial site of respiratory viral entry and the first line of defense against such infections. This early antiviral response is characterized by an increase in the production of proinflammatory cytokines such as TNF-α and IL-1β. dsRNA, which is a common factor present during the life cycle of both DNA and RNA viruses, is known to induce TNF-α and IL-1β in a variety of cells. In this work we provide data showing that dsRNA treatment induces TNF-α and IL-1β in human lung epithelial cells via two different mechanisms. Our data show that dsRNA activation of dsRNA-activated protein kinase (PKR) is associated with induction of TNF-α but not IL-1β expression. An inhibitor of PKR activation blocked the dsRNA-induced elevations in TNF-α but not IL-1β mRNA in epithelial cells. Data obtained from infection of epithelial cells with a vaccinia virus lacking the PKR inhibitory polypeptide, E3L, revealed that PKR activation was essential for TNF-α but not for IL-1β expression. In this report, we provide experimental support for the differential regulation of proinflammatory cytokine expression by dsRNA and viral infections in human airway epithelial cells.