POTENTIAL REQUIREMENT OF A FUNCTIONAL DOUBLE-STRANDED RNA-DEPENDENT PROTEIN-KINASE (PKR) FOR THE TUMORICIDAL ACTIVATION OF MACROPHAGES BY LIPOPOLYSACCHARIDE OR IFN-ALPHA-BETA, BUT NOT IFN-GAMMA

We analyzed the expression of the dsRNA-dependent protein kinase (PKR) during the activation of murine macrophages to the tumoricidal state by LPS and/or IFNs. LPS induced PKR expression in a dose-dependent man ner at levels that were comparable with those observed in response to IFNs. By using the PKR inhibitor 2-aminopurine (2-AP), we have shown t hat the pathways of macrophage tumoricidal activation elicited by LPS and IFN-alpha beta, but not by IFN-gamma, included a 2-AP-sensitive st ep. In fact, LPS- and IFN-alpha beta-induced activation was inhibited by 2-AP, whereas the activation by IFN-gamma was not affected by the p resence of the inhibitor. 2-AP did not affect the activation of protei n kinase C or protein kinase A in intact cells. In the presence of 2-A P the up-regulation of IFN-beta mRNA by LPS was specifically inhibited , whereas the expression of glyceraldehyde-3-phosphate dehydrogenase m RNA or the induction of PKR remained unchanged, thereby demonstrating that 2-AP inhibited selective macrophage genes. The differential sensi tivity to 2-AP suggested that the expression of a functional PKR may b e required for the macrophage tumoricidal response triggered by LPS an d IFN-alpha beta but not IFN-gamma.