A role for double-stranded RNA-activated protein kinase PKR in Mycobacterium-induced cytokine expression

Following infection of the host by Mycobacterium tuberculosis, induction of cytokines is a major defense mechanism to limit the pathogen invasion. Cytokines interact with each other to form an intertwined network of pathways. For example, IFN and TNF have been shown to interact through common pathways including IFN-inducible, dsRNA-activated serine/threonine protein kinase (PKR) induction. As a signal transducer, it has been conventionally known to regulate the induction of cytokine expression in response to virus infection through NF-kappa B. In light of the critical role of TNF in immunity and its cytotoxic effects mediated by PKR, we examined the role of the kinase in the regulation of immune response against M. tuberculosis using the interaction of bacillus Calmette-Guerin (BCG) and primary human blood monocytes as a model. Our results showed that BCG stimulates the induction of cytokine expression in human primary blood monocytes including TNF-alpha, IL-6, and IL-10. With the suppression of PKR by using PKR-mutant gene or 2-aminopurine as PKR inhibitor, we showed that the BCG-induced cytokine expression in human monocytes is regulated by the phosphorylation and activation of PKR. We also demonstrated that downstream of PKR induction is the activation of MAPK and translocation of NF-kappa B into the nucleus. NF-kappa B in turn mediates the transcription of specific cytokine genes. Taken together, PKR plays a critical role in the regulation of immune responses to mycobacterial infection and may serve as an important molecule in the innate antimycobacterial defense.