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B in Virus-Infected Macrophages Is Dependent on Mitochondrial Oxidative Stress and Intracellular Calcium: Downstream Involvement of the Kinases TGF-
-Activated Kinase 1, Mitogen-Activated Kinase/Extracellular Signal-Regulated Kinase Kinase 1, and IB Kinase 1
Department of Medical Microbiology and Immunology, University of Aarhus, Aarhus, Denmark
Efficient clearance of virus infections depends on the nature of the host response raised by the infected organism. A proinflammatory cell-mediated immune response is important for elimination of many viruses, including herpesviruses. Macrophages are intimately involved in generation of a proinflammatory response, the initiation of which involves activation of the transcription factor NF-
B. However, the mechanisms of HSV-induced NF-B activation are poorly understood. In this study we demonstrate that activation of NF-B by HSV in macrophages is dependent on a functional viral genome and proceeds through a mechanism involving the cellular IB kinase, as well as the upstream kinases TGF-
-activated kinase 1, mitogen-activated kinase/extracellular signal-regulated kinase kinase 1, and possibly NF-B-inducing kinase. Furthermore, we show that HSV triggers NF-B activation by a signaling pathway involving oxidative stress in mitochondria and intracellular calcium, because specific inhibition of mitochondria-derived reactive oxygen intermediates, as well as mitochondrial calcium channels, prevented NF-B activation. Together, these results point to mitochondria as cellular checkpoints able to initiate NF-B activation after virus infection and also show that the cellular NF-B-regulating kinases IB kinase, TGF--activated kinase 1, mitogen-activated kinase/extracellular signal-regulated kinase kinase 1, and possibly NF-B-inducing kinase, are essential components in the HSV-induced signaling pathway.
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