Activation of NF-kappa B in virus-infected macrophages is dependent on mitochondrial oxidative stress and intracellular calcium: downstream involvement of the kinases TGF-beta-activated kinase 1, mitogen-activated kinase/extracellular signal-regulated kinase kinase 1, and I kappa B kinase.
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-kappaB. However, the mechanisms of HSV-induced NF-kappaB activation are poorly understood. In this study we demonstrate that activation of NF-kappaB by HSV in macrophages is dependent on a functional viral genome and proceeds through a mechanism involving the cellular IkappaB kinase, as well as the upstream kinases TGF-beta-activated kinase 1, mitogen-activated kinase/extracellular signal-regulated kinase kinase 1, and possibly NF-kappaB-inducing kinase. Furthermore, we show that HSV triggers NF-kappaB 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-kappaB activation. Together, these results point to mitochondria as cellular checkpoints able to initiate NF-kappaB activation after virus infection and also show that the cellular NF-kappaB-regulating kinases IkappaB kinase, TGF-beta-activated kinase 1, mitogen-activated kinase/extracellular signal-regulated kinase kinase 1, and possibly NF-kappaB-inducing kinase, are essential components in the HSV-induced signaling pathway.
Mogensen
Trine H
TH
Department of Medical Microbiology and Immunology, University of Aarhus, Aarhus, Denmark. trine@microbiology.au.dk
Melchjorsen
Jesper
J
Höllsberg
Per
P
Paludan
Søren R
SR
D021581:Active Transport, Cell Nucleus / Q000235:genetics; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D020013:Calcium Signaling / Q000502:physiology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology; D002460:Cell Line; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D018946:Chemokine CCL5 / Q000096:biosynthesis / Q000235:genetics; D004789:Enzyme Activation; D005260:Female; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D017781:Genes, Immediate-Early / Q000187:drug effects; D051550:I-kappa B Kinase; D018836:Inflammation Mediators / Q000378:metabolism; D007424:Intracellular Fluid / Q000378:metabolism; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D048728:MAP Kinase Kinase Kinase 1; D020930:MAP Kinase Kinase Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000821:virology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology* / Q000821:virology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D052002:NF-kappa B p50 Subunit; D018384:Oxidative Stress; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D018139:Simplexvirus / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D051996:Transcription Factor RelA; D014162:Transfection; D014779:Virus Replication / Q000187:drug effects; D000097782:NF-kappaB-Inducing Kinase; D000099151:MAP Kinase Kinase Kinase 7
D000998:Antiviral Agents; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D018946:Chemokine CCL5; D051550:I-kappa B Kinase; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D048728:MAP Kinase Kinase Kinase 1; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D017346:Protein Serine-Threonine Kinases; D017382:Reactive Oxygen Species; D051996:Transcription Factor RelA; D000097782:NF-kappaB-Inducing Kinase; D000099151:MAP Kinase Kinase Kinase 7; C496564:Chuk protein, mouse; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse; C482578:Map3k1 protein, mouse