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.

Abstract

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.

• Authors: Trine H Mogensen, Jesper Melchjorsen, Per Höllsberg, Søren R Paludan
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 170 Issue 12 Pg. 6224-33 (Jun 15 2003) ISSN: 0022-1767 [Print] United States
• PMID: 12794154 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antiviral Agents
• Chemokine CCL5
• Inflammation Mediators
• Lipopolysaccharides
• NF-kappa B
• NF-kappa B p50 Subunit
• Reactive Oxygen Species
• Transcription Factor RelA
• Protein Serine-Threonine Kinases
• Chuk protein, mouse
• I-kappa B Kinase
• Ikbkb protein, mouse
• Ikbke protein, mouse
• Calcium-Calmodulin-Dependent Protein Kinases
• MAP Kinase Kinase Kinase 1
• MAP Kinase Kinase Kinases
• MAP kinase kinase kinase 7
• Map3k1 protein, mouse
• NF-kappa B kinase

Topics

• Active Transport, Cell Nucleus (genetics)
• Animals
• Antiviral Agents (pharmacology)
• Calcium Signaling (physiology)
• Calcium-Calmodulin-Dependent Protein Kinases (physiology)
• Cell Line
• Cell Nucleus (genetics, metabolism)
• Chemokine CCL5 (biosynthesis, genetics)
• Enzyme Activation
• Female
• Gene Expression Regulation, Viral (drug effects)
• Genes, Immediate-Early (drug effects)
• I-kappa B Kinase
• Inflammation Mediators (metabolism)
• Intracellular Fluid (metabolism)
• Lipopolysaccharides (antagonists & inhibitors, pharmacology)
• MAP Kinase Kinase Kinase 1
• MAP Kinase Kinase Kinases (biosynthesis, genetics, metabolism, physiology)
• Macrophages, Peritoneal (drug effects, enzymology, metabolism, virology)
• Mice
• Mice, Inbred C57BL
• Mitochondria (metabolism, physiology, virology)
• NF-kappa B (antagonists & inhibitors, metabolism, physiology)
• NF-kappa B p50 Subunit
• Oxidative Stress
• Protein Serine-Threonine Kinases (biosynthesis, genetics, metabolism, physiology)
• Reactive Oxygen Species (metabolism)
• Simplexvirus (drug effects, genetics, physiology)
• Transcription Factor RelA
• Transfection
• Virus Replication (drug effects)