Aarhus University Seal / Aarhus Universitets segl

Activation of NF-κB in virus-infected macrophages is dependent on mitochondrial oxidative stress and intracellular calcium: Downstream involvement of the kinases TGF-β-activated kinase 1, mitogen-activated kinase/extracellular signal-regulated kinase kinase 1, and IκB kinase

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

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-κB. However, the mechanisms of HSV-induced NF-κB activation are poorly understood. In this study we demonstrate that activation of NF-κB by HSV in macrophages is dependent on a functional viral genome and proceeds through a mechanism involving the cellular IκB kinase, as well as the upstream kinases TGF-β-activated kinase 1, mitogen-activated kinase/extracellular signal-regulated kinase kinase 1, and possibly NF-κB-inducing kinase. Furthermore, we show that HSV triggers NF-κB 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-κB activation. Together, these results point to mitochondria as cellular checkpoints able to initiate NF-κB activation after virus infection and also show that the cellular NF-κB-regulating kinases IκB kinase, TGF-β-activated kinase 1, mitogen-activated kinase/extracellular signal-regulated kinase kinase 1, and possibly NF-κB-inducing kinase, are essential components in the HSV-induced signaling pathway.

Original languageEnglish
JournalJournal of Immunology
Volume170
Issue12
Pages (from-to)6224-6233
Number of pages10
ISSN0022-1767
Publication statusPublished - 15 Jun 2003

See relations at Aarhus University Citationformats

ID: 176041025