NF-kappaB activation can mediate inhibition of human cytomegalovirus replication.
The activation of NF-kappaB has long been considered a positive factor for human cytomegalovirus (HCMV) replication. The HCMV immediate-early promoter, the initial transcriptional element in the HCMV replication cycle, is activated by the transcription factor NF-kappaB, and several HCMV gene products have been demonstrated to activate this transcription factor. However, the role of NF-kappaB in the full replication cycle of the virus has not been carefully examined. A series of experiments that demonstrate an important inhibitory role of NF-kappaB for HCMV replication in fibroblasts is presented here. Using both genetic and pharmaceutical methods, it was shown that blocking NF-kappaB activation in cell culture does not inhibit HCMV replication, but rather leads to a modest increase in replication. Two cytokines inhibitory for HCMV, tumour necrosis factor-alpha and interferon-gamma, no longer inhibit HCMV when NF-kappaB activation is blocked. Furthermore, forced expression of the NF-kappaB activating IkappaB kinase beta (IKKbeta), but not a kinase inactive mutant, also inhibits HCMV replication. In addition, it was shown that NF-kappaB signalling is essential for the production of an anti-viral factor in the supernatant of HCMV-infected fibroblasts, and identified interferon-beta as this factor. Thus, the role of NF-kappaB in fibroblasts is to activate a host defence against HCMV.
Eickhoff
Jan Eike
JE
Axxima Pharmaceuticals AG, Max-Lebsche-Platz 32, 81377 Munich, Germany.
Cotten
Matt
M
Axxima Pharmaceuticals AG, Max-Lebsche-Platz 32, 81377 Munich, Germany.
D000818:Animals; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000276:immunology / Q000502:physiology*; D005347:Fibroblasts; D006801:Humans; D051550:I-kappa B Kinase; D016899:Interferon-beta / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D014779:Virus Replication
D016328:NF-kappa B; D016899:Interferon-beta; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse