Lack of essential role of NF-kappa B p50, RelA, and cRel subunits in virus-induced type 1 IFN expression.
Type 1 IFNs (IFN-alphabeta) play pivotal roles in the host antiviral response and in TLR-induced signaling. IFN regulatory factor (IRF) and NF-kappaB transcription factors are thought to be crucial for virus-induced mRNA expression of IFN-beta. Although recent studies have demonstrated essential roles for IRF3 and IRF7, the definitive role of NF-kappaB factors in IFN-beta (or IFN-alpha) expression remains unknown. Using mice deficient in distinct members of the NF-kappaB family, we investigated NF-kappaB function in regulating type 1 IFN expression in response to Sendai virus and Newcastle disease virus infection. Surprisingly, IFN-beta and IFN-alpha expression was strongly induced following virus infection of mouse embryonic fibroblasts (MEFs) from p50(-/-), RelA/p65(-/-), cRel(-/-), p50(-/-)cRel(-/-), and p50(-/-)RelA(-/-) mice. Compared with wild-type MEFs, only RelA(-/-) and p50(-/-)RelA(-/-) MEFs showed a modest reduction in IFN-beta expression. To overcome functional redundancy between different NF-kappaB subunits, we expressed a dominant-negative IkappaBalpha protein in p50(-/-)RelA(-/-) MEFs to inhibit activation of remaining NF-kappaB subunits. Although viral infection of these cells failed to induce detectable NF-kappaB activity, both Sendai virus and Newcastle disease virus infection led to robust IFN-beta expression. Virus infection of dendritic cells or TLR9-ligand CpG-D19 treatment of plasmacytoid dendritic cells from RelA(-/-) or p50(-/-)cRel(-/-) mice also induced robust type 1 IFN expression. Our findings therefore indicate that NF-kappaB subunits p50, RelA, and cRel play a relatively minor role in virus-induced type 1 IFN expression.
Wang
Xingyu
X
Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center & Research Institute, University of South Florida, Tampa, FL 33612, USA.
Hussain
Sofia
S
Wang
Emilie-Jeanne
EJ
Wang
Xiuyan
X
Li
Ming O
MO
García-Sastre
Adolfo
A
Beg
Amer A
AA
D000818:Animals; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000821:virology; D053595:Embryonic Stem Cells / Q000276:immunology / Q000378:metabolism / Q000821:virology; D007370:Interferon Type I / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052002:NF-kappa B p50 Subunit / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D009522:Newcastle disease virus / Q000276:immunology*; D021122:Protein Subunits / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D020569:Proto-Oncogene Proteins c-rel / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D029082:Sendai virus / Q000276:immunology*; D051996:Transcription Factor RelA / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D007370:Interferon Type I; D052002:NF-kappa B p50 Subunit; D021122:Protein Subunits; D020569:Proto-Oncogene Proteins c-rel; C498144:Rela protein, mouse; D051996:Transcription Factor RelA