NF-kappaB1 (p50) homodimers differentially regulate pro- and anti-inflammatory cytokines in macrophages.
NF-kappaB/Rel is a family of transcription factors whose activation has long been linked to the production of inflammatory cytokines. Here, we studied NF-kappaB signaling in the regulation of the anti-inflammatory cytokine, interleukin-10 (IL-10). We identified a role for a single NF-kappaB family member, NF-kappaB1 (p50), in promoting the transcription of IL-10. The NF-kappaB ciselement on IL-10 proximal promoter was located to -55/-46, where p50 can homodimerize and form a complex with the transcriptional co-activator CREB-binding protein to activate transcription. The other Rel family members appear to play a negligible role in IL-10 transcription. Mice lacking p50 were more susceptible to lethal endotoxemia, and macrophages taken from p50-/- mice exhibit skewed cytokine responses to lipopolysaccharide, characterized by decreased IL-10 and increased tumor necrosis factor and IL-12. Taken together, our studies demonstrate that NF-kappaB1 (p50) homodimers can be transcriptional activators of IL-10. The reciprocal regulation of pro- and anti-inflammatory cytokine production by NF-kappaB1 (p50) may provide potential new ways to manipulate the innate immune response.
Cao
Shanjin
S
Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland 20742, USA.
Zhang
Xia
X
Edwards
Justin P
JP
Mosser
David M
DM
D000818:Animals; D001665:Binding Sites; D050882:CREB-Binding Protein / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D019281:Dimerization; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000166:cytology / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D052002:NF-kappa B p50 Subunit / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D021122:Protein Subunits / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014158:Transcription, Genetic
D016207:Cytokines; D008070:Lipopolysaccharides; D052002:NF-kappa B p50 Subunit; D021122:Protein Subunits; D016753:Interleukin-10; D050882:CREB-Binding Protein