NF-κB1 (p50) homodimers differentially regulate pro- and anti-inflammatory cytokines in macrophages

NF-kappa B/Rel is a family of transcription factors whose activation has long been linked to the production of inflammatory cytokines. Here, we studied NF-kappa B signaling in the regulation of the anti-inflammatory cytokine, interleukin-10 (IL-10). We identified a role for a single NF-kappa B family member, NF-kappa B1 (p50), in promoting the transcription of IL-10. The NF-kappa B cis-element 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-kappa B1 (p50) homodimers can be transcriptional activators of IL-10. The reciprocal regulation of pro-and anti-inflammatory cytokine production by NF-kappa B1 (p50) may provide potential new ways to manipulate the innate immune response.