Activation of macrophages by extracellular signals is mediated by a complex array of transcriptional events. Exposure of macrophages to pro-inflammatory cytokines, viral infection, bacterial lipopolysaccharide, or reactive oxygen intermediates induces activation of the NF-κB/Rel family of transcription factors. When activated, these proteins form hetero- or homodimers which bind to κB elements within the promoter regions of many genes involved in inflammation, including inducible nitric oxide synthase and tumor necrosis factor-α. In unstimulated macrophages, NF-κB/Rel proteins are retained in the cytoplasm by complex formation with IκB-α. Stimulation of the cells initiates degradation of IκB-α and translocation of Rel family transcription complexes to the nucleus. Using alveolar macrophages isolated from Balb/c mice or the murine macrophage-like cell line, RAW 264.7, we found that expression of IκB-α was confined to cells in the G-0/G-1 phase of the cell cycle. Cellular IκB-α levels and DNA content were assessed using propidium iodide staining and immunofluorescence in conjunction with flow cytometry. Macrophages in the G-0/G-1 phase of the cell cycle responded to activation of NF-κB by enhanced synthesis of IκB-α. Treatment of macrophages with hydroxyurea, which causes cells to arrest at the G-1/S interface, did not block activation-induced IκB-α biosynthesis. These data indicate that IκB-α expression is regulated during the cell cycle. The high proliferative state of monocytes during the neonatal period may result in a decreased activation potential and reduced production of inflammatory mediators. This may contribute to the increased susceptibility of neonates to invasive pathogens.
