Differential mechanisms of LPS-induced NFκB activation in macrophages and fibroblasts

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Abstract
Lipopolysaccharide is a prototypic stimulus of inflammatory gene expression which can act on a variety of cell types to produce different patterns of response. In the present report, the ability of LPS to stimulate NFKB activity was investigated in a fibroblast cell line (NIH3T3) and compared to LPS-induced response in a macrophage like cell line (RAW264.7). LPS was a potent stimulus of KB binding activity in both cell types though the protein composition of such binding activity varied. LPS caused nuclear translocation of KB binding activity in RAW 264.7 cells which contained NFKB1 (p50), RelA (p65), and high levels of c-Rel. Nuclei from LPS-stimulated NIH3T3 cells contained only NFKB1 and RelA but little c-Rel. Both cell types contain comparable levels of total c-Rel protein. Using two structurally distinct KB sequence motifs, LPS was shown to produce a different pattern of transacting activity in fibroblasts as compared to macrophages; both KB motifs were sensitive to LPS in RAW264.7 cells while only one of the two was functional in LPS-stimulated NIH3T3 cells. Thus LPS appears to utilize the NFKB family of transcription factors differentially depending upon the cell type being stimulated. Such differential activation of transcription factor family members may be an important determinant of the diverse nature of inflammatory response seen in different tissue settings.