Stimulus- and cell-type-specific regulation of CCAAT-enhancer binding protein isoforms in glomerular mesangial cells by lipopolysaccharide and cytokines

Binding sites for the CCAAT-enhancer binding protein (C/EBP) family are pre sent in the promoter regions of several genes that are known to be expresse d by mesangial cells (MC) during the pathogenesis of glomerular inflammator y diseases. The precise regulation of the C/EBP family by agents that are k nown to activate MC is, however, poorly understood. We report here the acti on of interleukin-1 (IL)-1 and, for the first time, lipopolysaccharide (LPS ), platelet-derived growth factor (PDGF), IL-6, interferon-gamma (IFN-gamma ) and tumour necrosis factor-alpha (TNF-alpha) on the C/EBP expression prof ile and functional DNA binding activity in primary rat MC. Both cell-type- and stimulus-specific regulation of C/EBP mRNA expression and DNA binding a ctivity were identified, with C/EBP alpha being induced by LPS, C/EBP beta by LPS, IL-1, TNF-alpha and C/EBP delta by LPS, IL-1, IFN-gamma, TNF-alpha and PDGF. Such differential regulation, particularly that of C/EBP beta, ma y be responsible for the mediator-specific differences in the expression of C/EBP-regulated genes in MC. Additionally, the involvement of potential po st-transcriptional mechanisms in the regulation of C/EBP delta were identif ied. These studies provide novel insights into the stimulus-specific regula tion of gene expression during renal diseases. (C) 2000 Elsevier Science B. V. All rights reserved.