Gene, stimulus and cell-type specific regulation of activator protein-1 inmesangial cells by lipopolysaccharide and cytokines

Activator protein-1 (AP-1) plays an important role in the regulation of gen e expression in mesangial cells (MC) during the pathogenesis of glomerular inflammatory disease. The precise regulation of the AP-1 family by agents t hat are known to activate MC is, however, poorly understood. The action of platelet-derived growth factor (PDGF) and, for the first time, lipopolysacc haride (LPS), interleukin-6 (IL-6), interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha) on AP-1 gene expression in MC was theref ore studied. Whilst the expression of JunD was not affected by any of the m ediators, the mRNA levels of c-fos and JunB were induced by LPS, IL-6, IFN- gamma, PDGF and TNF-alpha, and that of c-jun by LPS, IFN-gamma, PDGF and TN F-alpha. Electrophoretic mobility shift assays showed a time-dependent incr ease in AP-1 DNA binding activity with JunB representing the major mediator -inducible member involved in DNA-protein interactions. However, stimulus-s pecific changes in the kinetics and magnitude of AP-1 mRNA expression and D NA binding activity were identified and, additionally, the results showed t he potential existence of cell-type-specific mechanisms in the regulation o f the AP-1 family. These studies provide novel insights into the mediator-s pecific modulation of AP-1-regulated gene expression and the activation of MC in renal diseases. (C) 2000 Elsevier Science B.V. All rights reserved.