Interferon-gamma augments acute macrophage-mediated renal injury via a glucocorticoid-sensitive mechanism

SUMMARY: Macrophage migration inhibitory factor (MIF) promotes macrophage accumulation and leucocyte activation during inflammation. Macrophage migration inhibitory factor is upregulated in intrinsic renal cells in many types of kidney diseases, and has a pathogenic role in rat crescentic nephritis. However, little is known about the factors that regulate the production and secretion of MIF in kidney cells. In this study, we evaluated whether interferon-gamma (IFNg ), a cytokine implicated in the development of kidney disease and a potent inducer of MIF production in macrophages, could promote MIF synthesis and secretion from renal tubular epithelial cells. Northern blot analysis detected constitutive expression of MIF mRNA in rat tubular epithelial cells (NRK52E), which increased twofold after a 6-h stimulation with IFNg . Macrophage migration inhibitory factor protein was found only in the cytoplasm of NRK52E cells. Following IFNg stimulation, intracellular MIF in NRK52E cells was rapidly secreted with a maximal reduction of 50 after 20 min, which returned to normal levels after 2a??4 h. Rapid secretion of MIF in response to IFNg was also seen in rat mesangial cells. These findings indicate that IFNg induces rapid secretion of MIF by tubular epithelial cells, and suggest that this may be an important mechanism leading to inflammatory cell accumulation and activation during kidney disease.