CYTOKINE-INDUCED EXPRESSION OF LEUKEMIA INHIBITORY FACTOR IN RENAL MESANGIAL CELLS

Leukemia inhibitory factor (LIF) is a pleiotropic cytokine, which shares many characteristics with interleukin-6 (IL-6). Recent observations indicate a role for LIF in inflammatory processes. To examine the potential involvement of LIF in the regulation of mesangial cell behavior, we studied LIF expression in early primary cultures of rat and human mesangial cells, as well as the response of mesangial cells to exogenous LIF. Growing or growth-arrested rat mesangial cells constitutively expressed very low levels of LIF mRNA, barely detectable by Northern blot analysis. Strong induction of LIF mRNA expression was caused by cytokines, such as interleukin-1 beta (5 ng/ml), tumor necrosis factor alpha (100 ng/ml) and PDGF (100 ng/ml), as well as LPS (200 ng/ml). The induction was transient with a peak after three to five hours. Dexamethasone (0.1 mu M) almost completely inhibited the induction of LIF. Weak induction of LIF mRNA was observed after stimulation with basic fibroblast growth factor, endothelin and transforming growth factor beta. In combination with IL-1 beta, TGF beta showed synergistic effects on LIF induction. LIF itself or IL-6 had no effect on LIF mRNA expression. A similar induction pattern was observed for the expression of IL-6 mRNA. LIF protein was detected by specific ELISA in the supernatants of human mesangial cells stimulated with LPS or IL-IP. In addition, we found that mesangial cells not only express LIF but they are also target cells for LIF. Recombinant LIF effectively induced transient expression of the immediate early genes, c-fos, jun-B and Egr-1 in rat mesangial cells, with a maximum at 30 to 60 minutes. LIF was not mitogenic for mesangial cells. Our findings indicate that glomerular mesangial cells produce and react to LIF. As a cytokine with autocrine potential, LIF may play a physiological and/or pathophysiological role in the glomerulus, the exact nature and relevance of which remain to be explored.