LEUKEMIA INHIBITORY FACTOR AMELIORATES EXPERIMENTAL ANTI-GBM AB GLOMERULONEPHRITIS

Leukemia inhibitory factor (LIF) is a pleiotropic cytokine that has be en identified in acute and chronic inflammatory conditions such as rhe umatoid arthritis, sepsis, and renal allograft rejection. We investiga ted the glomerular expression of LIF at 30 minutes, and 3, 6, 9, 15 an d 24 hours after administration of anti-GBM Ab (N = 3) by the RNase pr otection assay. Control rats received rabbit sera and were sacrificed at 30 minutes, and 6 and 24 hours. LIF mRNA relative to GAPDH mRNA was detected at low levels within the glomeruli of occasional control rat s. However, with the induction of anti-GEM Ab GN, there was a marked i ncrease in LIF steady-state mRNA beginning at three hours which persis ted through 24 hours. LIF mRNA was also detected in cultured mesangial cells stimulated with IL-1 beta, identifying this cell type as a pote ntial glomerular source for this cytokine. To investigate the in vivo effect of LIF, Lewis rats were continuously infused with recombinant ( r) human (h) LIF (similar to 0.5 ng/hr) or saline vehicle i.p. with AL ZA osmotic pumps beginning at t = -24 hours (N = 8). All rats were inj ected with anti-GBM Ab intravenously at t = 0 (N = 16). LIF infusion d ecreased 24-hour urinary protein excretion by 85% (17 +/- 15 vs. 114 /- 37 mg/day, P = 0.0001) and was associated with a 60% decrease in gl omerular macrophage infiltration (0.8 +/- 0.2 vs. 2.0 +/- 0.6 ED-1 cel ls/glom, P = 0.0001). The administration of rhLIF did not affect the b inding of the anti-GBM Ab to glomeruli. The beneficial effects of LIF were associated with a decrease in glomerular MCP-1 (56%), IL-1 (41%) and TNF (17%) steady state mRNA expression The latter was associated w ith a 29% decrease in TNF-alpha protein expression within the glomerul ar lysate of nephritic rats administered LIF when compared with contro l rats. These data demonstrate a potential role for LIF in the therapy of anti-GEM Ab GN.