Tang W W, Qi M, Van G Y, Wariner G P, Samal B
Department of Pathology, Amgen Inc., Thousand Oaks, California, USA.
Kidney Int. 1996 Dec;50(6):1922-7. doi: 10.1038/ki.1996.514.
Leukemia inhibitory factor (LIF) is a pleiotropic cytokine that has been identified in acute and chronic inflammatory conditions such as rheumatoid arthritis, sepsis, and renal allograft rejection. We investigated the glomerular expression of LIF at 30 minutes, and 3, 6, 9, 15 and 24 hours after administration of anti-GBM Ab (N = 3) by the RNase protection 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 rats. However with the induction of anti-GBM Ab GN, there was a marked increase in LIF steady-state mRNA beginning at three hours which persisted through 24 hour. LIF mRNA was also detected in cultured mesangial cells stimulated with IL-1 beta, identifying this cell type as a potential glomerular source for this cytokine. To investigate the in vivo effect of LIF, Lewis rats were continuously infused with recombinant (r) human (h) LIF (approximately 0.5 ng/hr) or saline vehicle i.p. with ALZA osmotic pumps beginning at t = -24 hours (N = 8). All rats were injected with anti-GBM Ab intravenously at t = 0 (N = 16). LIF infusion decreased 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 glomerular macrophage infiltration (0.8 +/- 0.2 vs. 2.0 +/- 0.6 ED-1 cells/glom, P = 0.0001). The administration of rhLIF did not affect the binding 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 with a 29% decrease in TNF-alpha protein expression within the glomerular lysate of nephritic rats administered LIF when compared with control rats. These data demonstrate a potential role for LIF in the therapy of anti-GBM Ab GN.
白血病抑制因子（LIF）是一种多效性细胞因子，已在类风湿性关节炎、败血症和肾移植排斥等急慢性炎症性疾病中被发现。我们通过核糖核酸酶保护试验，研究了在注射抗肾小球基底膜抗体（anti-GBM Ab）后30分钟以及3、6、9、15和24小时LIF在肾小球中的表达情况（N = 3）。对照大鼠注射兔血清，并在30分钟、6小时和24小时后处死。在偶尔的对照大鼠肾小球内，相对于甘油醛-3-磷酸脱氢酶（GAPDH）mRNA，LIF mRNA的检测水平较低。然而，随着抗GBM抗体介导的肾小球肾炎（anti-GBM Ab GN）的诱导，从3小时开始LIF稳态mRNA显著增加，并持续至24小时。在用白细胞介素-1β（IL-1β）刺激的培养系膜细胞中也检测到了LIF mRNA，这表明该细胞类型是这种细胞因子潜在的肾小球来源。为了研究LIF的体内作用，从t = -24小时开始，使用ALZA渗透泵通过腹腔内持续输注重组（r）人（h）LIF（约0.5 ng/小时）或生理盐水载体对Lewis大鼠进行处理（N = 8）。所有大鼠在t = 0时静脉注射抗GBM抗体（N = 16）。LIF输注使24小时尿蛋白排泄减少了85%（17±15 vs. 114±37 mg/天，P = 0.0001），并且与肾小球巨噬细胞浸润减少60%相关（0.8±0.2 vs. 2.0±0.6 ED-1细胞/肾小球，P = 0.0001）。rhLIF的给药不影响抗GBM抗体与肾小球的结合。LIF的有益作用与肾小球中单核细胞趋化蛋白-1（MCP-1）（56%）、IL-1（41%）和肿瘤坏死因子（TNF）（17%）稳态mRNA表达的降低有关。与对照大鼠相比，这与接受LIF治疗的肾炎大鼠肾小球裂解物中TNF-α蛋白表达降低29%相关。这些数据证明了LIF在抗GBM抗体介导的肾小球肾炎治疗中的潜在作用。
