Moore K J, Yeh K, Naito T, Kelley V R
Immunogenetics and Transplantation, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
J Immunol. 1996 Jul 1;157(1):427-32.
The lpr mutation on the MRL background accelerates autoimmune nephritis in which macrophage (M phi) accumulation is prominent. Renal disease is absent in other strains with lpr. TNF-alpha and CSF-1 are increased in the kidney of MRL-lpr mice with loss of renal function. We have established that CSF-1 can incite renal injury in mice with the lpr mutation, and M phi from the MRL strain hyper-respond to this growth factor. We hypothesized that TNF-alpha enhanced the M phi response to CSF-1 in MRL-lpr mice. We now report that TNF-alpha enhanced CSF-1-induced bone marrow M phi proliferation in MRL-lpr mice, and not in congenic MRL +/+, normal C3H +/+, and BALB/c, or another strain with lpr (C3H-lpr). Using a gene transfer approach to deliver CSF-1 together with TNF-alpha into the kidney, we evaluated the impact on renal injury. Tubular epithelial cells genetically modified to produce CSF-1 (CSF-1-TEC) and TNF-alpha (TNF-TEC) placed under the renal capsule caused a greater accumulation of M phi in the implant site than CSF-1-TECs alone in MRL-lpr, but not MRL +/+ mice. We noted in tissues adjacent but not distal to the implanted TECs, an increase in M phi in the interstitium and surrounding glomeruli of MRL-lpr but not MRL +/+ mice. This indicated that CSF-1 and TNF-alpha released by TECs were responsible for promoting renal pathology. Taken together, these data suggest that the simultaneous expression of TNF-alpha and CSF-1 in the MRL-lpr kidney fosters M phi accumulation. We speculate that the increase in M phi in the kidney in response to CSF-1 and TNF-alpha is responsible for the rapid tempo of autoimmune renal injury in MRL-lpr mice.
MRL背景下的lpr突变会加速自身免疫性肾炎，其中巨噬细胞（M phi）的积累很突出。其他携带lpr的品系则没有肾脏疾病。在肾功能丧失的MRL - lpr小鼠的肾脏中，肿瘤坏死因子-α（TNF-α）和集落刺激因子-1（CSF-1）水平升高。我们已经证实，CSF-1可在携带lpr突变的小鼠中引发肾损伤，并且来自MRL品系的M phi对这种生长因子反应过度。我们推测，TNF-α增强了MRL - lpr小鼠中M phi对CSF-1的反应。我们现在报告，TNF-α增强了MRL - lpr小鼠而非同基因MRL +/+、正常C3H +/+、BALB/c或另一个携带lpr的品系（C3H - lpr）中CSF-1诱导的骨髓M phi增殖。使用基因转移方法将CSF-1与TNF-α一起导入肾脏，我们评估了对肾损伤的影响。在MRL - lpr小鼠而非MRL +/+小鼠中，经基因改造产生CSF-1（CSF-1 - TEC）和TNF-α（TNF - TEC）的肾小管上皮细胞置于肾被膜下，在植入部位导致M phi的积累比单独的CSF-1 - TEC更多。我们注意到，在植入的TEC相邻但非远端的组织中，MRL - lpr小鼠而非MRL +/+小鼠的间质和周围肾小球中的M phi增加。这表明TEC释放的CSF-1和TNF-α是促进肾脏病理变化的原因。综上所述，这些数据表明MRL - lpr肾脏中TNF-α和CSF-1的同时表达促进了M phi的积累。我们推测，肾脏中M phi对CSF-1和TNF-α的反应增加是MRL - lpr小鼠自身免疫性肾损伤快速进展速度的原因。
