MODULATION OF ANTIBODY-MEDIATED GLOMERULAR INJURY IN-VIVO BY IL-1RA, SOLUBLE IL-1 RECEPTOR, AND SOLUBLE TNF RECEPTOR
MODULATION OF ANTIBODY-MEDIATED GLOMERULAR INJURY IN-VIVO BY IL-1RA, SOLUBLE IL-1 RECEPTOR, AND SOLUBLE TNF RECEPTOR
复制标题
DOI：
10.1038/ki.1995.472
复制
发表时间：
1995-12-01
影响因子：
19.6
通讯作者：
REES, AJ
中科院分区：
文献类型：
--
作者：
KARKAR, AM;TAM, FWK;REES, AJ
NTN异源期肾小球损伤的严重程度取决于促炎细胞因子，包括TNF α和IL-1 β，并可被LPS增强。我们先前已经表明，针对IL-1 β和TNF的被动免疫部分消除了该模型中的LPS效应。本工作评价了用rh IL-1受体拮抗剂（IL-1 ra）阻断IL-1与其受体结合以及分别用rm可溶性IL-1受体1（sIL-1 Rt 1）和rh sTNF受体（sTNFr p55）中和IL-1和TNF对肾小球损伤的影响。用IL-1 ra、sIL-1 Rt 1或sTNFr预处理可部分消除LPS的作用，并将白蛋白排泄量从45 +/- 8、66 +/- 9和101 +/- 17 mg/24 h降至13 +/- 4 02）、14 +/- 4（P < 0.001）和21 +/- 7 mg/24 hr（P < 0.001）。同样，这些抑制剂降低肾小球毛细血管血栓的患病率和肾小球中性粒细胞浸润的强度。肾小球血栓形成从18 +/-3%、28 +/-5%和25 +/- 7%降至3 +/- 2%（P < 0.002），6 +/- 2%（P < 0.001），3 +/- 2（P < 0.001），肾小球中性粒细胞浸润从46 +/- 3、54 +/- 2和59 +/- 8降至19 +/- 2在切片中分别为25 +/-2（P <0.001）和28 +/-2中性粒细胞/50肾小球。同时给予可溶性IL-1和TNF受体可进一步降低肾小球损伤。在诱导肾炎后4小时，甚至在LPS注射后和诱导肾炎的同时给予这些抑制剂时，也观察到保护作用。所有三种治疗均降低循环TNF浓度（分别降至20%、34%和0%），但未检测到肾小球TNF基因表达。通过北方印迹的光密度分析评估，肾小球IL-1 β mRNA水平也分别降低了41%、53%和67%。与此相反，肾小球表达IL-1 ra不受其外源性管理，但轻度减少sIL-1 Rt 1和sTNFr，这表明宿主来源的IL-1 ra作为内源性负反馈介质在肾小球中的潜在作用。这些结果证实了IL-1和TNF直接参与LPS增强的hNTN，并证明了这些抑制剂在调节损伤中的效力，即使在LPS后和诱导肾炎时给药。它们比用多克隆抗体被动免疫更特异和有效，这表明它们在肾炎管理中的潜在用途。
The severity of glomerular injury in the heterologous phase of NTN is dependent on proinflammatory cytokines including TNF alpha and IL-1 beta, and can be enhanced by LPS. We have previously shown that passive immunization against IL-1 beta and TNF partialy abrogated the LPS effect in this model. In the present work, we have assessed the effects on glomerular injury of blocking the binding of IL-1 to its receptor by rh IL-1 receptor antagonist (IL-1ra) and by neutralizing IL-1 and TNF with rm soluble IL-1 receptor type1 (sIL-1Rt1) and rh sTNF receptor (sTNFr p55), respectively. Pretreatment with either IL-1ra, sIL-1Rt1, or sTNFr partially abrogated the effects of LPS and reduced albumin excretion from 45 +/- 8, 66 +/- 9, and 101 +/- 17 mg/24 hr to 13 +/- 4 (P < 0.02), 14 +/- 4 (P < 0.001), and 21 +/- 7 mg/24 hr (P < 0.001), respectively. Similarly, these inhibitors reduced the prevalence of glomerular capillary thrombi and the intensity of glomerular neutrophil infiltration. Glomerular thrombosis was reduced from 18 +/- 3%, 28 +/- 5%, and 25 +/- 7% to 3 +/- 2% (P < 0.002), 6 +/- 2% (P < 0.001), and 3 +/- 2 (P < 0.001), respectively, and glomerular neutrophil infiltration was reduced from 46 +/- 3, 54 +/- 2, and 59 +/- 8 to 19 +/- 2 (P < 0.001), 25 +/- 2 (P < 0.001), and 28 +/- 2 neutrophils/50 glomeruli in section, respectively. Coadministration of both soluble receptors of IL-1 and TNF caused a further decrease in glomerular injury. The protective effect was also noticed at four hours after induction of nephritis, and even when these inhibitors were administered after the LPS injection and at the same time of induction of nephritis. All three treatments reduced circulating TNF concentration (down to 20%, 34%, and 0%, respectively) but without detectable glomerular TNF gene expression. Glomerular IL-1 beta mRNA levels were also reduced by 41%, 53%, and 67%, respectively, when assessed by densitometric analysis of Northern blots. In contrast, the glomerular expression of IL-1ra was not affected by its exogenous administration but was mildly reduced by sIL-1Rt1 and sTNFr, which demonstrates the potential role for host derived IL-1ra as an endogenous negative feedback mediator in the glomerulus. These results confirm the direct involvement of IL-1 and TNF in LPS-enhanced hNTN and demonstrate the potency of these inhibitors in modulating injury even when administered after LPS and at time of induction of nephritis. They were more specific and effective than passive immunization with polyclonal antibodies, and this demonstrates their potential usefulness in the management of nephritis.