Brennan D C, Yui M A, Wuthrich R P, Kelley V E
Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115.
J Immunol. 1989 Dec 1;143(11):3470-5.
TNF and IL-1 are potent immunologic and inflammatory cytokines. We have previously reported increased levels of mRNA for TNF alpha and IL-1 beta in MRL-lpr mice with lupus nephritis. To determine whether the increased levels of TNF and IL-1 mRNA are a more general feature of mice with lupus nephritis we studied cytokine gene expression in female NZB x NZW F1 (NZB/W) mice by Northern blot analysis. Enhanced steady state levels of mRNA for TNF alpha and IL-1 beta, but not IL-1 alpha, were detected in the renal cortices of animals with lupus nephritis. To determine whether administration of TNF or IL-1 would accelerate renal injury and mortality, we injected murine rTNF alpha or rIL-1 alpha i.p. into female NZB/W or C3H/FeJ mice at two doses, 2.0 micrograms or 0.2 micrograms, three times weekly for 2 or 4 mo beginning at 2 or 4 mo of age. Administration of the lower dose of each cytokine accelerated renal disease and mortality rate when treatment was initiated at 4 mo of age. At the higher dose, neither cytokine promoted disease. Treatment administered from 2-4 mo of age did not accelerate renal disease. This observation suggests that in order to cause renal injury, these cytokines must interact with other pathologic features present in these animals after 4 mo of age. These findings support the hypothesis that TNF and IL-1 can contribute to nephritis in murine models of lupus. Taken together with previously published data, we propose that TNF and IL-1 have differential dose effects on renal disease. The dose of TNF and IL-1 and the stage of disease activity dictate the pathogenic action of these cytokines.
肿瘤坏死因子（TNF）和白细胞介素-1（IL-1）是强效的免疫和炎性细胞因子。我们之前报道过，患有狼疮性肾炎的MRL-lpr小鼠中TNFα和IL-1β的mRNA水平升高。为了确定TNF和IL-1 mRNA水平升高是否是狼疮性肾炎小鼠更普遍的特征，我们通过Northern印迹分析研究了雌性新西兰黑鼠与新西兰白鼠杂交一代（NZB/W）小鼠的细胞因子基因表达。在患有狼疮性肾炎的动物的肾皮质中检测到TNFα和IL-1β的mRNA稳态水平增强，但IL-1α没有。为了确定给予TNF或IL-1是否会加速肾损伤和死亡率，我们以2.0微克或0.2微克两种剂量腹腔注射小鼠重组TNFα或重组IL-1α到雌性NZB/W或C3H/FeJ小鼠中，从2或4月龄开始，每周三次，共2或4个月。当在4月龄开始治疗时，给予每种细胞因子的较低剂量会加速肾病和死亡率。在较高剂量时，两种细胞因子均未促进疾病发展。在2至4月龄进行的治疗并未加速肾病。这一观察结果表明，为了导致肾损伤，这些细胞因子必须在4月龄后与这些动物中存在的其他病理特征相互作用。这些发现支持了TNF和IL-1可导致狼疮小鼠模型肾炎的假说。结合先前发表的数据，我们提出TNF和IL-1对肾病有不同的剂量效应。TNF和IL-1的剂量以及疾病活动阶段决定了这些细胞因子的致病作用。
