Contributions of IL-1β and IL-1α to crescentic glomerulonephritis in mice
Contributions of IL-1β and IL-1α to crescentic glomerulonephritis in mice
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DOI：
10.1097/01.asn.0000115704.86897.f4
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发表时间：
2004-04-01
影响因子：
13.6
通讯作者：
Tipping, PG
中科院分区：
文献类型：
--
作者：
Timoshanko, JR;Kitching, AR;Tipping, PG
白细胞介素-1（IL-1）是一种多效性促炎细胞因子，具有两种不同的亚型（IL-1 α和IL-1 β），通过相同的IL-1 I型受体（IL-1 RI）发出信号。IL-1 β在人类和实验性增生性肾小球肾炎（GN）中的作用已得到证实，但IL-1 α的参与很少受到关注。为了确定IL-1 α和IL-1 β的联合作用，并分析IL-1 β的特异性作用，我们在遗传性缺乏I型IL-1受体的小鼠中研究了抗肾小球基底膜球蛋白诱导的新月体肾炎的发生。（IL-1 RI-/-），其对IL-1 α和IL-1 β均无反应，或单独IL-1 β IL-1 β-/-与品系匹配的对照（WT）相比，小鼠显示新月体形成和肾小球T细胞和巨噬细胞募集显著减少。在IL-1 RI-/-小鼠中未观察到这些损伤指数的额外降低。然而，与IL-1 β-/-小鼠相比，IL-1 RI-/-小鼠表现出更强的功能性肾保护，蛋白尿显著减少，血清肌酐降低，表明IL-1 α对这些损伤参数有显著作用。与IL-1 β-/-或WT小鼠相比，IL-1 RI-/-小鼠的致肾抗原（羊球蛋白）抗体血清滴度较低，肾小球补体沉积减少。这表明，在缺乏对IL-1 α和IL-1 β的反应的情况下，体液介质的衰减提供了额外的功能保护，使其免受肾损伤，这在单独缺乏IL-1 β的情况下是看不到的。这些研究表明，IL-1 β而不是IL-1 α有助于新月体形成和炎性细胞募集，而IL-1 α而不是IL-1 β有助于肾小球损伤的体液机制。
Interleukin-1 (IL-1) is a pleiotropic proinflammatory cytokine with two distinct isoforms (IL-1alpha and IL-1beta) that signal through the same IL-1 type I receptor (IL-1RI). Contributions of IL-1beta have been demonstrated in human and experimental proliferative glomerulonephritis (GN), but the involvement of IL-1alpha has received little attention. To determine the combined contribution of IL-1alpha and IL- 1beta and to dissect the specific contribution of IL- 1beta, the development of antiglomerular basement membrane globulin-induced crescentic GN was studied in mice genetically deficient in either the IL- I receptor type I (IL-1RI-/-), which are unresponsive to both IL-1alpha and IL-1beta, or IL-1beta alone IL-1beta-/- mice showed significant reductions in crescent formation and glomerular T cell and macrophage recruitment compared with strain matched controls (WT). No additional reductions of these indices of injury were observed in IL-1RI-/- mice. However, IL-1RI-/- mice showed greater functional renal protection with significantly less proteinuria and reduced serum creatinine compared with IL-1beta-/- mice, suggesting a significant contribution of IL-1alpha to these parameters of injury. IL-1RI-/- mice had lower serum titers of antibody to the nephritogenic antigen (sheep globulin) and reduced glomerular deposition of complement compared with either IL-1beta-/- or WT mice. This suggests that in the absence of responses to both IL-1alpha and IL-1beta, attenuation of humoral mediators provides additional functional protection from renal injury that is not seen in the absence of IL-1beta alone. These studies indicate that IL-1beta but not IL-1alpha contributes to crescent formation and inflammatory cell recruitment, whereas IL-1alpha but not IL-1beta contributes to humoral mechanisms of glomerular injury.