IL-10 regulation of lupus in the NZM2410 murine model
IL-10 regulation of lupus in the NZM2410 murine model
复制标题
DOI：
10.1038/labinvest.3700468
复制
发表时间：
2006-11-01
影响因子：
5
通讯作者：
Morel, Laurence
中科院分区：
文献类型：
--
作者：
Blenman, Kim R. M.;Duan, Byian;Morel, Laurence
多项研究已经报道，在SLE患者和狼疮小鼠模型中，IL-10水平很高。IL-10是一种调节性细胞因子，主要由B细胞和髓系细胞产生，B细胞使用这种细胞因子支持其增殖，髓系细胞使用IL-10减少促炎反应。IL-10也是由CD4(+)T调节细胞亚群产生的。通过反复给予抗IL-10中和抗体、基因消融或注射重组细胞因子对IL-10水平的不同调节显示出相互矛盾的结果，这可能反映了这种细胞因子对狼疮病理发生的两个主要效应臂--B细胞和炎症的相反作用。我们研究了IL-10在狼疮B6新的同源基因模型中的作用。Sle1.Sle2.Sle3(B6.TC)，由三个NZM2410衍生的SLE易感基因座在C57BL/6背景上组合而成。在这个模型中，我们首先研究了IL-10升高的来源，发现它是由于大量的CD4(+)T细胞产生细胞因子，以及大大增加的B1-a细胞池，这是产生IL-10的主要部分。然后，我们使用AAV介导的骨骼肌基因传递在年轻的B6中过表达IL-10。TC小鼠和7个月龄以下疾病标志物的表达。我们在这里表明，低水平IL-10的持续过度表达显著延迟了抗核自身抗体的产生，并减少了临床肾炎。B细胞表型基本未受影响，而T细胞活性显著降低。这突出了T细胞激活在这一模型中所起的关键作用，并表明这一途径可以有效地作为治疗干预的靶点。这些结果还强化了IL-10发挥多种功能的观点，并建议谨慎地将高水平的IL-10等同于系统性自身免疫中增加的发病机制。
Multiple studies have reported high levels of IL-10 in SLE patients and in murine models of lupus. IL-10 is a regulatory cytokine mainly produced by B cells, which use this cytokine to support their proliferation, and by myeloid cells, which use IL-10 to reduce proinflammatory responses. IL-10 is also produced by a subset of CD4(+) T regulatory cells. Various manipulations of IL-10 levels with repeated administrations of anti-IL-10 neutralizing antibodies, genetic ablation or injections of recombinant cytokine have shown contradictory results, which is likely to reflect the opposite effects of this cytokine on the two major effector arms of lupus pathologenesis, namely B cells and inflammation. We have investigated the role of IL-10 in a novel congenic model of lupus, B6. Sle1. Sle2. Sle3 (B6. TC), which consists of the three NZM2410-derived SLE susceptibility loci combined on a C57BL/6 background. We first investigated in this model the source of elevated IL-10 and shown that it results from a larger number of CD4(+) T cells producing the cytokine, and from a greatly increased B1-a cell pool, which is the main IL-10 producing compartment. We have then used AAV-mediated skeletal muscle gene delivery to overexpress IL-10 in young B6. TC mice and follow disease marker expression up to 7 months of age. We show here that continuous overexpression of low levels of IL-10 significantly delayed antinuclear auto-antibody production and decreased clinical nephritis. B cell phenotypes were largely unaffected, while T-cell activation was significantly reduced. This highlighted the pivotal role played by T-cell activation in this model, and suggested that this pathway could be effectively targeted for therapeutic interventions. These results also reinforce the notion that IL-10 exerts multiple functions and commend caution in equating high levels of IL-10 and increased pathogenesis in systemic autoimmunity.