Fernando Maria Ruweka, Reyes Jose Luis, Iannuzzi Jordan, Leung Gabriella, McKay Derek Mark
Gastrointestinal Research Group, Inflammation Research Network, Department of Physiology and Pharmacology, The Calvin Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
PLoS One. 2014 Apr 15;9(4):e94188. doi: 10.1371/journal.pone.0094188. eCollection 2014.
Macrophages are important innate immune cells that are associated with two distinct phenotypes: a pro-inflammatory (or classically activated) subset with prototypic macrophage functions such as inflammatory cytokine production and bactericidal activity, and an anti-inflammatory (or alternatively activated (AAM)) subset linked with wound healing and tissue repair processes. In this study, we examined the effect of interlukein-6 on human and murine macrophage polarization. The results indicate that despite being commonly associated with pro-inflammatory functions and being implicated in the pathogenesis/pathophysiology of numerous inflammatory diseases, interleukin-6 can enhance the polarization of AAMs, based on increased expression of hallmark markers: arginase-1, Ym1 and CD206; this effect required the AAM differentiating cytokines, IL-4 and IL-13. Co-treatment of AAMs with IL-6 resulted in spontaneous release of IL-10, suppressed LPS-induced nitric oxide production and inhibited cytokine production by activated CD4+ T cells - immunoregulatory features not observed in the 'parent' IL-4+IL-13-induced AAM. The effect of IL-6 required signal transducer and activator of transcription (STAT)-3, was partially dependent on up-regulation of the IL4Rα chain, and was independent of autocrine IL-10. In the presence of IFNγ, IL-6 promoted the production of IL-1β and TNFα suggesting that this cytokine can enhance the phenotype to which a macrophage has committed. This finding may explain the pleiotrophic nature of IL-6, where it is associated with the perpetuation and enhancement of disease in inflammatory situations, but is also necessary for resolution of inflammation and adequate wound healing to occur in others. Thus, the potential benefit of IL-6 in promoting an AAM, with its' anti-inflammatory and wound healing ability, may need to be considered in immunotherapies aimed at in vivo modulation or inhibition of IL-6.
巨噬细胞是重要的固有免疫细胞，与两种不同的表型相关：一种是促炎（或经典活化）亚群，具有原型巨噬细胞功能，如炎症细胞因子产生和杀菌活性；另一种是抗炎（或替代性活化（AAM））亚群，与伤口愈合和组织修复过程相关。在本研究中，我们检测了白细胞介素-6对人和小鼠巨噬细胞极化的影响。结果表明，尽管白细胞介素-6通常与促炎功能相关，并涉及多种炎症性疾病的发病机制/病理生理学，但基于标志性标志物精氨酸酶-1、Ym1和CD206表达的增加，白细胞介素-6可增强AAM的极化；这种效应需要AAM分化细胞因子IL-4和IL-13。IL-6与AAM共同处理导致IL-10的自发释放，抑制脂多糖诱导的一氧化氮产生，并抑制活化的CD4+T细胞产生细胞因子——这些免疫调节特征在“亲本”IL-4+IL-13诱导的AAM中未观察到。IL-6的作用需要信号转导和转录激活因子（STAT）-3，部分依赖于IL4Rα链的上调，且不依赖于自分泌的IL-10。在干扰素γ存在的情况下，IL-6促进IL-1β和TNFα的产生，表明这种细胞因子可增强巨噬细胞已确定的表型。这一发现可能解释了IL-6的多效性本质，即在炎症情况下它与疾病的持续存在和加重相关，但在其他情况下对于炎症的消退和充分的伤口愈合也是必需的。因此，在旨在体内调节或抑制IL-6的免疫治疗中，可能需要考虑IL-6在促进具有抗炎和伤口愈合能力的AAM方面的潜在益处。
