Translational Immunology Unit, Institut Pasteur, Université Paris Cité, 75015 Paris, France; Frontiers of Innovation in Research and Education PhD Program, CRI Doctoral School, Paris, France.
Translational Immunology Unit, Institut Pasteur, Université Paris Cité, 75015 Paris, France.
Cell Rep. 2022 Jun 28;39(13):110989. doi: 10.1016/j.celrep.2022.110989.
The interleukin-12 (IL-12) family comprises the only heterodimeric cytokines mediating diverse functional effects. We previously reported a striking bimodal IL-12p70 response to lipopolysaccharide (LPS) stimulation in healthy donors. Herein, we demonstrate that interferon β (IFNβ) is a major upstream determinant of IL-12p70 production, which is also associated with numbers and activation of circulating monocytes. Integrative modeling of proteomic, genetic, epigenomic, and cellular data confirms IFNβ as key for LPS-induced IL-12p70 and allowed us to compare the relative effects of each of these parameters on variable cytokine responses. Clinical relevance of our findings is supported by reduced IFNβ-IL-12p70 responses in patients hospitalized with acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or chronically infected with hepatitis C (HCV). Importantly, these responses are resolved after viral clearance. Our systems immunology approach defines a better understanding of IL-12p70 and IFNβ in healthy and infected persons, providing insights into how common genetic and epigenetic variation may impact immune responses to bacterial infection.
白细胞介素-12（IL-12）家族是唯一介导多种功能效应的异二聚体细胞因子。我们之前报道了健康供体中脂多糖（LPS）刺激下白细胞介素-12p70 反应的惊人双峰模式。在此，我们证明干扰素β（IFNβ）是 LPS 诱导产生白细胞介素-12p70 的主要上游决定因素，这也与循环单核细胞的数量和激活有关。对蛋白质组学、遗传学、表观基因组学和细胞数据的综合建模证实了 IFNβ 是 LPS 诱导产生白细胞介素-12p70 的关键因素，并使我们能够比较这些参数中的每一个对可变细胞因子反应的相对影响。我们的发现具有临床相关性，因为急性严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）感染或慢性丙型肝炎（HCV）感染住院患者的 IFNβ-IL-12p70 反应减少。重要的是，这些反应在病毒清除后得到解决。我们的系统免疫学方法更好地理解了健康和感染人群中的白细胞介素-12p70 和 IFNβ，为了解常见遗传和表观遗传变异如何影响对细菌感染的免疫反应提供了线索。
