Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, OR;
Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, OR.
Immunohorizons. 2022 Jul 5;6(7):416-429. doi: 10.4049/immunohorizons.2200025.
The three types of IFN have roles in antimicrobial immunity and inflammation that must be properly balanced to maintain tissue homeostasis. For example, IFNs are elevated in the context of inflammatory bowel disease and may synergize with inflammatory cytokines such as TNF-α to promote tissue damage. Prior studies suggest that in mouse intestinal epithelial cells (IECs), type III IFNs are preferentially produced during viral infections and are less cytotoxic than type I IFN. In this study, we generated human IEC organoid lines from biopsies of ileum, ascending colon, and sigmoid colon of three healthy subjects to establish the baseline responses of normal human IECs to types I, II, and III IFN. We found that all IFN types elicited responses that were qualitatively consistent across intestinal biopsy sites. However, IFN types differed in magnitude of STAT1 phosphorylation and identity of genes in their downstream transcriptional programs. Specifically, there was a core transcriptional module shared by IFN types, but types I and II IFN stimulated unique transcriptional modules beyond this core gene signature. The transcriptional modules of type I and II IFN included proapoptotic genes, and expression of these genes correlated with potentiation of TNF-α cytotoxicity. These data define the response profiles of healthy human IEC organoids across IFN types, and they suggest that cytotoxic effects mediated by TNF-α in inflamed tissues may be amplified by a simultaneous high-magnitude IFN response.
三种类型的 IFN 在抗菌免疫和炎症中发挥作用，必须适当平衡以维持组织内稳态。例如，在炎症性肠病的情况下，IFN 会升高，并且可能与 TNF-α 等炎症细胞因子协同作用以促进组织损伤。先前的研究表明，在小鼠肠上皮细胞（IEC）中，III 型 IFN 在病毒感染期间优先产生，并且比 I 型 IFN 的细胞毒性更小。在这项研究中，我们从三个健康受试者的回肠、升结肠和乙状结肠活检中生成了人类 IEC 类器官系，以建立正常人类 IEC 对 I、II 和 III 型 IFN 的基线反应。我们发现所有 IFN 类型的反应在肠活检部位都是定性一致的。然而，IFN 类型在 STAT1 磷酸化的幅度和下游转录程序中基因的身份上存在差异。具体而言，存在一个由 IFN 类型共享的核心转录模块，但 I 型和 II 型 IFN 刺激了超出该核心基因特征的独特转录模块。I 型和 II 型 IFN 的转录模块包括促凋亡基因，并且这些基因的表达与 TNF-α 细胞毒性的增强相关。这些数据定义了健康人类 IEC 类器官在 IFN 类型上的反应谱，并表明 TNF-α 在炎症组织中介导的细胞毒性作用可能会被同时发生的高幅度 IFN 反应放大。
