IL-1 家族成员 IL-38 在人类和小鼠系统性疾病模型中主要被表征为抗炎细胞因子。在这里，我们研究了 IL-38 在小鼠小肠 (SI) 中的作用。 SI 免疫染色显示 IL-38 表达部分局限于肠干细胞。肠道类器官培养物揭示 IL-38 通过诱导 WNT3a 增加类器官大小，从而发挥生长因子的作用。相比之下，IL-38缺陷小鼠的类器官发育得更慢。与野生型类器官相比，这种大小的减小可能是由于肠道干性标记物（即 Fzd5、Ephb2 和 Olfm4）表达下调所致。 IL-38 与 IL-1R6 和 IL-1R9 的结合仍存在争议。因此，为了分析 IL-38 信号传导的分子机制，我们还检查了 IL-1R9 缺陷小鼠的类器官。出乎意料的是，这些类器官虽然明显小于野生型，但却对 IL-38 做出反应，表明 IL-1R9 不参与干细胞隐窝中的 IL-38 信号传导。然而，IL-1R6 的沉默使类器官无法对 IL-38 的生长特性做出反应，因此表明 IL-1R6 是隐窝室中 IL-38 使用的主要受体。在野生型小鼠的类器官中，IL-38 刺激诱导低浓度的 IL-1β，从而有助于类器官的生长。然而，高浓度的 IL-1β 对培养物产生有害影响，而重组 IL-38 处理可防止这种影响。总体而言，我们的数据证明了 IL-38 作为生长因子和 SI 中的抗炎分子的重要调节功能，可维持体内平衡。

The IL-1 Family member IL-38 has been characterized primarily as an antiinflammatory cytokine in human and mouse models of systemic diseases. Here, we examined the role of IL-38 in the murine small intestine (SI). Immunostaining of SI revealed that IL-38 expression partially confines to intestinal stem cells. Cultures of intestinal organoids reveal IL-38 functions as a growth factor by increasing organoid size via inducing WNT3a. In contrast, organoids from IL-38-deficient mice develop more slowly. This reduction in size is likely due to the downregulation of intestinal stemness markers (i.e., Fzd5, Ephb2, and Olfm4) expression compared with wild-type organoids. The IL-38 binding to IL-1R6 and IL-1R9 is still a matter of debate. Therefore, to analyze the molecular mechanisms of IL-38 signaling, we also examined organoids from IL-1R9-deficient mice. Unexpectedly, these organoids, although significantly smaller than wild type, respond to IL-38, suggesting that IL-1R9 is not involved in IL-38 signaling in the stem cell crypt. Nevertheless, silencing of IL-1R6 disabled the organoid response to the growth property of IL-38, thus suggesting IL-1R6 as the main receptor used by IL-38 in the crypt compartment. In organoids from wild-type mice, IL-38 stimulation induced low concentrations of IL-1β which contribute to organoid growth. However, high concentrations of IL-1β have detrimental effects on the cultures that were prevented by treatment with recombinant IL-38. Overall, our data demonstrate an important regulatory function of IL-38 as a growth factor, and as an antiinflammatory molecule in the SI, maintaining homeostasis.