Hospital of Stomatology, Sun Yat-sen University, Guangzhou 510055, Guangdong, China; Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510080, Guangdong, China; Guangdong Provincial Key Laboratory of Stomatology, Guangzhou 510080, Guangdong, China.
Department of Periodontology, Stomatological Hospital, Southern Medical University, Guangzhou 510280, Guangdong, China.
Biochem Pharmacol. 2023 Oct;216:115796. doi: 10.1016/j.bcp.2023.115796. Epub 2023 Sep 9.
Oral lichen planus (OLP) is a chronic T cell-mediated mucocutaneous disease characterized by T cell infiltration at the connective tissue-epithelium interface. Traditionally, topical corticosteroids are used as the first-line drugs to treat OLP. However, long-term use of corticosteroids may lead to drug tolerance, secondary candidiasis, and autoimmune adrenal insufficiency. Although topical tacrolimus has often been recommended for short-term use in corticosteroid-refractory OLP, the precise role of tacrolimus in epithelial cells remains elusive. This study showed that tacrolimus could directly upregulate the expression of IL-37 in human gingival epithelial cells by promoting the TGF-βRI/Smad3 pathway independently of calcineurin inhibition and MAPKs. In contrast, dexamethasone, one of the corticosteroids, did not have the same effect. Moreover, IL-37 could inhibit the proliferation of activated T cells and the secretion of effector cytokines and alleviate epithelial cell apoptosis and death caused by activated T cells ina co-culturesystem. Furthermore, compared with healthy controls, IL-37 and p-Smad3 levels significantly increased in the oral mucosa affected by OLP, especially in the epithelium. IL-37 might have mediated a negative feedback mechanism to curb excessive inflammation in OLP. However, the expression of IL-37 was not associated with the infiltration of CD8 T cells and Tregs in OLP, implying that IL-37 might mostly affect T cell activation rather than T cell differentiation and migration. Overall, this study discovered a potential novel mechanism by which tacrolimus might indirectly inhibit T cell-mediated immune damage by upregulating IL-37 in human gingival epithelial cells.
口腔扁平苔藓（OLP）是一种慢性 T 细胞介导的黏膜疾病，其特征是在结缔组织-上皮界面有 T 细胞浸润。传统上，局部皮质类固醇被用作治疗 OLP 的一线药物。然而，长期使用皮质类固醇可能导致药物耐受、继发念珠菌病和自身免疫性肾上腺功能不全。虽然局部他克莫司常被推荐用于治疗皮质类固醇难治性 OLP 的短期使用，但他克莫司在上皮细胞中的确切作用仍不清楚。本研究表明，他克莫司可通过促进 TGF-βRI/Smad3 通路而不依赖钙调神经磷酸酶抑制和 MAPKs 来直接上调人牙龈上皮细胞中 IL-37 的表达。相比之下，皮质类固醇中的一种地塞米松则没有相同的作用。此外，IL-37 可抑制活化 T 细胞的增殖和效应细胞因子的分泌，并减轻活化 T 细胞在共培养系统中引起的上皮细胞凋亡和死亡。此外，与健康对照组相比，在受 OLP 影响的口腔黏膜中，IL-37 和 p-Smad3 水平显著升高，尤其是在上皮中。IL-37 可能介导了一种负反馈机制，以遏制 OLP 中过度的炎症。然而，IL-37 的表达与 OLP 中 CD8 T 细胞和 Tregs 的浸润无关，这意味着 IL-37 可能主要影响 T 细胞的活化，而不是 T 细胞的分化和迁移。总体而言，本研究发现了一种潜在的新机制，即他克莫司可能通过上调人牙龈上皮细胞中的 IL-37 来间接抑制 T 细胞介导的免疫损伤。
