Cyclophilin A is a key positive and negative feedback regulator within interleukin‐6 trans‐signaling pathway
Cyclophilin A is a key positive and negative feedback regulator within interleukin‐6 trans‐signaling pathway
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DOI：
10.1096/fj.202101044rrr
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发表时间：
2021-10
期刊：
影响因子：
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通讯作者：
Xiaohan Luan;Wenxian Yang;X. Bai;Heqiao Li;Huizi Li;Wenhui Fan;Hengming Zhang;Wenjun Liu;Lei Sun
中科院分区：
文献类型：
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作者：
Xiaohan Luan;Wenxian Yang;X. Bai;Heqiao Li;Huizi Li;Wenhui Fan;Hengming Zhang;Wenjun Liu;Lei Sun
亲环蛋白A （CypA）是亲环蛋白家族的一员，在微生物感染、炎症性疾病和癌症中起着至关重要的作用。白细胞介素- 6 （IL - 6）是一种多效性细胞因子，在炎症、免疫反应、造血和肿瘤增殖等方面发挥着多种作用。IL - 6与可溶性IL - 6受体（sIL - 6R）结合可诱导促炎反式信号传导，这比IL - 6与膜结合IL - 6受体结合引发的抗炎经典信号传导更强。本研究发现，在IL - 6和sIL - 6R的作用下，CypA抑制泛素化介导的IL - 6膜受体gp130的降解，并增强其二聚化，从而积极调节IL - 6反式信号传导，增加下游iNOS、IL - 6和CypA的表达。此外，CypA的表达可受细胞因子信号1抑制因子（SOCS1）的负调控。SOCS1的SH2和Box结构域与CypA相互作用，促进其与K48相关的泛素化介导的降解，从而抑制IL - 6反式信号通路。总的来说，我们的研究结果揭示了CypA在IL - 6反式信号通路的正反馈和负反馈调节中的重要作用。
Cyclophilin A (CypA), a member of the cyclophilin family, plays a vital role in microorganismal infections, inflammatory diseases, and cancers. Interleukin‐6 (IL‐6) is a pleiotropic cytokine, exerting variety of effects on inflammation, immune response, hematopoiesis, and tumor proliferation. Binding of IL‐6 to soluble IL‐6 receptor (sIL‐6R) induces pro‐inflammatory trans‐signaling, which has been described to be stronger than anti‐inflammatory classic signaling triggered by the binding of IL‐6 to membrane‐bound IL‐6 receptor. Here we found that upon the treatment of IL‐6 and sIL‐6R, CypA inhibited the ubiquitination‐mediated degradation of IL‐6 membrane receptor gp130 and enhanced its dimerization, thereby positively regulated the IL‐6 trans‐signaling and increased the expression of downstream iNOS, IL‐6, and CypA. Furthermore, CypA expression could be negatively regulated by suppressor of cytokine signaling 1 (SOCS1). The SH2 and Box domains of SOCS1 interacted with CypA and promoted its K48‐linked ubiquitination‐mediated degradation, which inhibited the IL‐6 trans‐signaling pathway. Collectively, our findings reveal an important role of CypA in the positive and negative feedback regulation of the IL‐6 trans‐signaling pathway.