Cyclophilin A is a key positive and negative feedback regulator within interleukin‐6 trans‐signaling pathway

• Published in: The FASEB journal 2021-11, Vol.35 (11), p.e21958-n/a
• Main Authors: Luan, Xiaohan, Yang, Wenxian, Bai, Xiaoyuan, Li, Heqiao, Li, Huizi, Fan, Wenhui, Zhang, He, Liu, Wenjun, Sun, Lei
• Format: Article
• Language: English
• Subjects: cyclophilin A; gp130; interleukin‐6; SOCS1; ubiquitination
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.202101044RRR

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.