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Updated: Oct 18, 2025

Myeloid Innate Signaling Pathway Regulation by MALT1 Paracaspase Activity
Published on: January 7, 2019
Cyclophilin A is a key positive and negative feedback regulator within interleukin-6 trans-signaling pathway
Xiaohan Luan1,2, Wenxian Yang1,2, Xiaoyuan Bai1,2
1CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
Abstract:
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.
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