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

FASEB J. 2021 Nov;35(11):e21958. doi: 10.1096/fj.202101044RRR.

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.

Keywords: SOCS1; cyclophilin A; gp130; interleukin-6; ubiquitination.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Cyclophilin A / physiology*
  • HEK293 Cells
  • Humans
  • Interleukin-6 / metabolism*
  • Receptors, Interleukin-6 / metabolism*
  • Signal Transduction
  • Suppressor of Cytokine Signaling 1 Protein / metabolism*

Substances

  • IL6 protein, human
  • IL6R protein, human
  • Interleukin-6
  • Receptors, Interleukin-6
  • SOCS1 protein, human
  • Suppressor of Cytokine Signaling 1 Protein
  • Cyclophilin A