Glycosaminoglycans bind human IL‐27 and regulate its activity

Abstract

IL-27 is a cytokine of the IL-12 family, composed of EBI3 and IL-27p28. IL-27 regulates immune responses and also other physiological processes including hematopoiesis, angiogenesis, and bone formation. Its receptor, composed of IL-27Rα and gp130, activates the STAT pathway. Here, we show that different glycosaminoglycans (GAGs) modulate human IL-27 activity in vitro. We find that soluble heparin and heparan sulfate efficiently inhibit human IL-27 activity as shown by decreased STAT signaling and downstream biological effects. In contrast, membrane-bound heparan sulfate seems to positively regulate IL-27 activity. Our biochemical studies demonstrate that soluble GAGs directly bind to human IL-27, consistent with in silico analyses, and prevent its binding to IL-27Rα. Although murine IL-27 also bound to GAGs in vitro, its activity was less efficiently inhibited by soluble GAGs. Lastly, we show that two heparin-derivatives, low molecular weight heparin and fondaparinux, that like unfractionated heparin are used in clinics, had weaker or no effect on human IL-27 activity. Together, our data identify GAGs as new players in the regulation of human IL-27 activity that might act under physiological conditions and may also have a clinical impact in heparin-treated patients.

VSIG4 interaction with heparan sulfates inhibits VSIG4–complement binding

“…For example, sulfation of cell surface proteoglycans is required for IL-10-mediated effects on monocytes and macrophages whereas IL-10 interacting with soluble HS can inhibit these same effects, and similarly opposite consequences of soluble versus cell-anchored HS are observed for IL-27-mediated effects on T-cell activation ( Salek-Ardakani et al. 2000 ; Cavé et al. 2020 ).…”

Glycosaminoglycans: Participants in Microvascular Coagulation of Sepsis

“…to human and mouse IL-27, thereby regulating the activation of STAT1 and STAT3 112 . Furthermore, STAT3 mediates endothelial dysfunction and plays a key role in sepsis-induced multiple organ failure by inducing disseminated intravascular coagulation (DIC) 71,113 .…”

“… 109 Cavé et al proved that GAGs bind to human and mouse IL-27, thereby regulating the activation of STAT1 and STAT3. 110 Furthermore, STAT3 mediates endothelial dysfunction and plays a key role in sepsis-induced multiple organ failure by inducing disseminated intravascular coagulation. 71 111 Beckman et al, using vascular endothelial cells, found that JAK-STAT inhibition limited the secretion of pro-adhesive and procoagulant factors.…”