Sgp130Fc regulates IL-6/JAK2/STAT3 trans-signaling pathway in rat vocal fold fibroblast activation

Acute vocal fold injury activates rat vocal fold fibroblasts (VFFs) and upregulates IL-6 expression. We investigated whether soluble gp130Fc (sgp130Fc) modulates IL-6 trans-signaling via the JAK2/STAT3 pathway. We established a vocal fold injury model, isolated primary VFFs, and silenced JAK2 expression using siRNA. The cultured cells were then treated with exogenous IL-6 and/or sgp130Fc. We found that vocal fold injury activated VFFs, concomitant with a significant increase in IL-6 expression, and these alterations were reversed by JAK2 silencing. Treatment with exogenous IL-6 further enhanced the expression of COL-1, α-SMA, IL-6, and JAK2/STAT3 pathway components at both transcriptional and translational levels in VFFs, confirming its activating role in both transfected and non-transfected groups. Exogenous sgp130Fc regulates JAK2 signaling and attenuates the upregulation of COL-1, α-SMA and IL-6 protein expression and STAT3 phosphorylation levels induced by exogenous IL-6. JAK2 silencing partially reversed the activated VFF phenotype, concomitant with reduced mRNA and protein expression of COL-1, α-SMA, IL-6, and JAK2/STAT3 pathway components. Additionally, this intervention attenuated the regulatory effect of sgp130Fc on IL-6 trans-signaling. In conclusion, our data suggest involvement of IL-6 trans-signaling pathways during VFF activation. Exogenous sgp130Fc can inhibit IL-6 trans-signaling transduction and alleviate exogenous IL-6-induced VFF activation and STAT3 phosphorylation, and its effects may be dependent on JAK2 signaling. These insights position the IL-6 trans-signaling pathway as a critical regulator of VFF activation and suggest sgp130Fc as a potential therapeutic strategy for vocal fold fibrosis, while its applicability warrants further in vivo validation.