Knockdown of versican 1 in lung fibroblasts aggravates Lipopolysaccharide-induced acute inflammation through up-regulation of the SP1-Toll-like Receptor 2-NF-κB Axis: a potential barrier to promising Versican-targeted therapy.

Abstract

Versican participates in various pathological processes like inflammation and fibrosis and is a potential therapeutic target for inflammatory diseases. Versican 1 (V1) has increased expression in inflammatory diseases, but its role is unclear. We explored the effects of V1 on acute lung inflammation to determine whether targeting V1 had therapeutic potential. Human fetal lung fibroblast (HFL1) was transfected with or without V1-inhibiting lentivirus and treated with LPS. The expression levels of inflammatory cytokines, V1, cellular signaling pathway and Toll-like receptors (TLRs) were detected by qPCR, ELISA and western blot. The migration and adhesion of neutrophils and monocytes to HFL1s were performed. The activity of transcriptional factors was determined by dual-luciferase reporter assay. Inflammatory factors increased dramatically and continuously with V1 knockdown and LPS stimulation (P<0.01), orchestrating migration of inflammatory cells and an enhanced inflammatory reaction. V1-knockdown increased TLR2 (P<0.01) and activated the NF-κB pathway, which was partially reversed with a TLR2 neutralizing antibody and an NF-κB inhibitor. Explosion of LPS-induced inflammation was induced by knockdown of V1 via the SP1-TLR2-NF-κB axis. Increased expression of V1 might be protective in acute inflammation, and an infection-induced cytokine storm might be a severe complication of V1-targeted interventions.