Posttranscriptional gene expression regulation in CpG-activated macrophages depends on FXR1P RNA-binding protein

Abstract

An RNA-binding protein (RBP) was recently identified, FXR1P, which regulates tumour necrosis factor (TNF) gene expression at the posttranscriptional level in response to lipopolysaccharide, was recently identified resulting in higher TNF production in macrophages from FXR1 knockout (KO) mice compared with wild-type (WT) macrophages. In this study, the importance of FXR1P in the induction of TNF by toll-like receptor 7 (TLR7) ligand S28463 and TLR9 ligand CpG is evaluated. The results clearly reveal a much higher level of TNF protein expression in FXR1-KO than in WT macrophages following stimulation with CpG but not with S28463. To better understand the molecular mechanism, both the steady-state levels and the stability of TNF mRNA were assessed. It was found that the TNF mRNA steady-state level was more elevated in CpG-stimulated FXR1-KO macrophages, while the stability of TNF mRNA was not affected in CpG-stimulated FXR1-KO macrophages. It was also established that FXR1P is involved in regulating the expression of several other inflammatory cytokines and chemokines. Together, the data clearly demonstrate the importance of FXR1P RBP in the regulation of a wide spectrum of inflammatory genes and suggest an important role of MAP signalling in the response of macrophages to selected TLR ligands, including CpG.