Soluble IFN Receptor Potentiates In Vivo Type I IFN Signaling and Exacerbates TLR4-Mediated Septic Shock

摘要: Circulating levels of a soluble type I IFNR are elevated in diseases, such as chronic inflammation, infections, and cancer, but whether it functions an antagonist, agonist, or transporter is unknown. In this study, we elucidate the vivo importance IFNAR, (s)IFNAR2a, which generated by alternative splicing Ifnar2 gene. A transgenic mouse model was established to mimic 10-15-fold expression sIFNAR2a observed some human diseases. We lines, designated SolOX, transgene mRNA protein-expression patterns mirrored endogenous SolOX were demonstrated be more susceptible LPS-mediated septic shock, disease IFN plays crucial role. This effect independent "classical" proinflammatory cytokines, TNF-α IL-6, whose unchanged. Because increased did not affect kinetics interferonemia, receptor does potentiate its ligand signaling improving pharmacokinetics. Mechanistically, likely facilitate signaling, spleen cells overexpressing sIFNAR2a, displayed quicker, higher, sustained activation STAT1 STAT3. Thus, important agonist actions pathophysiological processes also modulate therapeutic efficacy clinically administered IFNs.