Pro-IL-1β activates NF-κB independently of maturation

Abstract Interleukin-1β (IL-1β) is an essential pro-inflammatory cytokine which functions as a key factor in innate immunity. The precursor protein, pro-IL-1β, has long been regarded as an inactive form in innate immune responses. Here, we unveil the biological function and regulation of pro-IL-1β in activating the NF-κB signaling pathway, which is distinct from IL-1β signaling. The expression and release of pro-IL-1β are induced by inflammatory stimuli and then pro-IL-1β acutely activates the gene transcription driven by NF-κB in a dose dependent manner. This activity is resistant to IL-1 receptor antagonist (IL-1Ra). The signal transduction triggered by pro-IL-1β relies on MyD88 and endocytosis. We further demonstrate that the N-terminal pro-peptide primarily contributes to this activity. Furthermore, we identify TLR7 and TLR8 as the binding partners of pro-IL-1β in vitro and as the potential receptors mediating pro-IL-1β-induced NF-κB activation. Collectively, this study sheds light on the unique cytokine function of pro-IL-1β and provides new insights into the functional characterization of pro-cytokines in innate immunity. Competing Interest Statement The authors have declared no competing interest.