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

Abstract

Interleukin-1{beta} (IL-1{beta}) is an essential pro-inflammatory cytokine which functions as a key factor in innate immunity. The precursor protein, pro-IL-1{beta}, has long been regarded as an inactive form in innate immune responses. Here, we unveil the biological function and regulation of pro-IL-1{beta} in activating the NF-{kappa}B signaling pathway, which is distinct from IL-1{beta} signaling. The expression and release of pro-IL-1{beta} are induced by inflammatory stimuli and then pro-IL-1{beta} acutely activates the gene transcription driven by NF-{kappa}B in a dose dependent manner. This activity is resistant to IL-1 receptor antagonist (IL-1Ra). The signal transduction triggered by pro-IL-1{beta} 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-1{beta} in vitro and as the potential receptors mediating pro-IL-1{beta}-induced NF-{kappa}B activation. Collectively, this study sheds light on the unique cytokine function of pro-IL-1{beta} and provides new insights into the functional characterization of pro-cytokines in innate immunity.