| Cleaved IL‑1β (Asp117) refers to the mature, bioactive form of interleukin‑1β generated from the cytosolic precursor pro‑IL‑1β by site‑specific proteolysis at the caspase‑1 recognition motif between Asp116 and Ala117, a step that converts an inactive leaderless cytokine into a secreted mediator of innate immune signaling. Pro‑IL‑1β is induced by “priming” signals such as Toll‑like receptor ligands that activate NF‑κB and drive IL1B transcription, and the zymogen remains confined to the cytosol until inflammasome activation brings pro‑caspase‑1 into proximity with adaptor proteins like ASC and NLR family receptors, leading to caspase‑1 autoproteolysis, assembly of the active heterodimeric enzyme, and cleavage of pro‑IL‑1β at Asp116–Ala117 to generate the C‑terminal fragment that exposes a mature receptor‑binding surface. The Asp117‑terminated species engages the IL‑1 receptor type I in conjunction with the accessory protein IL‑1RAcP, initiating recruitment of MyD88, IRAK kinases, and TRAF6 and propagating signals through NF‑κB and MAPK cascades that drive transcription of additional inflammatory mediators, adhesion molecules, and chemokines, thereby amplifying leukocyte recruitment and effector functions. Maturation at Asp117 also licenses unconventional secretion, as caspase‑1 activity not only processes IL‑1β but also cleaves gasdermin D to form membrane pores that support rapid release during pyroptosis, while biochemical dissection of IL‑1β trafficking shows that the cleaved cytokine accumulates at PIP2‑rich plasma membrane ruffles via a polybasic motif and can exit more slowly through caspase‑1–independent, gasdermin D–independent routes once the maturation step has occurred. The processed Asp117 form is therefore a direct biochemical readout of canonical inflammasome pathway engagement and is widely used as a surrogate marker of caspase‑1 activation in macrophages, monocytes, and other myeloid cells exposed to microbial products, sterile danger signals, or metabolic stress. At a tissue level, accumulation of mature IL‑1β contributes to chronic inflammatory settings such as cancer, where tumor‑associated immune and stromal cells produce and release the cleaved cytokine after sequential priming and inflammasome activation; IL‑1β then shapes the tumor microenvironment by promoting angiogenesis, matrix remodeling, and myeloid cell recruitment, linking the presence of Asp117‑terminal IL‑1β to protumor inflammatory circuits. Genetic or pharmacologic disruption of inflammasome components, caspase‑1, or IL‑1β signaling reduces the generation or action of the Asp117 species and alters disease phenotypes in models of infection, fibrosis, and tumor growth. |
