Steps in the processing and secretion of IL-1β. (A) TLR ligands such as endotoxin trigger gene expression and synthesis of the IL-1β precursor, which remains diffusely in the cytosol. In the same cell, inactive procaspase-1 is bound to components of the IL-1β inflammasome, which contains the products of the NALP-3 gene. The IL-1β inflammasome is kept in an inactive state by binding to a large molecular weight putative inhibitor. (B) After TLR signals, there is a transient uncoupling of the inhibitor and NALP-3 gene products from procaspase-1, which then colocalizes with the IL-1β in secretory lysosomes. (C) Activation of the nucleotide receptor P2X7 by ATP or LL37 initiates the efflux of potassium from the cell via a potassium channel. The efflux of potassium activates the autocatalytic processing of procaspase-1. Active caspase-1 cleaves the IL-1β precursor in an active cytokine. (D) The efflux of potassium ions results in the influx of calcium ions, which in turn activate phospholipases. Phosphatidylcholine-specific phospholipase C (PC-PLA-2) facilitates lysosomal exocytosis and secretion of IL-1.

Systemic manifestations of IL-1β. Active IL-1β is secreted by many cell types including monocytes and macrophages (center). IL-1β enters the circulation and triggers IL-1 receptors on the hypothalamic vascular network resulting in synthesis of cyclooxygenase-2, which causes brain levels of prostaglandin E2 to rise, thus activating the thermoregulatory center for fever production (reference 27). In the periphery, IL-1β activates IL-1 receptors on the endothelium resulting in rashes and the production of IL-6. Circulating IL-6 stimulates liver hepatocytes to synthesize several acute phase proteins, which accounts for the increase in erythrocyte sedimentation rate in SoJIA. IL-1 also acts on the bone marrow to increase mobilization of granulocyte progenitors and mature neutrophils, resulting in peripheral neutrophilia. IL-1–induced IL-6 increases platelet production, which results in thrombocytosis. IL-1 also causes decreased response to erythropoietin, which causes anemia.