A novel secretory pathway for interleukin-1β, a protein lacking a signal sequence

Interleukin 1 (IL-1) is a major soluble mediator of inflammation. Two human IL-1 genes, α and β, have been isolated, which encode polypeptides with only 20-30% amino acid sequence homology. Unlike most secreted proteins, the two cytokines do not have a signal sequence, an unexpected finding in view of their biological role. Here we show that IL-1β is actively secreted by activated human monocytes via a pathway of secretion different from the classical endoplasmic reticulum - Golgi route. Drugs which block the intracellular transport of IL-6, of tumour necrosis factor α and of other secretory proteins do not inhibit secretion of IL-1β. Secretion of IL-1β is blocked by methylamine, low temperature or serum free medium, and is increased by raising the culture temperature to 42°C or by the presence of calcium ionophores, brefeldin A, monensin, dinitrophenol or carbonyl cyanide chlorophenylhydrazone. IL-1β is contained in part within intracellular vesicles which protect it from protease digestion. In U937 cells large amounts of IL-1β are made but none is secreted. In these cells IL-1β is not found in the vesicular fraction, and all the protein is accessible to protease digestion. This suggests that intracellular vesicles that contain IL-1β are part of the protein secretory pathway. We conclude that IL-1β is released by activated monocytes via a novel mechanism of secretion which may involve translocation of intracellular membranes and is increased by stress conditions.