A novel secretory pathway for interleukin‐1 beta, a protein lacking a signal sequence.

Interleukin 1 (IL‐1) is a major soluble mediator of inflammation. Two human IL‐1 genes, alpha and beta, 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‐1 beta 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 alpha and of other secretory proteins do not inhibit secretion of IL‐1 beta. Secretion of IL‐1 beta is blocked by methylamine, low temperature or serum free medium, and is increased by raising the culture temperature to 42 degrees C or by the presence of calcium ionophores, brefeldin A, monensin, dinitrophenol or carbonyl cyanide chlorophenylhydrazone. IL‐1 beta is contained in part within intracellular vesicles which protect it from protease digestion. In U937 cells large amounts of IL‐1 beta are made but none is secreted. In these cells IL‐1 beta is not found in the vesicular fraction, and all the protein is accessible to protease digestion. This suggests that intracellular vesicles that contain IL‐1 beta are part of the protein secretory pathway. We conclude that IL‐1 beta is released by activated monocytes via a novel mechanism of secretion which may involve translocation of intracellular membranes and is increased by stress conditions.

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