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.
Rubartelli
A
A
Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
Cozzolino
F
F
Talio
M
M
Sitia
R
R
D020126:Brefeldin A; D003517:Cyclopentanes / Q000494:pharmacology; D006358:Hot Temperature; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism*; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008744:Methylamines / Q000494:pharmacology; D008985:Monensin / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D013347:Subcellular Fractions / Q000032:analysis
D003517:Cyclopentanes; D007375:Interleukin-1; D008070:Lipopolysaccharides; D008744:Methylamines; D020126:Brefeldin A; D008985:Monensin; C027451:methylamine