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

EMBO J. 1990 May;9(5):1503-10.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Brefeldin A
  • Cyclopentanes / pharmacology
  • Hot Temperature
  • Humans
  • Interleukin-1 / metabolism*
  • Kinetics
  • Lipopolysaccharides / pharmacology
  • Methylamines / pharmacology
  • Monensin / pharmacology
  • Monocytes / drug effects
  • Monocytes / metabolism*
  • Protein Processing, Post-Translational / drug effects
  • Subcellular Fractions / analysis

Substances

  • Cyclopentanes
  • Interleukin-1
  • Lipopolysaccharides
  • Methylamines
  • Brefeldin A
  • Monensin
  • methylamine