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.

Eukaryotic cells are able to discriminate between native and non-native polypeptides, selectively transporting the former to their final destinations. Secretory proteins are scrutinized at the endoplasmic reticulum (ER)-Golgi interface. Recent findings reveal novel features of the underlying molecular mechanisms, with several chaperone networks cooperating in assisting the maturation of complex proteins and being selectively induced to match changing synthetic demands.'Public' and 'private' chaperones, some of which enriched in specializes subregions, operate for most or selected substrates, respectively. Moreover, sequential checkpoints are distributed along the early secretory pathway, allowing efficiency and fidelity in protein secretion.

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The role of autophagy in plasma cells is unknown. Here we found notable autophagic activity in both differentiating and long-lived plasma cells and investigated its function through the use of mice with conditional deficiency in the essential autophagic molecule Atg5 in B cells. Atg5(-/-) differentiating plasma cells had a larger endoplasmic reticulum (ER) and more ER stress signaling than did their wild-type counterparts, which led to higher expression of the transcriptional repressor Blimp-1 and immunoglobulins and more antibody secretion. The enhanced immunoglobulin synthesis was associated with less intracellular ATP and more death of mutant plasma cells, which identified an unsuspected autophagy-dependent cytoprotective trade-off between immunoglobulin synthesis and viability. In vivo, mice with conditional deficiency in Atg5 in B cells had defective antibody responses, complete selection in the bone marrow for plasma cells that escaped Atg5 deletion and fewer antigen-specific long-lived bone marrow plasma cells than did wild-type mice, despite having normal germinal center responses. Thus, autophagy is specifically required for plasma cell homeostasis and long-lived humoral immunity.

Upon encounter with antigen, B lymphocytes differentiate into Ig-secreting plasma cells. This step involves a massive development of secretory organelles, most notably the endoplasmic reticulum. To analyze the relationship between organelle reshaping and Ig secretion, we performed a dynamic proteomics study of B lymphoma cells undergoing in vitro terminal differentiation. By clustering proteins according to temporal expression patterns, it appeared that B cells anticipate their secretory role in a multistep process. Metabolic capacity and secretory machinery expand first to accommodate the mass production of IgM that follows.