The three cytokines IL-1β, IL-18, and IL-1α share related but distinct secretory routes

Abstract

Interleukin (IL)-1 family cytokines potently regulate inflammation, with the majority of the IL-1 family proteins being secreted from immune cells via unconventional pathways. In many cases, secretion of IL-1 cytokines appears to be closely coupled to cell death, yet the secretory mechanisms involved remain poorly understood. Here, we studied the secretion of the three best-characterized members of the IL-1 superfamily, IL-1α, IL-1β, and IL-18, in a range of conditions and cell types, including murine bone marrow–derived and peritoneal macrophages, human monocyte–derived macrophages, HeLa cells, and mouse embryonic fibroblasts. We discovered that IL-1β and IL-18 share a common secretory pathway that depends upon membrane permeability and can operate in the absence of complete cell lysis and cell death. We also found that the pathway regulating the trafficking of IL-1α is distinct from the pathway regulating IL-1β and IL-18. Although the release of IL-1α could also be dissociated from cell death, it was independent of the effects of the membrane-stabilizing agent punicalagin, which inhibited both IL-1β and IL-18 release. These results reveal that in addition to their role as danger signals released from dead cells, IL-1 family cytokines can be secreted in the absence of cell death. We propose that models used in the study of IL-1 release should be considered context-dependently.

Association between Prolonged Intermittent Renal Replacement Therapy and All-Cause Mortality in COVID-19 Patients Undergoing Invasive Mechanical Ventilation: a Retrospective Cohort Study

“…IL-1β is known as a lymphocyte-stimulating factor, produced by activated monocytemacrophages. 45,46 It plays an immunomodulatory role to induce synthesis of acute phase protein causing fever and cachexia, active antigen-presenting cell and T cells, and promote the proliferation and secretion of antibodies of B cells in innate and acquired immunity. 47 preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in In our study, cTnI and NT-proBNP were associated with increased risk of mortality in patients with CRRT.…”

Inflammasome signaling and regulation of interleukin-1 family cytokines

“…Inflammasome activity during cell death liberates IL-1α from dying cells, as caspase-1 and caspase-5 cleave IL-1R2 to enable subsequent IL-1α processing, cellular release, and signaling (Zheng et al, 2013). Intriguingly, IL-1α appears able to be secreted from living cells in some circumstances (Tapia et al, 2019), such as the senescence-associated secretory phenotype (Gardner et al, 2015; Wiggins et al, 2019). The mechanism underpinning IL-1α secretion from living cells awaits clarification.…”

Priming is dispensable for NLRP3 inflammasome activation in human monocytes

“…The effect of punicalagin on inflammasome activation resembles that of GSDMD KO [42][43][44]. Similar to pro-IL-18, GSDMD is constitutively expressed in unprimed THP-1 and human monocytes.…”

“…To determine whether inflammasome-induced cell death in unprimed monocytes was involved in the release of mIL-18 and mIL-37, we tested the effect of the polyphenolic compound punicalagin. Punicalagin inhibits plasma membrane permeability, as well as mIL-1β and mIL-18 release induced by inflammasome, whilst allowing caspase-1 activation [42,43]. In unprimed THP-1 cells, 15 minute pre-treatment with 50 µM punicalagin prior to nigericin significantly blocked IL-18 release ( Fig 5A).…”