title: Intracellular interleukin-1 receptor 2 binding prevents cleavage and activity of interleukin-1α, controlling necrosis-induced sterile inflammation.
abstract: Necrosis can induce profound inflammation or be clinically silent. However, the mechanisms underlying such tissue specificity are unknown. Interleukin-1α (IL-1α) is a key danger signal released upon necrosis that exerts effects on both innate and adaptive immunity and is considered to be constitutively active. In contrast, we have shown that necrosis-induced IL-1α activity is tightly controlled in a cell type-specific manner. Most cell types examined expressed a cytosolic IL-1 receptor 2 (IL-1R2) whose binding to pro-IL-1α inhibited its cytokine activity. In cell types exhibiting a silent necrotic phenotype, IL-1R2 remained associated with pro-IL-1α. Cell types possessing inflammatory necrotic phenotypes either lacked IL-1R2 or had activated caspase-1 before necrosis, which degraded and dissociated IL-1R2 from pro-IL-1α. Full IL-1α activity required cleavage by calpain after necrosis, which increased its affinity for IL-1 receptor 1. Thus, we report a cell type-dependent process that fundamentally governs IL-1α activity postnecrosis and the mechanism allowing conditional release of this blockade.
authors: Division of Cardiovascular Medicine, Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors: Yue
authors: Y
authors: Zheng
authors: Melanie
authors: M
authors: Humphry
authors: Janet J
authors: JJ
authors: Maguire
authors: Martin R
authors: MR
authors: Bennett
authors: Murray C H
authors: MC
authors: Clarke
mesh_terms: D000818:Animals; D002154:Calpain / Q000235:genetics / Q000276:immunology; D020170:Caspase 1 / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D053582:Interleukin-1alpha / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D009336:Necrosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D009928:Organ Specificity; D011485:Protein Binding; D011498:Protein Precursors / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D059748:Proteolysis; D053574:Receptors, Interleukin-1 Type II / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C508592:IL1R2 protein, human; D053582:Interleukin-1alpha; D011498:Protein Precursors; D053574:Receptors, Interleukin-1 Type II; D002154:Calpain; D020170:Caspase 1
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