RESUMO
Interleukin-1ß (IL-1ß) is activated by inflammasome-associated caspase-1 in rare autoinflammatory conditions and in a variety of other inflammatory diseases. Therefore, IL-1ß activity must be fine-tuned to enable anti-microbial responses whilst limiting collateral damage. Here, we show that precursor IL-1ß is rapidly turned over by the proteasome and this correlates with its decoration by K11-linked, K63-linked and K48-linked ubiquitin chains. The ubiquitylation of IL-1ß is not just a degradation signal triggered by inflammasome priming and activating stimuli, but also limits IL-1ß cleavage by caspase-1. IL-1ß K133 is modified by ubiquitin and forms a salt bridge with IL-1ß D129. Loss of IL-1ß K133 ubiquitylation, or disruption of the K133:D129 electrostatic interaction, stabilizes IL-1ß. Accordingly, Il1bK133R/K133R mice have increased levels of precursor IL-1ß upon inflammasome priming and increased production of bioactive IL-1ß, both in vitro and in response to LPS injection. These findings identify mechanisms that can limit IL-1ß activity and safeguard against damaging inflammation.
Assuntos
Caspase 1/genética , Inflamassomos/genética , Interleucina-1beta/genética , Complexo de Endopeptidases do Proteassoma/genética , Processamento de Proteína Pós-Traducional , Animais , Caspase 1/imunologia , Células HEK293 , Humanos , Inflamassomos/imunologia , Inflamação , Interleucina-1beta/imunologia , Lipopolissacarídeos/administração & dosagem , Macrófagos/imunologia , Macrófagos/patologia , Camundongos , Camundongos Knockout , Cultura Primária de Células , Complexo de Endopeptidases do Proteassoma/imunologia , Proteólise , Espécies Reativas de Oxigênio/imunologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Ubiquitina/genética , Ubiquitina/imunologia , UbiquitinaçãoRESUMO
Soluble CD52 is a small glycoprotein that suppresses T-cell activation, but its effect on innate immune cell function is unknown. Here we demonstrate that soluble CD52 inhibits Toll-like receptor and tumor necrosis factor receptor signaling to limit activation of NF-κB and thereby suppress the production of inflammatory cytokines by macrophages, monocytes and dendritic cells. At higher concentrations, soluble CD52 depletes the short-lived pro-survival protein MCL-1, contributing to activation of the BH3-only proteins BAX and BAK to cause intrinsic apoptotic cell death. In vivo, administration of soluble CD52 suppresses lipopolysaccharide (LPS)-induced cytokine secretion and other features of endotoxic shock, whereas genetic deletion of CD52 exacerbates LPS responses. Thus, soluble CD52 exhibits broad immune suppressive effects that signify its potential as an immunotherapeutic agent.