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Stimulation of Toll-like receptor 3 and 4 induces interleukin-1β maturation by caspase-8
The cytokine interleukin (IL)-1β is a key mediator of the inflammatory response and has been implicated in the pathophysiology of acute and chronic inflammation. IL-1β is synthesized in response to many stimuli as an inactive pro–IL-1β precursor protein that is further processed by caspase-1 into ma...
Autores principales: | , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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The Rockefeller University Press
2008
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2526192/ https://www.ncbi.nlm.nih.gov/pubmed/18725521 http://dx.doi.org/10.1084/jem.20071632 |
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author | Maelfait, Jonathan Vercammen, Elisabeth Janssens, Sophie Schotte, Peter Haegman, Mira Magez, Stefan Beyaert, Rudi |
author_facet | Maelfait, Jonathan Vercammen, Elisabeth Janssens, Sophie Schotte, Peter Haegman, Mira Magez, Stefan Beyaert, Rudi |
author_sort | Maelfait, Jonathan |
collection | PubMed |
description | The cytokine interleukin (IL)-1β is a key mediator of the inflammatory response and has been implicated in the pathophysiology of acute and chronic inflammation. IL-1β is synthesized in response to many stimuli as an inactive pro–IL-1β precursor protein that is further processed by caspase-1 into mature IL-1β, which is the secreted biologically active form of the cytokine. Although stimulation of membrane-bound Toll-like receptors (TLRs) up-regulates pro–IL-1β expression, activation of caspase-1 is believed to be mainly initiated by cytosolic Nod-like receptors. In this study, we show that polyinosinic:polycytidylic acid (poly[I:C]) and lipopolysaccharide stimulation of macrophages induces pro–IL-1β processing via a Toll/IL-1R domain–containing adaptor-inducing interferon-β–dependent signaling pathway that is initiated by TLR3 and TLR4, respectively. Ribonucleic acid interference (RNAi)–mediated knockdown of the intracellular receptors NALP3 or MDA5 did not affect poly(I:C)-induced pro–IL-1β processing. Surprisingly, poly(I:C)- and LPS-induced pro–IL-1β processing still occurred in caspase-1–deficient cells. In contrast, pro–IL-1β processing was inhibited by caspase-8 peptide inhibitors, CrmA or vFLIP expression, and caspase-8 knockdown via RNAi, indicating an essential role for caspase-8. Moreover, recombinant caspase-8 was able to cleave pro–IL-1β in vitro at exactly the same site as caspase-1. These results implicate a novel role for caspase-8 in the production of biologically active IL-1β in response to TLR3 and TLR4 stimulation. |
format | Text |
id | pubmed-2526192 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2008 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-25261922009-03-01 Stimulation of Toll-like receptor 3 and 4 induces interleukin-1β maturation by caspase-8 Maelfait, Jonathan Vercammen, Elisabeth Janssens, Sophie Schotte, Peter Haegman, Mira Magez, Stefan Beyaert, Rudi J Exp Med Brief Definitive Reports The cytokine interleukin (IL)-1β is a key mediator of the inflammatory response and has been implicated in the pathophysiology of acute and chronic inflammation. IL-1β is synthesized in response to many stimuli as an inactive pro–IL-1β precursor protein that is further processed by caspase-1 into mature IL-1β, which is the secreted biologically active form of the cytokine. Although stimulation of membrane-bound Toll-like receptors (TLRs) up-regulates pro–IL-1β expression, activation of caspase-1 is believed to be mainly initiated by cytosolic Nod-like receptors. In this study, we show that polyinosinic:polycytidylic acid (poly[I:C]) and lipopolysaccharide stimulation of macrophages induces pro–IL-1β processing via a Toll/IL-1R domain–containing adaptor-inducing interferon-β–dependent signaling pathway that is initiated by TLR3 and TLR4, respectively. Ribonucleic acid interference (RNAi)–mediated knockdown of the intracellular receptors NALP3 or MDA5 did not affect poly(I:C)-induced pro–IL-1β processing. Surprisingly, poly(I:C)- and LPS-induced pro–IL-1β processing still occurred in caspase-1–deficient cells. In contrast, pro–IL-1β processing was inhibited by caspase-8 peptide inhibitors, CrmA or vFLIP expression, and caspase-8 knockdown via RNAi, indicating an essential role for caspase-8. Moreover, recombinant caspase-8 was able to cleave pro–IL-1β in vitro at exactly the same site as caspase-1. These results implicate a novel role for caspase-8 in the production of biologically active IL-1β in response to TLR3 and TLR4 stimulation. The Rockefeller University Press 2008-09-01 /pmc/articles/PMC2526192/ /pubmed/18725521 http://dx.doi.org/10.1084/jem.20071632 Text en © 2008 Maelfait et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/). |
spellingShingle | Brief Definitive Reports Maelfait, Jonathan Vercammen, Elisabeth Janssens, Sophie Schotte, Peter Haegman, Mira Magez, Stefan Beyaert, Rudi Stimulation of Toll-like receptor 3 and 4 induces interleukin-1β maturation by caspase-8 |
title | Stimulation of Toll-like receptor 3 and 4 induces interleukin-1β maturation by caspase-8 |
title_full | Stimulation of Toll-like receptor 3 and 4 induces interleukin-1β maturation by caspase-8 |
title_fullStr | Stimulation of Toll-like receptor 3 and 4 induces interleukin-1β maturation by caspase-8 |
title_full_unstemmed | Stimulation of Toll-like receptor 3 and 4 induces interleukin-1β maturation by caspase-8 |
title_short | Stimulation of Toll-like receptor 3 and 4 induces interleukin-1β maturation by caspase-8 |
title_sort | stimulation of toll-like receptor 3 and 4 induces interleukin-1β maturation by caspase-8 |
topic | Brief Definitive Reports |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2526192/ https://www.ncbi.nlm.nih.gov/pubmed/18725521 http://dx.doi.org/10.1084/jem.20071632 |
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