dc.date.accessioned | 2019-09-30T05:28:31Z | |
dc.date.available | 2019-09-30T05:28:31Z | |
dc.date.created | 2019-09-21T12:07:02Z | |
dc.date.issued | 2019 | |
dc.identifier.citation | Torp, May-Kristin Yang, Kuan Ranheim, Trine Lauritzen, Knut Husø Alfsnes, Katrine Vinge, Leif Erik Aukrust, Pål Stensløkken, Kåre-Olav Yndestad, Arne Sandanger, Øystein . Mammalian target of rapamycin (mTOR) and the proteasome attenuates IL-1β expression in primary mouse cardiac fibroblasts. Frontiers in Immunology. 2019, 10:1285, 1-14 | |
dc.identifier.uri | http://hdl.handle.net/10852/70586 | |
dc.description.abstract | Background: IL-1β is a highly potent pro-inflammatory cytokine and its secretion is tightly regulated. Inactive pro-IL-1β is transcribed in response to innate immune receptors activating NFκB. If tissue damage occurs, danger signals released from necrotic cells, such as ATP, can activate NLRP3-inflammasomes (multiprotein complexes consisting of NLRP3, ASC, and active caspase-1) which cleaves and activates pro-IL-1β. NLRP3 activation also depends on NEK7 and mitochondrial ROS-production. Thus, IL-1β secretion may be regulated at the level of each involved component. We have previously shown that NLRP3-dependent IL-1β release can be induced in cardiac fibroblasts by pro-inflammatory stimuli. However, anti-inflammatory mechanisms targeting IL-1β release in cardiac cells have not been investigated. mTOR is a key regulator of protein metabolism, including autophagy and proteasome activity. In this study we explored whether autophagy or proteasomal degradation are regulators of NLRP3 inflammasome activation and IL-1β release from cardiac fibroblasts.
Methods and Results: Serum starvation selectively reduced LPS/ATP-induced IL-1β secretion from cardiac fibroblasts. However, no other inflammasome components, nor mitochondrial mass, were affected. The mTOR inhibitor rapamycin restored pro-IL-1β protein levels as well as LPS/ATP-induced IL-1β release from serum starved cells. However, neither serum starvation nor rapamycin induced autophagy in cardiac fibroblasts. Conversely, chloroquine and bafilomycin A (inhibitors of autophagy) and betulinic acid (a proteasome activator) effectively reduced LPS-induced pro-IL-1β protein levels. Key findings were reinvestigated in human monocyte-derived macrophages.
Conclusion: In cardiac fibroblasts, mTOR inhibition selectively favors pro-IL-1β synthesis while proteasomal degradation and not autophagy is the major catabolic anti-inflammatory mechanism for degradation of this cytokine. | |
dc.language | EN | |
dc.publisher | Frontiers Media S.A. | |
dc.rights | Attribution 4.0 International | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | |
dc.title | Mammalian target of rapamycin (mTOR) and the proteasome attenuates IL-1β expression in primary mouse cardiac fibroblasts | |
dc.type | Journal article | |
dc.creator.author | Torp, May-Kristin | |
dc.creator.author | Yang, Kuan | |
dc.creator.author | Ranheim, Trine | |
dc.creator.author | Lauritzen, Knut Husø | |
dc.creator.author | Alfsnes, Katrine | |
dc.creator.author | Vinge, Leif Erik | |
dc.creator.author | Aukrust, Pål | |
dc.creator.author | Stensløkken, Kåre-Olav | |
dc.creator.author | Yndestad, Arne | |
dc.creator.author | Sandanger, Øystein | |
cristin.unitcode | 185,51,12,51 | |
cristin.unitname | Hjertefysiologigruppen | |
cristin.ispublished | true | |
cristin.fulltext | original | |
cristin.qualitycode | 1 | |
dc.identifier.cristin | 1727454 | |
dc.identifier.bibliographiccitation | info:ofi/fmt:kev:mtx:ctx&ctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=Frontiers in Immunology&rft.volume=10:1285&rft.spage=1&rft.date=2019 | |
dc.identifier.jtitle | Frontiers in Immunology | |
dc.identifier.volume | 10:1285 | |
dc.identifier.startpage | 1 | |
dc.identifier.endpage | 14 | |
dc.identifier.doi | http://dx.doi.org/10.3389/fimmu.2019.01285 | |
dc.identifier.urn | URN:NBN:no-73718 | |
dc.type.document | Tidsskriftartikkel | |
dc.type.peerreviewed | Peer reviewed | |
dc.source.issn | 1664-3224 | |
dc.identifier.fulltext | Fulltext https://www.duo.uio.no/bitstream/handle/10852/70586/2/Mammalian%2BTarget%2Bof%2BRapamycin%2B%2528mTOR%2529%2Band%2Bthe%2BProteasome%2BAttenuates%2BIL-1%25CE%25B2%2BExpression%2Bin%2BPrimary%2BMouse%2BCardiac%2BFibroblasts.pdf | |
dc.type.version | PublishedVersion | |
dc.relation.project | NFR/240099/F20 | |