mTORC2 inhibition by JR-AB2-011 improves IL-1β-induced inflammation, catabolic response, and apoptosis in human chondrocytes through IκB-α/NF-κB p65
Osteoarthritis (OA) is a very common chronic joint condition marked by inflammation and cartilage loss. mTOR is a well-known mediator of inflammation, cell survival, and aging; however, its role in OA has not been determined. To explore the role of mTORC2 in OA-and associated pathological changes, w...
Saved in:
Published in | Cellular and Molecular Biology Vol. 70; no. 9; pp. 37 - 43 |
---|---|
Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
France
08.10.2024
|
Subjects | |
Online Access | Get full text |
Cover
Loading…
Abstract | Osteoarthritis (OA) is a very common chronic joint condition marked by inflammation and cartilage loss. mTOR is a well-known mediator of inflammation, cell survival, and aging; however, its role in OA has not been determined. To explore the role of mTORC2 in OA-and associated pathological changes, we examined the contribution of mTORC2-mediated Akt, rictor and IκB-α/NF-κB p65 pathway in interleukin (IL)-1β-treated human chondrocytes. We focused on the protein expression of proinflammatory cytokines and catabolic and apoptotic factors, including TNF-α, IL-6, iNOS, MMP13, Bax, and caspase3, which may occur through this signalling pathway in IL-1β-treated chondrocytes. Chondrocytes were cultured and treated with either 2 ng/mL IL‑1β alone or in combination with increasing concentrations of JR-AB2-011 (50, 100, or 250 µM), a selective mTORC2 inhibitor. The protein levels of phosphorylated (p)‑Akt, Akt, rictor, p-NF-κB p65, NF-κB p65, IκB-α, p-IκB-α, iNOS, MMP13, Bax, and caspase3 were evaluated by Western blotting. In IL-1β-stimulated chondrocytes, mTORC2 activity was increased with increased phosphorylation of Akt and expression of rictor. IL-1β increased the expression of p-IκBα, p-NF-κB p65, NF-κB p65, IL-6, TNF-α, iNOS, Bax, and caspase3 proteins and decreased the expression of IκB-α. All of these IL-1β-induced alterations were prevented by JR-AB2-011. The main novel finding in the present study is that selective mTORC2 inhibition by JR-AB2-011 prevents the inflammatory, catabolic, and apoptotic responses induced by IL-1β via modulation of IκB-α/NF-κB activity. Therefore, we demonstrated a previously unknown function of mTORC2 inhibition that seems to be a potential therapeutic target for OA. |
---|---|
AbstractList | Osteoarthritis (OA) is a very common chronic joint condition marked by inflammation and cartilage loss. mTOR is a well-known mediator of inflammation, cell survival, and aging; however, its role in OA has not been determined. To explore the role of mTORC2 in OA-and associated pathological changes, we examined the contribution of mTORC2-mediated Akt, rictor and IκB-α/NF-κB p65 pathway in interleukin (IL)-1β-treated human chondrocytes. We focused on the protein expression of proinflammatory cytokines and catabolic and apoptotic factors, including TNF-α, IL-6, iNOS, MMP13, Bax, and caspase3, which may occur through this signalling pathway in IL-1β-treated chondrocytes. Chondrocytes were cultured and treated with either 2 ng/mL IL‑1β alone or in combination with increasing concentrations of JR-AB2-011 (50, 100, or 250 µM), a selective mTORC2 inhibitor. The protein levels of phosphorylated (p)‑Akt, Akt, rictor, p-NF-κB p65, NF-κB p65, IκB-α, p-IκB-α, iNOS, MMP13, Bax, and caspase3 were evaluated by Western blotting. In IL-1β-stimulated chondrocytes, mTORC2 activity was increased with increased phosphorylation of Akt and expression of rictor. IL-1β increased the expression of p-IκBα, p-NF-κB p65, NF-κB p65, IL-6, TNF-α, iNOS, Bax, and caspase3 proteins and decreased the expression of IκB-α. All of these IL-1β-induced alterations were prevented by JR-AB2-011. The main novel finding in the present study is that selective mTORC2 inhibition by JR-AB2-011 prevents the inflammatory, catabolic, and apoptotic responses induced by IL-1β via modulation of IκB-α/NF-κB activity. Therefore, we demonstrated a previously unknown function of mTORC2 inhibition that seems to be a potential therapeutic target for OA. Osteoarthritis (OA) is a very common chronic joint condition marked by inflammation and cartilage loss. mTOR is a well-known mediator of inflammation, cell survival, and aging; however, its role in OA has not been determined. To explore the role of mTORC2 in OA-and associated pathological changes, we examined the contribution of mTORC2-mediated Akt, rictor and IκB-α/NF-κB p65 pathway in interleukin (IL)-1β-treated human chondrocytes. We focused on the protein expression of proinflammatory cytokines and catabolic and apoptotic factors, including TNF-α, IL-6, iNOS, MMP13, Bax, and caspase3, which may occur through this signalling pathway in IL-1β-treated chondrocytes. Chondrocytes were cultured and treated with either 2 ng/mL IL‑1β alone or in combination with increasing concentrations of JR-AB2-011 (50, 100, or 250 µM), a selective mTORC2 inhibitor. The protein levels of phosphorylated (p)‑Akt, Akt, rictor, p-NF-κB p65, NF-κB p65, IκB-α, p-IκB-α, iNOS, MMP13, Bax, and caspase3 were evaluated by Western blotting. In IL-1β-stimulated chondrocytes, mTORC2 activity was increased with increased phosphorylation of Akt and expression of rictor. IL-1β increased the expression of p-IκBα, p-NF-κB p65, NF-κB p65, IL-6, TNF-α, iNOS, Bax, and caspase3 proteins and decreased the expression of IκB-α. All of these IL-1β-induced alterations were prevented by JR-AB2-011. The main novel finding in the present study is that selective mTORC2 inhibition by JR-AB2-011 prevents the inflammatory, catabolic, and apoptotic responses induced by IL-1β via modulation of IκB-α/NF-κB activity. Therefore, we demonstrated a previously unknown function of mTORC2 inhibition that seems to be a potential therapeutic target for OA.Osteoarthritis (OA) is a very common chronic joint condition marked by inflammation and cartilage loss. mTOR is a well-known mediator of inflammation, cell survival, and aging; however, its role in OA has not been determined. To explore the role of mTORC2 in OA-and associated pathological changes, we examined the contribution of mTORC2-mediated Akt, rictor and IκB-α/NF-κB p65 pathway in interleukin (IL)-1β-treated human chondrocytes. We focused on the protein expression of proinflammatory cytokines and catabolic and apoptotic factors, including TNF-α, IL-6, iNOS, MMP13, Bax, and caspase3, which may occur through this signalling pathway in IL-1β-treated chondrocytes. Chondrocytes were cultured and treated with either 2 ng/mL IL‑1β alone or in combination with increasing concentrations of JR-AB2-011 (50, 100, or 250 µM), a selective mTORC2 inhibitor. The protein levels of phosphorylated (p)‑Akt, Akt, rictor, p-NF-κB p65, NF-κB p65, IκB-α, p-IκB-α, iNOS, MMP13, Bax, and caspase3 were evaluated by Western blotting. In IL-1β-stimulated chondrocytes, mTORC2 activity was increased with increased phosphorylation of Akt and expression of rictor. IL-1β increased the expression of p-IκBα, p-NF-κB p65, NF-κB p65, IL-6, TNF-α, iNOS, Bax, and caspase3 proteins and decreased the expression of IκB-α. All of these IL-1β-induced alterations were prevented by JR-AB2-011. The main novel finding in the present study is that selective mTORC2 inhibition by JR-AB2-011 prevents the inflammatory, catabolic, and apoptotic responses induced by IL-1β via modulation of IκB-α/NF-κB activity. Therefore, we demonstrated a previously unknown function of mTORC2 inhibition that seems to be a potential therapeutic target for OA. |
Author | Malik, Kafait U Aktas-Sukuroglu, Ayca Sabrie, Zainab Temiz-Resitoglu, Meryem Tiftik, Rukiye Nalan Kalkan, Taskın Sahan-Firat, Seyhan |
Author_xml | – sequence: 1 givenname: Meryem surname: Temiz-Resitoglu fullname: Temiz-Resitoglu, Meryem email: meryemtemiz88@gmail.com organization: Department of Pharmacology, Faculty of Pharmacy, Mersin University, Mersin, Turkey. meryemtemiz88@gmail.com – sequence: 2 givenname: Zainab surname: Sabrie fullname: Sabrie, Zainab email: zainabsabrie93@gmail.com organization: Department of Pharmacology, Faculty of Pharmacy, Mersin University, Mersin, Turkey. zainabsabrie93@gmail.com – sequence: 3 givenname: Rukiye Nalan surname: Tiftik fullname: Tiftik, Rukiye Nalan email: nalantiftik@yahoo.com organization: Department of Pharmacology, Faculty of Medicine, Mersin University, Mersin, Turkey. nalantiftik@yahoo.com – sequence: 4 givenname: Taskın surname: Kalkan fullname: Kalkan, Taskın email: taskin.klkn@gmail.com organization: Department of Pharmacology, Faculty of Pharmacy, Mersin University, Mersin, Turkey. taskin.klkn@gmail.com – sequence: 5 givenname: Ayca surname: Aktas-Sukuroglu fullname: Aktas-Sukuroglu, Ayca email: aktasayca@mersin.edu.tr organization: Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Mersin University, Mersin, Turkey. aktasayca@mersin.edu.tr – sequence: 6 givenname: Kafait U surname: Malik fullname: Malik, Kafait U email: kmalik@uthsc.edu organization: Department of Pharmacology, Addiction Science and Toxicology, College of Medicine, University of Tennessee, Center for Health Sciences, Memphis, TN, USA. kmalik@uthsc.edu – sequence: 7 givenname: Seyhan surname: Sahan-Firat fullname: Sahan-Firat, Seyhan email: seyhansahan06@gmail.com organization: Department of Pharmacology, Faculty of Pharmacy, Mersin University, Mersin, Turkey. seyhansahan06@gmail.com |
BackLink | https://www.ncbi.nlm.nih.gov/pubmed/39380280$$D View this record in MEDLINE/PubMed |
BookMark | eNo9kcFu1DAURS1URIfSPSvkJYt65tmOE3vZjigMGlGpKhI7y3YcYimxQ5wgzZ_wG7DkI-abyNDCys_SPVd677xEZzFFj9BrCmtaVFRsXG83DFixrmCt1uIZWlFaCkKF_HKGVkALQUQp4Rxd5hwsAJNQyFK-QOdccXn6rtCP_uHufstwiG2wYQopYnvAH-_J9Q0jQCkO_TCm7z7j3Z7Q4y8SYj07Xy9A05m-NyfkCjszGZu64PDo85Bi9lfYxBqbIQ1TyiEvedzOvYnYtSnWY3KHaSmd2jHNX1u8O_6-Icefm0-3ZJnwUIpX6Hljuuwvn94L9Pn23cP2A9nfvd9tr_fEUa4EqZq6aZgDpqrClCVtwHIAoZi13NYSnFVKga2ZYk1R-oZbIYpK-FpWXDqQ_AK9fexd1vw2-zzpPmTnu85En-asOV3uCFDKUxQeo25MOY--0cMYejMeNAX9V4lelOiTEl2BVlosyJun9tn2vv4P_BPA_wC6kosx |
ContentType | Journal Article |
DBID | CGR CUY CVF ECM EIF NPM AAYXX CITATION 7X8 |
DOI | 10.14715/cmb/2024.70.9.5 |
DatabaseName | Medline MEDLINE MEDLINE (Ovid) MEDLINE MEDLINE PubMed CrossRef MEDLINE - Academic |
DatabaseTitle | MEDLINE Medline Complete MEDLINE with Full Text PubMed MEDLINE (Ovid) CrossRef MEDLINE - Academic |
DatabaseTitleList | MEDLINE MEDLINE - Academic |
Database_xml | – sequence: 1 dbid: NPM name: PubMed url: https://proxy.k.utb.cz/login?url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed sourceTypes: Index Database – sequence: 2 dbid: EIF name: MEDLINE url: https://proxy.k.utb.cz/login?url=https://www.webofscience.com/wos/medline/basic-search sourceTypes: Index Database |
DeliveryMethod | fulltext_linktorsrc |
Discipline | Biology |
EISSN | 1165-158X |
EndPage | 43 |
ExternalDocumentID | 10_14715_cmb_2024_70_9_5 39380280 |
Genre | Journal Article |
GroupedDBID | 29B 5GY ALMA_UNASSIGNED_HOLDINGS CGR CUY CVF ECM EIF KQ8 NPM AAYXX CITATION F5P 7X8 |
ID | FETCH-LOGICAL-c1395-7fdff2c02974a661f0b300592bb3bd80cb9990bd292f46ef3b55475ed8738c083 |
ISSN | 0145-5680 1165-158X |
IngestDate | Sat Oct 26 01:58:13 EDT 2024 Wed Oct 16 15:14:59 EDT 2024 Thu Oct 24 09:59:12 EDT 2024 |
IsDoiOpenAccess | false |
IsOpenAccess | true |
IsPeerReviewed | true |
IsScholarly | true |
Issue | 9 |
Language | English |
LinkModel | OpenURL |
MergedId | FETCHMERGED-LOGICAL-c1395-7fdff2c02974a661f0b300592bb3bd80cb9990bd292f46ef3b55475ed8738c083 |
Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
OpenAccessLink | https://cellmolbiol.org/index.php/CMB/article/download/5653/3416 |
PMID | 39380280 |
PQID | 3114500688 |
PQPubID | 23479 |
PageCount | 7 |
ParticipantIDs | proquest_miscellaneous_3114500688 crossref_primary_10_14715_cmb_2024_70_9_5 pubmed_primary_39380280 |
PublicationCentury | 2000 |
PublicationDate | 2024-Oct-08 2024-10-08 20241008 |
PublicationDateYYYYMMDD | 2024-10-08 |
PublicationDate_xml | – month: 10 year: 2024 text: 2024-Oct-08 day: 08 |
PublicationDecade | 2020 |
PublicationPlace | France |
PublicationPlace_xml | – name: France |
PublicationTitle | Cellular and Molecular Biology |
PublicationTitleAlternate | Cell Mol Biol (Noisy-le-grand) |
PublicationYear | 2024 |
SSID | ssib002804868 ssj0030361 ssj0030360 |
Score | 2.4421868 |
Snippet | Osteoarthritis (OA) is a very common chronic joint condition marked by inflammation and cartilage loss. mTOR is a well-known mediator of inflammation, cell... |
SourceID | proquest crossref pubmed |
SourceType | Aggregation Database Index Database |
StartPage | 37 |
SubjectTerms | Apoptosis - drug effects Cells, Cultured Chondrocytes - drug effects Chondrocytes - metabolism Humans Imidazoles Inflammation - metabolism Inflammation - pathology Interleukin-1beta - metabolism Mechanistic Target of Rapamycin Complex 2 - antagonists & inhibitors Mechanistic Target of Rapamycin Complex 2 - metabolism NF-KappaB Inhibitor alpha - metabolism Osteoarthritis - drug therapy Osteoarthritis - metabolism Osteoarthritis - pathology Proto-Oncogene Proteins c-akt - metabolism Quinoxalines Rapamycin-Insensitive Companion of mTOR Protein - genetics Rapamycin-Insensitive Companion of mTOR Protein - metabolism Signal Transduction - drug effects Transcription Factor RelA - metabolism Tumor Necrosis Factor-alpha - metabolism |
Title | mTORC2 inhibition by JR-AB2-011 improves IL-1β-induced inflammation, catabolic response, and apoptosis in human chondrocytes through IκB-α/NF-κB p65 |
URI | https://www.ncbi.nlm.nih.gov/pubmed/39380280 https://www.proquest.com/docview/3114500688 |
Volume | 70 |
hasFullText | 1 |
inHoldings | 1 |
isFullTextHit | |
isPrint | |
link | http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwnV1bj9JAFJ7g-uKL0XjDW8bEfTDsQK-0fQQCLrvIRgIJ8aXptFNtgJYAfWB_iX9DH_0R_A3_hudML9S4JqsvpZnQHjLn49zmXAh56xt4Zqty5vkOOCgaxzvFYn4A-qZtcp_LcrEP4_b5zLiYm_Na7Wclaynd8aZ_fWNdyf9wFdaAr1gl-w-cLV8KC3AP_IUrcBiut-Lxano16WmNKP4ScZl6hcbkxYR1upgIoWIJ5CbBtrLDEVNPe_1TWAcfPMUzf6APYMgKF3GfMY7DsUlwY5OlzYoisdNbJ-tdgo1Lojif6QcyExsd-HuM2hajfoaSQqfL5CdKyPGA5WuNdTaroWyKIJZLmQCLBFbFiN5G0RIKRwQl0XbPloK93-S5l3IGiKiELqZiFV2zCU42SD4vUxnbFeBDrMqwkcfzcWGfZJFY-WAU7iKpBibpItoL0DHL47_k0lsu8qHN3naB1nZXjavREc3I0vMqAl1tm0w15fhi0Hc3rOVaIBtfkqPdqYj0rCfNH5oGlDp25fBXHGtqgHLTUppO0zzq1SKXYHzlDmajkTvtz6d3yF0NJCLmHl5-rPh5NnY-lGWbxW_Lj9SRTAuItCokfjeh_uIXSfto-oDczx0b2slQ-pDURPyIfM0QSo8IpXxPjwilBUIpIvTwvUAnraLzjJbYpAU2zyiAgpbIhO9TiUxaRSbNkUmHhx9ddvjWAjzCHQUsPiazQX_aO2f5LBDmg49iMisMwlDzcdSa4YFNGSocBy04IFx0HtiKz8HTUXigOVpotEWoc7CTLVMEtqXbPvgZT8hJnMTiGaGOHmgK2G7wAh2jCdz2QsvyA9O2QzDXeZ28K7bXXWctX1x0lZEVLrDCRVa4luI6rlknb4r9d0Eu42GbF4sk3bq6qhomFmDZdfI0Y0z5Nh0QgDx_founX5B7R1y_JCe7TSpegR28468lhn4Btx6xCA |
link.rule.ids | 315,783,787,27938,27939 |
linkProvider | Colorado Alliance of Research Libraries |
openUrl | ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=mTORC2+inhibition+by+JR-AB2-011+improves+IL-1%CE%B2-induced+inflammation%2C+catabolic+response%2C+and+apoptosis+in+human+chondrocytes+through+I%CE%BAB-%CE%B1%2FNF-%CE%BAB+p65&rft.jtitle=Cellular+and+molecular+biology+%28Noisy-le-Grand%2C+France%29&rft.au=Temiz-Resitoglu%2C+Meryem&rft.au=Sabrie%2C+Zainab&rft.au=Tiftik%2C+Rukiye+Nalan&rft.au=Kalkan%2C+Task%C4%B1n&rft.date=2024-10-08&rft.issn=1165-158X&rft.eissn=1165-158X&rft.volume=70&rft.issue=9&rft.spage=37&rft_id=info:doi/10.14715%2Fcmb%2F2024.70.9.5&rft.externalDBID=NO_FULL_TEXT |
thumbnail_l | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/lc.gif&issn=0145-5680&client=summon |
thumbnail_m | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/mc.gif&issn=0145-5680&client=summon |
thumbnail_s | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/sc.gif&issn=0145-5680&client=summon |