Basal and IL-1β enhanced chondrocyte chemotactic activity on monocytes are co-dependent on both IKKα and IKKβ NF-κB activating kinases

Abstract IKKα and IKKβ are essential kinases for activating NF-κB transcription factors that regulate cellular differentiation and inflammation. By virtue of their small size, chemokines support the crosstalk between cartilage and other joint compartments and contribute to immune cell chemotaxis in...

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Autores principales:	Eleonora Olivotto, Manuela Minguzzi, Stefania D’Adamo, Annalisa Astolfi, Spartaco Santi, Mariagrazia Uguccioni, Kenneth B. Marcu, Rosa Maria Borzì
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/00c09dde5874444aa957f124a45639f9
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spelling	oai:doaj.org-article:00c09dde5874444aa957f124a45639f92021-11-08T10:46:31ZBasal and IL-1β enhanced chondrocyte chemotactic activity on monocytes are co-dependent on both IKKα and IKKβ NF-κB activating kinases10.1038/s41598-021-01063-22045-2322https://doaj.org/article/00c09dde5874444aa957f124a45639f92021-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-01063-2https://doaj.org/toc/2045-2322Abstract IKKα and IKKβ are essential kinases for activating NF-κB transcription factors that regulate cellular differentiation and inflammation. By virtue of their small size, chemokines support the crosstalk between cartilage and other joint compartments and contribute to immune cell chemotaxis in osteoarthritis (OA). Here we employed shRNA retroviruses to stably and efficiently ablate the expression of each IKK in primary OA chondrocytes to determine their individual contributions for monocyte chemotaxis in response to chondrocyte conditioned media. Both IKKα and IKKβ KDs blunted both the monocyte chemotactic potential and the protein levels of CCL2/MCP-1, the chemokine with the highest concentration and the strongest association with monocyte chemotaxis. These findings were mirrored by gene expression analysis indicating that the lowest levels of CCL2/MCP-1 and other monocyte-active chemokines were in IKKαKD cells under both basal and IL-1β stimulated conditions. We find that in their response to IL-1β stimulation IKKαKD primary OA chondrocytes have reduced levels of phosphorylated NFkappaB p65pSer536 and H3pSer10. Confocal microscopy analysis revealed co-localized p65 and H3pSer10 nuclear signals in agreement with our findings that IKKαKD effectively blunts their basal level and IL-1β dependent increases. Our results suggest that IKKα could be a novel OA disease target.Eleonora OlivottoManuela MinguzziStefania D’AdamoAnnalisa AstolfiSpartaco SantiMariagrazia UguccioniKenneth B. MarcuRosa Maria BorzìNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Eleonora Olivotto Manuela Minguzzi Stefania D’Adamo Annalisa Astolfi Spartaco Santi Mariagrazia Uguccioni Kenneth B. Marcu Rosa Maria Borzì Basal and IL-1β enhanced chondrocyte chemotactic activity on monocytes are co-dependent on both IKKα and IKKβ NF-κB activating kinases
description	Abstract IKKα and IKKβ are essential kinases for activating NF-κB transcription factors that regulate cellular differentiation and inflammation. By virtue of their small size, chemokines support the crosstalk between cartilage and other joint compartments and contribute to immune cell chemotaxis in osteoarthritis (OA). Here we employed shRNA retroviruses to stably and efficiently ablate the expression of each IKK in primary OA chondrocytes to determine their individual contributions for monocyte chemotaxis in response to chondrocyte conditioned media. Both IKKα and IKKβ KDs blunted both the monocyte chemotactic potential and the protein levels of CCL2/MCP-1, the chemokine with the highest concentration and the strongest association with monocyte chemotaxis. These findings were mirrored by gene expression analysis indicating that the lowest levels of CCL2/MCP-1 and other monocyte-active chemokines were in IKKαKD cells under both basal and IL-1β stimulated conditions. We find that in their response to IL-1β stimulation IKKαKD primary OA chondrocytes have reduced levels of phosphorylated NFkappaB p65pSer536 and H3pSer10. Confocal microscopy analysis revealed co-localized p65 and H3pSer10 nuclear signals in agreement with our findings that IKKαKD effectively blunts their basal level and IL-1β dependent increases. Our results suggest that IKKα could be a novel OA disease target.
format	article
author	Eleonora Olivotto Manuela Minguzzi Stefania D’Adamo Annalisa Astolfi Spartaco Santi Mariagrazia Uguccioni Kenneth B. Marcu Rosa Maria Borzì
author_facet	Eleonora Olivotto Manuela Minguzzi Stefania D’Adamo Annalisa Astolfi Spartaco Santi Mariagrazia Uguccioni Kenneth B. Marcu Rosa Maria Borzì
author_sort	Eleonora Olivotto
title	Basal and IL-1β enhanced chondrocyte chemotactic activity on monocytes are co-dependent on both IKKα and IKKβ NF-κB activating kinases
title_short	Basal and IL-1β enhanced chondrocyte chemotactic activity on monocytes are co-dependent on both IKKα and IKKβ NF-κB activating kinases
title_full	Basal and IL-1β enhanced chondrocyte chemotactic activity on monocytes are co-dependent on both IKKα and IKKβ NF-κB activating kinases
title_fullStr	Basal and IL-1β enhanced chondrocyte chemotactic activity on monocytes are co-dependent on both IKKα and IKKβ NF-κB activating kinases
title_full_unstemmed	Basal and IL-1β enhanced chondrocyte chemotactic activity on monocytes are co-dependent on both IKKα and IKKβ NF-κB activating kinases
title_sort	basal and il-1β enhanced chondrocyte chemotactic activity on monocytes are co-dependent on both ikkα and ikkβ nf-κb activating kinases
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/00c09dde5874444aa957f124a45639f9
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Basal and IL-1β enhanced chondrocyte chemotactic activity on monocytes are co-dependent on both IKKα and IKKβ NF-κB activating kinases

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