Ceramide kinase regulates TNF-α-induced immune responses in human monocytic cells

Abstract Ceramide kinase (CERK) phosphorylates ceramide to produce ceramide-1-phosphate (C1P), which is involved in the development of metabolic inflammation. TNF-α modulates inflammatory responses in monocytes associated with various inflammatory disorders; however, the underlying mechanisms remain...

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Autores principales:	Fatema Al-Rashed, Zunair Ahmad, Ashley J. Snider, Reeby Thomas, Shihab Kochumon, Motasem Melhem, Sardar Sindhu, Lina M. Obeid, Fahd Al-Mulla, Yusuf A. Hannun, Rasheed Ahmad
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/2cd04aab0a024548a7b6682f41f39173
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spelling	oai:doaj.org-article:2cd04aab0a024548a7b6682f41f391732021-12-02T15:51:14ZCeramide kinase regulates TNF-α-induced immune responses in human monocytic cells10.1038/s41598-021-87795-72045-2322https://doaj.org/article/2cd04aab0a024548a7b6682f41f391732021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-87795-7https://doaj.org/toc/2045-2322Abstract Ceramide kinase (CERK) phosphorylates ceramide to produce ceramide-1-phosphate (C1P), which is involved in the development of metabolic inflammation. TNF-α modulates inflammatory responses in monocytes associated with various inflammatory disorders; however, the underlying mechanisms remain not fully understood. Here, we investigated the role of CERK in TNF-α-induced inflammatory responses in monocytes. Our results show that disruption of CERK activity in monocytes, either by chemical inhibitor NVP-231 or by small interfering RNA (siRNA), results in the defective expression of inflammatory markers including CD11c, CD11b and HLA-DR in response to TNF-α. Our data show that TNF-α upregulates ceramide phosphorylation. Inhibition of CERK in monocytes significantly reduced the secretion of IL-1β and MCP-1. Similar results were observed in CERK-downregulated cells. TNF-α-induced phosphorylation of JNK, p38 and NF-κB was reduced by inhibition of CERK. Additionally, NF-κB/AP-1 activity was suppressed by the inhibition of CERK. Clinically, obese individuals had higher levels of CERK expression in PBMCs compared to lean individuals, which correlated with their TNF-α levels. Taken together, these results suggest that CERK plays a key role in regulating inflammatory responses in human monocytes during TNF-α stimulation. CERK may be a relevant target for developing novel therapies for chronic inflammatory diseases.Fatema Al-RashedZunair AhmadAshley J. SniderReeby ThomasShihab KochumonMotasem MelhemSardar SindhuLina M. ObeidFahd Al-MullaYusuf A. HannunRasheed AhmadNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Fatema Al-Rashed Zunair Ahmad Ashley J. Snider Reeby Thomas Shihab Kochumon Motasem Melhem Sardar Sindhu Lina M. Obeid Fahd Al-Mulla Yusuf A. Hannun Rasheed Ahmad Ceramide kinase regulates TNF-α-induced immune responses in human monocytic cells
description	Abstract Ceramide kinase (CERK) phosphorylates ceramide to produce ceramide-1-phosphate (C1P), which is involved in the development of metabolic inflammation. TNF-α modulates inflammatory responses in monocytes associated with various inflammatory disorders; however, the underlying mechanisms remain not fully understood. Here, we investigated the role of CERK in TNF-α-induced inflammatory responses in monocytes. Our results show that disruption of CERK activity in monocytes, either by chemical inhibitor NVP-231 or by small interfering RNA (siRNA), results in the defective expression of inflammatory markers including CD11c, CD11b and HLA-DR in response to TNF-α. Our data show that TNF-α upregulates ceramide phosphorylation. Inhibition of CERK in monocytes significantly reduced the secretion of IL-1β and MCP-1. Similar results were observed in CERK-downregulated cells. TNF-α-induced phosphorylation of JNK, p38 and NF-κB was reduced by inhibition of CERK. Additionally, NF-κB/AP-1 activity was suppressed by the inhibition of CERK. Clinically, obese individuals had higher levels of CERK expression in PBMCs compared to lean individuals, which correlated with their TNF-α levels. Taken together, these results suggest that CERK plays a key role in regulating inflammatory responses in human monocytes during TNF-α stimulation. CERK may be a relevant target for developing novel therapies for chronic inflammatory diseases.
format	article
author	Fatema Al-Rashed Zunair Ahmad Ashley J. Snider Reeby Thomas Shihab Kochumon Motasem Melhem Sardar Sindhu Lina M. Obeid Fahd Al-Mulla Yusuf A. Hannun Rasheed Ahmad
author_facet	Fatema Al-Rashed Zunair Ahmad Ashley J. Snider Reeby Thomas Shihab Kochumon Motasem Melhem Sardar Sindhu Lina M. Obeid Fahd Al-Mulla Yusuf A. Hannun Rasheed Ahmad
author_sort	Fatema Al-Rashed
title	Ceramide kinase regulates TNF-α-induced immune responses in human monocytic cells
title_short	Ceramide kinase regulates TNF-α-induced immune responses in human monocytic cells
title_full	Ceramide kinase regulates TNF-α-induced immune responses in human monocytic cells
title_fullStr	Ceramide kinase regulates TNF-α-induced immune responses in human monocytic cells
title_full_unstemmed	Ceramide kinase regulates TNF-α-induced immune responses in human monocytic cells
title_sort	ceramide kinase regulates tnf-α-induced immune responses in human monocytic cells
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/2cd04aab0a024548a7b6682f41f39173
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Ceramide kinase regulates TNF-α-induced immune responses in human monocytic cells

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