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...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2021-04-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-021-87795-7 |
| _version_ | 1818843993693224960 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-19T05:06:42Z |
| format | Article |
| id | doaj.art-2cd04aab0a024548a7b6682f41f39173 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-19T05:06:42Z |
| publishDate | 2021-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-2cd04aab0a024548a7b6682f41f391732022-12-21T20:34:54ZengNature PortfolioScientific Reports2045-23222021-04-0111111410.1038/s41598-021-87795-7Ceramide kinase regulates TNF-α-induced immune responses in human monocytic cellsFatema Al-Rashed0Zunair Ahmad1Ashley J. Snider2Reeby Thomas3Shihab Kochumon4Motasem Melhem5Sardar Sindhu6Lina M. Obeid7Fahd Al-Mulla8Yusuf A. Hannun9Rasheed Ahmad10Immunology & Microbiology Department, Dasman Diabetes InstituteRoyal College of Surgeons in IrelandStony Brook Cancer Center and Department of Medicine, Stony Brook UniversityImmunology & Microbiology Department, Dasman Diabetes InstituteImmunology & Microbiology Department, Dasman Diabetes InstituteGenetics and Bioinformatics Department, Dasman Diabetes InstituteAnimal and Imaging Core Facility, Dasman Diabetes InstituteStony Brook Cancer Center and Department of Medicine, Stony Brook UniversityGenetics and Bioinformatics Department, Dasman Diabetes InstituteStony Brook Cancer Center and Department of Medicine, Stony Brook UniversityImmunology & Microbiology Department, Dasman Diabetes InstituteAbstract 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.https://doi.org/10.1038/s41598-021-87795-7 |
| spellingShingle | 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 Scientific Reports |
| title | 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_short | 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 |
| url | https://doi.org/10.1038/s41598-021-87795-7 |
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