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

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)8259
Number of pages1
JournalScientific Reports
Volume11
Issue number1
DOIs
Publication statusPublished - 15 Apr 2021

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