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

• Published in: Scientific reports 2021-04, Vol.11 (1), p.8259-8259, Article 8259
• Main Authors: Al-Rashed, Fatema, Ahmad, Zunair, Snider, Ashley J., Thomas, Reeby, Kochumon, Shihab, Melhem, Motasem, Sindhu, Sardar, Obeid, Lina M., Al-Mulla, Fahd, Hannun, Yusuf A., Ahmad, Rasheed
• Format: Article
• Language: English
• Subjects: 631/250; 692/53; CD11b antigen; CD11c antigen; Ceramide; Ceramide kinase; Histocompatibility antigen HLA; Humanities and Social Sciences; IL-1β; Immune response; Inflammation; Inflammatory diseases; Monocyte chemoattractant protein 1; Monocytes; multidisciplinary; NF-κB protein; Phosphorylation; Science; Science (multidisciplinary); siRNA; Transcription factors; Tumor necrosis factor-α
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-87795-7

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.