Identification of an acid sphingomyelinase ceramide kinase pathway in the regulation of the chemokine CCL5 [S]

Newcomb, Benjamin; Rhein, Cosima; Mileva, Izolda; Ahmad, Rasheed; Clarke, Christopher J.; Snider, Justin; Obeid, Lina M.; Hannun, Yusuf A.

doi:10.1194/jlr.m084202

Cited by 22 publications

(12 citation statements)

References 72 publications

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“…It was shown that p38 signaling was implicated in nSMase2 phosphorylation and activation 52 . Our data are corroborated by a previous study 40 showing that disrupting CERK activity by either NVP-231 or siRNA decreases the TNF-α-induced phosphorylation of p38 MAPK, JNK, and NF-κB. TNF-α binding to its cognate receptor on cell surface phosphorylates the downstream c-Jun and NF-κβ, resulting in the activation of several inflammatory genes.…”

Section: Discussionsupporting

confidence: 91%

“…Our findings specifically show that CERK inhibition or its downregulation in monocytic cells significantly blocks the production of critical inflammatory mediators including IL-1β and MCP-1. We reported previously in one of our study that knockdown of CERK led to a significant decrease in CCL5 mRNA and protein expression following TNF-α stimulation 40 . IL-1β and MCP-1 are the major proinflammatory mediators produced mostly by the activated monocytes/macrophages.…”

Section: Discussionmentioning

confidence: 51%

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

Al-Rashed

Ahmad

Snider

et al. 2021

Sci Rep

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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.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 51%

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

Al-Rashed

Ahmad

Snider

et al. 2021

Sci Rep

Self Cite

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show abstract

“…It was previously shown that p38 signaling was implicated in nSMase2 phosphorylation and activation. Our data are corroborated by a previous study 31 showing that disrupting CERK activity by either NVP-231 or siRNA decreases the TNF-α-induced phosphorylation of p38 MAPK, JNK, and NF-κB. TNF-α binding to its cognate receptor on cell surface receptor phosphorylates the downstream c-Jun and NF-κβ, resulting in the activation of several inflammatory genes.…”

Section: Discussionsupporting

confidence: 91%

Ceramide Kinase Regulates TNF-α-induced Immune Responses in Human Monocytic Cells

Al-Rashed

Ahmad

Snider

et al. 2021

Preprint

Self Cite

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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 the 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 deficient cells. Phosphorylation of JNK, p38 and NF-κB resulting from TNF-α stimulation 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 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.

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“…Ceramide kinase (CerK) phosphorylates ceramide to form ceramide-1-phosphate (C1P), a molecule involved in proliferation, migration and inflammation [ 37 ] via the production of several cytokines and chemokines [ 38 ]. C1P-enhanced pancreatic tumor cell migration and invasion are dependent upon PI3K, Akt1, mTOR1, ERK1-2, and RhoA/ROCK signaling pathways [ 39 ].…”

Section: Sphingolipids In Cancermentioning

confidence: 99%

Cholesterol and Sphingolipid Enriched Lipid Rafts as Therapeutic Targets in Cancer

Codini

Garcia‐Gil

Albi

2021

IJMS

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Lipid rafts are critical cell membrane lipid platforms enriched in sphingolipid and cholesterol content involved in diverse cellular processes. They have been proposed to influence membrane properties and to accommodate receptors within themselves by facilitating their interaction with ligands. Over the past decade, technical advances have improved our understanding of lipid rafts as bioactive structures. In this review, we will cover the more recent findings about cholesterol, sphingolipids and lipid rafts located in cellular and nuclear membranes in cancer. Collectively, the data provide insights on the role of lipid rafts as biomolecular targets in cancer with good perspectives for the development of innovative therapeutic strategies.

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Identification of an acid sphingomyelinase ceramide kinase pathway in the regulation of the chemokine CCL5 [S]

Cited by 22 publications

References 72 publications

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

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

Ceramide Kinase Regulates TNF-α-induced Immune Responses in Human Monocytic Cells

Cholesterol and Sphingolipid Enriched Lipid Rafts as Therapeutic Targets in Cancer

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