Neutral sphingomyelinase 2 regulates inflammatory responses in monocytes/macrophages induced by TNF-α
Abstract Obesity is associated with elevated levels of TNF-α and proinflammatory CD11c monocytes/macrophages. TNF-α mediated dysregulation in the plasticity of monocytes/macrophages is concomitant with pathogenesis of several inflammatory diseases, including metabolic syndrome, but the underlying me...
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| Published in: | The Journal of immunology (1950) Vol. 204; no. 1_Supplement; pp. 59 - 59.26 |
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| Main Authors: | , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
01-05-2020
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| Online Access: | Get full text |
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| Summary: | Abstract
Obesity is associated with elevated levels of TNF-α and proinflammatory CD11c monocytes/macrophages. TNF-α mediated dysregulation in the plasticity of monocytes/macrophages is concomitant with pathogenesis of several inflammatory diseases, including metabolic syndrome, but the underlying mechanisms are incompletely understood. Since neutral sphingomyelinase 2 (nSMase2; product of the sphingomyelin phosphodiesterase 3 gene, SMPD3) is a key enzyme for ceramide production involved in inflammation, we investigated whether the nSMase2 contributed to the inflammatory changes in the monocytes/macrophages induced by TNF-α. In this study, we demonstrate that the disruption of nSMase2 activity in monocytes/macrophages either by chemical inhibitor GW4869 or small interfering RNA (siRNA) against SMPD3 results in defects in the TNF-α mediated expression of CD11c. Furthermore, blockage of nSMase in monocytes/macrophages inhibited the secretion of IL-1b and MCP-1. However, inhibition aSMase activity did not attenuate CD11c expression and secretion of IL-1b and MCP-1. Phosphorylation of JNK, p38 and NF-κB resulting from TNF-α stimulation was also attenuated by the inhibition of nSMase. Moreover, NF-kB/AP-1 activity was blocked by the inhibition of nSMase2. Our human data show that SMPD3 gene expression was not only found to be elevated in obese individuals but also positively corelate with TNF-α elevated expression. These findings indicate that nSMase acts, in a part, as a master switch in the TNF-α mediated inflammatory responses in monocytes/macrophages. |
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| ISSN: | 0022-1767 1550-6606 |
| DOI: | 10.4049/jimmunol.204.Supp.59.26 |