| First Author | Thuy AV | Year | 2022 |
| Journal | Int J Mol Sci | Volume | 23 |
| Issue | 21 | PubMed ID | 36361636 |
| Mgi Jnum | J:331578 | Mgi Id | MGI:7386013 |
| Doi | 10.3390/ijms232112848 | Citation | Thuy AV, et al. (2022) The Impact of Sphingosine Kinases on Inflammation-Induced Cytokine Release and Vascular Endothelial Barrier Integrity. Int J Mol Sci 23(21) |
| abstractText | Sphingosine kinases type 1 and 2 (SphK1/2) are required for the production of the immune modulator sphingosine 1-phosphate (S1P). SphK1 deficient mice (SphK1(-/-)) revealed 50% reduced S1P in plasma, while SphK2(-/-) mice demonstrated 2-3 times increased S1P levels in plasma. Since plasma S1P is a potent inducer of vascular endothelial cell (VEC) barrier stability, we hypothesized that higher and lower levels of S1P in SphK2(-/-) and SphK1(-/-) mice, respectively, compared to wild type (wt) mice should translate into decreased and increased severity of induced systemic inflammation due to improved or damaged VEC barrier maintenance. To our surprise, both SphK1(-/-) and SphK2(-/-) mice showed improved survival rate and earlier recovery from inflammation-induced weight loss compared to wt mice. While no difference was observed in VEC barrier stability by monitoring Evans blue leakage into peripheral tissues, SphK1(-/-) mice demonstrated a distinct delay and SphK2(-/-) mice an improved resolution of early pro-inflammatory cytokine release in plasma. Ex vivo cell culture experiments demonstrated that bone marrow-derived dendritic cells (BMDC) generated from SphK1(-/-) and SphK2(-/-) mice responded with decreased interferon-gamma (IFN-gamma) production upon stimulation with lipopolysaccharides (LPS) compared to wt BMDC, while activation-induced cytokine expression of lymphocytes and macrophages was not majorly altered. Ex vivo stimulation of macrophages with IFN-gamma resulted in increased cytokine release. These results suggest that SphK1/2 are involved in production and secretion of IFN-gamma by DC. DC-derived IFN-gamma subsequently stimulates the production and secretion of a large panel of inflammatory cytokines by macrophages, which belong to the main cytokine-releasing cells of the early innate immune response. Inhibitors of SphK1/2 may therefore be attractive targets to dampen the early cytokine response of macrophages as part of the innate immune response. |
