Figure 6.

Sphingosine kinase (SphK)–endothelin-converting enzyme 1 (Ece1) positive feedback loop. Synthesis of endothelin 1 (Edn1) triggers activation of phospholipase C (PLC), which leads to activation of protein kinase C (PKC) and SphK. Inhibition of SphK with sphingosine kinase inhibitor II suppresses not only several inflammatory cytokines, but also decreases levels of Ece1, which is known to act upstream of SphK. The data support the existence of a positive feedback loop between SphK and the Ece1/Edn1 axis. DAG, diacylglycerol; ET-1, endothelin 1; InsP3, inositol triphosphate; PIP2, phospholipid phosphatidyl inositol 4,5-bisphophate; S1P, sphingosine-1-phosphate.