Functionally, nSMase2 was found to be upstream of the TNF-α-stimulated expression of vascular cell adhesion molecule-1 (VCAM) and intercellular adhesion molecule-1 (ICAM) in lung epithelial cells (Clarke et al., 2007) and was important for TNF-α induced activation of endothelial nitric oxide synthase (eNOS) in human endothelial cells (De Palma et al., 2006). In smooth muscle cells, nSMase2 was important for TNF-α-mediated ERK activation, DNA synthesis, and cell proliferation (Tellier et al., 2007). Interestingly, in the latter two cases, nSMase2 appeared to function upstream of sphingosine kinase 1, as a source of ceramide for subsequent production of sphingosine-1-phosphate. More recently, nSMase2 was implicated in TNF-α induced modulation of synaptic plasticity by controlling the membrane insertion of NMDA receptors (Wheeler et al., 2009). Finally, aside from TNF-α, nSMase2 was also implicated in induction of the inducible nitric oxide synthase (iNOS) by lipopolysaccharide (LPS) in C6 rat glioma cells (Won et al., 2004).
