Consistent with the stimulation of N-SMase activity by cytokines, studies have also shown that nSMase2 plays a role in the inflammatory response (Clarke and Hannun, 2006; Clarke et al., 2006; Nikolova-Karakashian et al., 2008). Among the various inflammatory stimuli, TNF-α is one of the widest studied activators of nSMase2. In MCF-7 cells, long term stimulation with TNF-α induced approximately 40% activation of overexpressed nSMase2 (Marchesini et al., 2003) while acute stimulation with TNF-α was also found to increase nSMase2 activity in a number of cell lines including A549, HUVEC, and smooth muscle cells (Clarke et al., 2007; De Palma et al., 2006; Tellier et al., 2007). In smooth muscle cells, activation of nSMase2 by TNF was reported to be downstream of furin, MT1-MMP and MMP2 whereas in A549 cells, nSMase2 activation was dependent on p38 MAPK (Clarke et al., 2007; Tellier et al., 2007). Notably, in addition to activation, TNF was also found to induce relocalization of nSMase2 to the PM in A549 lung epithelial cells and this was also dependent on p38 MAPK as well as requiring PKC-delta (Clarke
