In addition to the above reports, insight into the role of nSMase2 in aging-associated inflammation has come from the Karakashian group. Initial studies reported the activation of N-SMase by interleukin 1-beta (IL-1β) (Nikolova-Karakashian et al., 1997), and it was subsequently found that nSMase2 overexpression enhanced IL-1β-stimulated JNK activation in primary rat hepatocytes (Karakashian et al., 2004). Moreover, the regulation of JNK phosphorylation and the ubiquitination of the IL-1β receptor-associated kinase (IRAK) were dependent on the ceramide-activated protein phosphatase, PP2A – presumably acting downstream of nSMase2 (Karakashian et al., 2004). In further studies, the same group noted increased sensitivity to IL-1β in aging rats. Investigating this mechanistically, it was found that hepatocytes from aged rats had increased N-SMase activity whereas expression levels of other pathways components including IL-1β receptor I, JNK, IRAK-1, and transforming growth factor-beta-activated kinase-1 were not significantly different. This suggested that enhanced N-SMase activity is a key part of the mechanism underlying IL-1β hypersensitivity. Consistent with this, it was reported that nSMase2 overexpression in hepatocytes from young rats leads to reduced IRAK-1 degradation and increased JNK phosphorylation whereas
