**5. Ceramide 1-phosphate and the control of inflammation**

Inflammation is, in principle, a beneficial process for protecting the organism against infection or injury. However, it can be detrimental when it becomes out of control. Apart from the classical signaling pathways and metabolites that are involved in the regulation of inflammation, it is now well accepted that ceramides are key elements in the inflammatory response (Lamour & Chalfant, 2005; Wijesinghe et al., 2008; Gomez-Munoz et al., 2010). For instance, it was reported that activation of A-SMase and the subsequent formation of ceramides play an important role in pulmonary infections as it facilitates internalization of bacteria into lung epithelial cells (Gulbins & Kolesnick, 2003). In this context, inhibition of A-SMase by C1P could be important to reduce or prevent infection in the lung.

Inflammatory mediators include chemokines, cytokines, vasoactive amines, products of proteolytic cascades, phospholipases, or lipids such as eicosanoids and sphingolipids. A major mediator of inflammation is PLA2 activity. In particular, group IV cytosolic cPLA2 ( or cPLA2-alpha) has been involved in receptor-dependent and independent production of eicosanoids, which are major components of inflammatory responses. Sphingolipids, including ceramides, have also been described as key mediators of inflammation (Hayakawa et al., 1996; Serhan et al., 1996; Manna & Aggarwal, 1998; Newton et al., 2000). More recently a role for ceramide in the development of allergic asthmatic responses and airway inflammation was established (Masini et al., 2008), and exogenous addition of C2 ceramide to cultured astrocytes induced 12-lipoxigenase leading to generation of reactive oxygen species (ROS) and inflammation (Prasad et al., 2008). Also, A-SMase-derived ceramide was involved in platelet activating factor (PAF)-mediated pulmonary edema (Goggel et al., 2004). Subsequently, it was proposed that at least some of the proinflammatory effects of ceramides might in fact be mediated by its further metabolite C1P. The first report on the regulation of arachidonic acid (AA) release and the production of prostaglandins by C1P was from the laboratory of Charles Chalfant (Pettus et al., 2003b). This group demonstrated that C1P was able to stimulate AA release and prostanoid synthesis in A549 lung adenocarcinoma cells. In a follow up report, the same group showed that the mechanism whereby C1P stimulates AA release occurs through direct activation of cPLA2 (Pettus et al., 2004). Subsequently, it was found that C1P is a positive allosteric activator of cPLA2-alpha, and that it enhances the interaction of the enzyme with PC (Subramanian et al., 2005). In further work, the same group demonstrated that activation of cPLA2-alpha by C1P is chain length-specific; in particular, C1P bearing acyl chains equal or higher than six carbons were able to efficiently activate cPLA2-alpha in vitro, whereas shorter acyl chains (in particular C2-C1P) were unable to activate the enzyme. It was concluded that the biological activity of C2-C1P does not occur via eicosanoid synthesis (Wijesinghe et al., 2008). Also, C1P was shown to act in coordination with S1P to ensure maximal production of prostaglandins. Specifically, S1P was shown to induce cyclooxigenase-2 (COX-2) activity, which then uses cPLA2-derived AA as substrate to synthesize prostaglandins (Pettus et al., 2005). Further details on the role of C1P in inflammatory response can be found in different reviews (Chalfant & Spiegel, 2005; Lamour et al., 2007; Wijesinghe et al., 2007), Wijesinghe et al., and recent work by Murayama and coworkers (Nakamura et al., 2011).
