Figure 8.

A scheme summarizing the signaling pathway through which PKD mediates NF-κB activation and the role of PKD in multiple pathological processes associated with pancreatitis. Our previous studies identified PKD as a convergent point for PKCδ and ε activation in the signal pathways initiated through CCK or CCh G-protein receptors and mediated NF-κB activation in pancreatic acinar cells (Yuan et al., 2008). Here with both in vitro and in vivo rat pancreatitis models, we found that activated PKD regulates NF-κB activation in CCK/cerulein-induced pancreatitis through promoting IκB protein phosphorylation and degradation. Activation of NF-κB results in inflammation and pancreatitis. Small molecule PKD inhibitors can block this pathobiologic process. This scheme also summarized the role of PKD in multiple pathological processes associated with pancreatitis. CCK/cerulein-induced PKD activation promotes necrosis in pancreatitis by regulating multiple cell death signaling proteins (Yuan et al., 2012); Active PKD also mediates amylase secretion and zymogen activation through regulating cathepsin B (Thrower et al., 2011). These pathologic responses can be blocked when PKD is inhibited by small molecule PKD inhibitors, resulting in amelioration of the severity of pancreatitis. All these effects indicate that PKD may represent a potential therapeutic target in pancreatitis. See the text and references (Yuan et al., 2008, 2012; Thrower et al., 2011) for details.