Abstract
Protein Kinase C (PKC) is a family composed of phospholipid-dependent serine/threonine kinases that are master regulators of inflammatory signaling. The activity of different PKCs is context-sensitive and these kinases can be positive or negative regulators of signaling pathways. The delta isoform (PKCδ) is a critical regulator of the inflammatory response in cancer, diabetes, ischemic heart disease, and neurodegenerative diseases. Recent studies implicate PKCδ as an important regulator of the inflammatory response in sepsis. PKCδ, unlike other members of the PKC family, is unique in its regulation by tyrosine phosphorylation, activation mechanisms, and multiple subcellular targets. Inhibition of PKCδ may offer a unique therapeutic approach in sepsis by targeting neutrophil-endothelial cell interactions. In this review, we will describe the overall structure and function of PKCs, with a focus on the specific phosphorylation sites of PKCδ that determine its critical role in cell signaling in inflammatory diseases such as sepsis. Current genetic and pharmacological tools, as well as in vivo models, that are used to examine the role of PKCδ in inflammation and sepsis are presented and the current state of emerging tools such as microfluidic assays in these studies is described.
Highlights
Studies with PKCδ−/− mice and PKCδ inhibitors indicate a role for PKCδ in regulating neutrophil trafficking to the lung in response to inflammation triggered by bacterial sepsis, asbestos, stroke/reperfusion injury, LPS, or pancreatitis [19,20,24,47,104,105,106,107]
ICAM-1 and VCAM-1 are crucial vascular endothelial cell adhesion molecules involved in neutrophil recruitment and are up-regulated by proinflammatory cytokines released during sepsis [120]; their expression was, attenuated by the administration of the PKCδ peptide inhibitor [47]
Using our bioinspired microfluidic assay (bMFA), we showed that PKCδ regulates radiation-induced neutrophil-endothelial cell interaction and endothelial cell function, and that PKCδ inhibition dramatically attenuated ionizing radiation (IR)-induced endothelium permeability and significantly decreased neutrophil migration across IR treated endothelial cells [26]
Summary
We have identified PKCδ as an import regulator of the inflammatory response in sepsis [8,19,22,43,44,45,46,47]. Multiple cell types express PKCδ and proinflammatory mediators involved in the septic response activate this kinase [44,48]. PKCδ is involved in NF-κB activation, adhesion molecule expression, the release of inflammatory mediators important in neutrophil transmigration, and regulation of endothelial cell permeability [23,47]. PKCδ is an important signaling element in the regulation of neutrophil-endothelial crosstalk, neutrophil adherence/rolling/migration, and vascular endothelial damage [8,19,21,22,23,46,47]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
