Department of Mechanical Engineering, College of Engineering, Temple University, Philadelphia, PA 19122, USA.
Department of Bioengineering, College of Engineering, Temple University, Philadelphia, PA 19122, USA.
Int J Mol Sci. 2019 Mar 26;20(6):1498. doi: 10.3390/ijms20061498.
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.
蛋白激酶 C（PKC）是一个由磷脂依赖性丝氨酸/苏氨酸激酶组成的家族，是炎症信号的主要调节因子。不同 PKC 的活性是上下文敏感的，这些激酶可以是信号通路的正调节剂或负调节剂。δ 同工型（PKCδ）是癌症、糖尿病、缺血性心脏病和神经退行性疾病中炎症反应的关键调节因子。最近的研究表明，PKCδ 是脓毒症中炎症反应的重要调节因子。PKCδ 与 PKC 家族的其他成员不同，其独特之处在于其酪氨酸磷酸化、激活机制和多个亚细胞靶标调节。抑制 PKCδ 通过靶向中性粒细胞-内皮细胞相互作用，可能为脓毒症提供一种独特的治疗方法。在这篇综述中，我们将描述 PKC 的总体结构和功能，重点介绍 PKCδ 的特定磷酸化位点，这些位点决定了其在炎症性疾病（如脓毒症）中细胞信号转导中的关键作用。目前用于研究 PKCδ 在炎症和脓毒症中的作用的遗传和药理学工具以及体内模型，以及这些研究中新兴工具（如微流控分析）的现状也将进行描述。
