Baig Mirza S, Liu Dongfang, Muthu Kannan, Roy Anjali, Saqib Uzma, Naim Adnan, Faisal Syed M, Srivastava Mansi, Saluja Rohit
Centre for Biosciences and Biomedical Engineering (BSBE), Indian Institute of Technology Indore (IITI), Indore, India.
Centre for Inflammation & Epigenetics, Houston Methodist Research Institute, Houston, Department of Microbiology and Immunology, Weill Cornell Medical College, Cornell University, New York, NY, USA.
Int Immunopharmacol. 2017 Jul;48:211-218. doi: 10.1016/j.intimp.2017.04.028. Epub 2017 May 18.
Inflammation could be described as a physiological response of the body to tissue injury, pathogen invasion, and irritants. During the inflammatory phase, cells of both the innate as well as adaptive immune system are activated and recruited to the site of inflammation. These mediators are downstream targets for the transcription factors; activator protein-1 (AP1), nuclear factor kappa-light-chain-enhancer (NF-κB), signal transducers and activators of transcription factors (STAT1), as well as interferon regulatory factors (IRFs), which control the expression of most immunomodulatory genes. There is a significant increase in active p38 mitogen-activated protein kinase (p38MAK) immediately after lipopolysaccharide (LPS) stimulation, which results in the activation of AP-1 transcription factor and expression of proinflammatory cytokines, IL-12 and IL-23. We studied the novel mechanism of p38 MAPK activation through the formation of a heterotrimeric complex of Protein kinase C delta type (PKCδ), Toll-Interleukin 1 Receptor (TIR) Domain Containing Adaptor Protein (TIRAP), and p38 proteins. TIRAP serves as an adaptor molecule which brings PKCδ and p38 in close proximity. The complex facilitates the activation of p38MAPK by PKCδ. Therefore, we propose that disruption of the heterotrimeric complex may be a good strategy to dampen the inflammatory response. Structure-based design of small molecules or peptides targetting PKCδ-TIRAP or TIRAP-p38 interfaces would be beneficial for therapy in AP1 mediated inflammatory diseases.
炎症可被描述为机体对组织损伤、病原体入侵和刺激物的一种生理反应。在炎症阶段，先天免疫系统和适应性免疫系统的细胞都会被激活并募集到炎症部位。这些介质是转录因子的下游靶点，包括激活蛋白-1（AP1）、核因子κB轻链增强子（NF-κB）、信号转导子和转录激活子（STAT1）以及干扰素调节因子（IRF），它们控制着大多数免疫调节基因的表达。脂多糖（LPS）刺激后，活性p38丝裂原活化蛋白激酶（p38MAK）会立即显著增加，这会导致AP-1转录因子的激活以及促炎细胞因子IL-12和IL-23的表达。我们研究了通过蛋白激酶Cδ型（PKCδ）、含Toll样白细胞介素1受体（TIR）结构域的接头蛋白（TIRAP）和p38蛋白形成异源三聚体复合物来激活p38丝裂原活化蛋白激酶（p38 MAPK）的新机制。TIRAP作为一种接头分子，使PKCδ和p38紧密靠近。该复合物促进PKCδ对p38MAPK的激活。因此，我们提出破坏异源三聚体复合物可能是减轻炎症反应的一个好策略。基于结构设计靶向PKCδ-TIRAP或TIRAP-p38界面的小分子或肽，将有利于治疗AP1介导的炎症性疾病。
