LPS induced inflammatory responses in human peripheral blood mononuclear cells is mediated through NOX4 and Giα dependent PI-3kinase signalling

Bacterial infections are one of the dominant causes of acute exacerbations in chronic obstructive pulmonary disease (COPD). Lipopolysaccharide (LPS) is the most abundant component within the cell wall of Gram-negative bacteria. It can stimulate the release of interleukin 8 (IL-8, CXCL8, CXC ligand 8) and other inflammatory cytokines in various cell types, leading to an acute inflammatory response towards pathogens [1]. These responses are initiated by the activation of the TLR signalling through adaptor proteins, and include induction of gene expression via the activation of the NF-κB and AP-1 signal transduction pathways [2]. Bacterial LPS has been extensively used in models studying inflammation as it mimics many inflammatory effects of cytokines, such as TNF-α, IL-1β or IL-6. The cellular receptor transducing the LPS signal has been identified as Toll-like receptor 4 (TLR4) [3-5]. Binding of LPS to TLR4 leads to the activation of NF-κB through the recruitment and activation of MyD88, IL-1R kinase (IRAK), TNFR associated factor 6 (TRAF-6), as well as NADPH oxidase (Nox) [2,6,7]. NF-κB plays a crucial role in regulating the transcription of genes related to innate immunity and inflammation responses and several studies indicate its activation is controlled by reactive oxygen species (ROS) in immune modulation in the lungs and in monocytes [8-11].Several studies searching for novel anti-inflammatory agents have led to the identification of a key role for phosphatidylinositol 3-kinase (PI3K) in transducing receptor-mediated signalling during inflammation in chronic inflammatory diseases, such as COPD [12]. The PI3K family is divided into three classes (I, II and III) depending on their structure, substrate and function [13]. The class I PI3Ks are further subdivided into class IA (p110α, p110β and p110δ) and class IB (p110γ). All class I PI3Ks mediate fundamental signalling pathways and cellular processes that orchestrate cell growth, proliferation, migration and surv