title: Gram-positive and Gram-negative bacteria synergize with oxidants to release CXCL8 from innate immune cells.
abstract: We have recently demonstrated that oxidants can activate monocytes via an action on Toll-like receptor (TLR) 2; however, it is unclear what functional consequence this has on immune surveillance for Gram-negative and -positive bacteria. Gram-negative and -positive bacteria and their related pathogen-associated molecular patterns (PAMPs) are sensed by TLR4 and TLR2, respectively. In the current study, we used a human monocyte cell line to show that oxidants prime cells to subsequent challenge with Gram-negative or -positive bacteria as well as PAMPs specific for TLR4 (LPS), TLR2/1 (Pam(3)CSK4), TLR2/6 (FSL-1), Nod1 (FK565), and Nod2 (MDP Lys 18). Similarly, activation of TLR4 with LPS primed for subsequent activation of cells by agonists of the TLR2/6 or TLR2/1 complex. However, no synergy was noted when cells were costimulated with Pam(3)CSK4 and FSL-1. We then tested blood (and isolated monocytes) derived from healthy smokers, which is oxidant primed, making it more sensitive to bacterial or PAMP stimulation when compared with blood of nonsmokers. Thus an oxidant stimulation, possibly via an action on TLR2 or associated transduction pathways, provides a signal that initiates inflammatory responses and sensitizes cells to pathogenic insults.
authors.affiliation: Cardiothoracic Pharmacology, National Heart and Lung Institute, Imperial College London, Dovehouse Street, London, United Kingdom. m.paul-clark@imperial.ac.uk
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Paul-Clark
authors.forename: Rosalinda
authors.initials: R
authors.lastname: Sorrentino
authors.forename: Lucy K
authors.initials: LK
authors.lastname: Bailey
authors.forename: Shiranee
authors.initials: S
authors.lastname: Sriskandan
authors.forename: Jane A
authors.initials: JA
authors.lastname: Mitchell
mesh_terms: D002460:Cell Line; D019069:Cell Respiration / Q000187:drug effects; D004075:Diglycerides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects; D006090:Gram-Negative Bacteria / Q000502:physiology*; D006094:Gram-Positive Bacteria / Q000502:physiology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007113:Immunity, Innate; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism*; D055666:Lipopeptides; D008070:Lipopolysaccharides / Q000494:pharmacology; D008954:Models, Biological; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism / Q000382:microbiology; D053474:Nod1 Signaling Adaptor Protein / Q000819:agonists; D009842:Oligopeptides / Q000494:pharmacology; D016877:Oxidants / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012907:Smoking / Q000097:blood; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors; D051216:Toll-Like Receptor 6 / Q000037:antagonists & inhibitors
chemical_list: C508606:CXCL8 protein, human; D004075:Diglycerides; C460864:FSL-1 lipoprotein, synthetic; D016209:Interleukin-8; D055666:Lipopeptides; D008070:Lipopolysaccharides; C119067:NOD1 protein, human; D053474:Nod1 Signaling Adaptor Protein; D009842:Oligopeptides; D016877:Oxidants; C508075:Pam(3)CSK(4) peptide; D010455:Peptides; C495342:TLR2 protein, human; C495345:TLR4 protein, human; C495368:TLR6 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051216:Toll-Like Receptor 6; D006861:Hydrogen Peroxide