title: CD14 and complement crosstalk and largely mediate the transcriptional response to Escherichia coli in human whole blood as revealed by DNA microarray.
abstract: Systemic inflammation like in sepsis is still lacking specific diagnostic markers and effective therapeutics. The first line of defense against intruding pathogens and endogenous damage signals is pattern recognition by e.g., complement and Toll-like receptors (TLR). Combined inhibition of a key complement component (C3 and C5) and TLR-co-receptor CD14 has been shown to attenuate certain systemic inflammatory responses. Using DNA microarray and gene annotation analyses, we aimed to decipher the effect of combined inhibition of C3 and CD14 on the transcriptional response to bacterial challenge in human whole blood. Importantly, combined inhibition reversed the transcriptional changes of 70% of the 2335 genes which significantly responded to heat-inactivated Escherichia coli by on average 80%. Single inhibition was less efficient (p<0.001) but revealed a suppressive effect of C3 on 21% of the responding genes which was partially counteracted by CD14. Furthermore, CD14 dependency of the Escherichia coli-induced response was increased in C5-deficient compared to C5-sufficient blood. The observed crucial distinct and synergistic roles for complement and CD14 on the transcriptional level correspond to their broad impact on the inflammatory response in human blood, and their combined inhibition may become inevitable in the early treatment of acute systemic inflammation.
authors.affiliation: Research Laboratory and Department of Laboratory Medicine, Nordland Hospital, Bodø, Norway.
authors.forename: Corinna
authors.initials: C
authors.lastname: Lau
authors.affiliation: Department of Informatics, University of Oslo, Oslo, Norway; Bioinformatics Core Facility and Institute for Medical Informatics, Oslo University Hospital, Oslo, Norway.
authors.forename: Ståle
authors.initials: S
authors.lastname: Nygård
authors.affiliation: Research Laboratory and Department of Laboratory Medicine, Nordland Hospital, Bodø, Norway.
authors.forename: Hilde
authors.initials: H
authors.lastname: Fure
authors.affiliation: Department of Medical Biochemistry, OUS, Ullevaal, Oslo, Norway.
authors.forename: Ole Kristoffer
authors.initials: OK
authors.lastname: Olstad
authors.affiliation: Norwegian Computing Center, Oslo, Norway.
authors.forename: Marit
authors.initials: M
authors.lastname: Holden
authors.affiliation: Faculty of Health Sciences, University of Tromsø, Tromsø, Norway; Division of Medicine, Nordland Hospital, Bodø, Norway.
authors.forename: Knut Tore
authors.initials: KT
authors.lastname: Lappegård
authors.affiliation: Research Laboratory and Department of Laboratory Medicine, Nordland Hospital, Bodø, Norway; Faculty of Health Sciences, University of Tromsø, Tromsø, Norway.
authors.forename: Ole-Lars
authors.initials: OL
authors.lastname: Brekke
authors.affiliation: Center of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Terje
authors.initials: T
authors.lastname: Espevik
authors.affiliation: Department of Informatics, University of Oslo, Oslo, Norway; Bioinformatics Core Facility and Institute for Medical Informatics, Oslo University Hospital, Oslo, Norway; Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; Department of Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway.
authors.forename: Eivind
authors.initials: E
authors.lastname: Hovig
authors.affiliation: Research Laboratory and Department of Laboratory Medicine, Nordland Hospital, Bodø, Norway; Faculty of Health Sciences, University of Tromsø, Tromsø, Norway; Center of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway; Institute of Immunology, Oslo University Hospital Rikshospitalet and University of Oslo, Oslo, Norway.
authors.forename: Tom Eirik
authors.initials: TE
authors.lastname: Mollnes
mesh_terms: D003165:Complement System Proteins / Q000378:metabolism*; D004926:Escherichia coli / Q000235:genetics*; D015870:Gene Expression; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D014158:Transcription, Genetic
chemical_list: D018950:Lipopolysaccharide Receptors; D003165:Complement System Proteins