title: Monocytes from cystic fibrosis patients are locked in an LPS tolerance state: down-regulation of TREM-1 as putative underlying mechanism.
abstract: Cystic Fibrosis (CF) is an inherited pleiotropic disease that results from abnormalities in the gene that codes for the chloride channel, Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). CF patients are frequently colonized by several pathogens, but the mechanisms that allow colonization in spite of apparently functional immune systems are incompletely understood. In this paper we show that blood peripheral monocytes isolated from CF patients are found in an endotoxin tolerance state, yet this is not due to a deficient TLR activation. On the other hand, levels of the amplifier of inflammatory responses, TREM-1 (Triggering Receptor Expressed on Myeloid cells), are notably down-regulated in monocytes from patients, in comparison to those extracted from healthy volunteers. Furthermore, the soluble form of TREM-1 (sTREM-1) was not detected in the sera of patients. Additionally, and in strict contrast to patients who suffer from Chronic Obstructive Pulmonary Disease (COPD), CF monocytes challenged ex vivo with LPS neither up-regulated membrane-anchored TREM-1 nor sTREM-1. Finally, similar levels of PGE(2) expression and p65 translocation into the nucleus were found in both patients and healthy volunteers, thus suggesting that TREM-1 regulation is neither controlled by PGE(2) levels nor by p65 activation in this case. However, PU.1 translocation into the nucleus was significantly higher in CF monocytes than in controls, suggesting a role for this transcription factor in the control of TREM-1 expression. We conclude that down-regulation of TREM-1 expression in cystic fibrosis patients is at least partly responsible for the endotoxin tolerance state in which their monocytes are locked.
authors.affiliation: Research Unit, La Paz Hospital, Madrid, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: del Fresno
authors.forename: Vanesa
authors.initials: V
authors.lastname: Gómez-Piña
authors.forename: Vanesa
authors.initials: V
authors.lastname: Lores
authors.forename: Alessandra
authors.initials: A
authors.lastname: Soares-Schanoski
authors.forename: Irene
authors.initials: I
authors.lastname: Fernández-Ruiz
authors.forename: Blas
authors.initials: B
authors.lastname: Rojo
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Alvarez-Sala
authors.forename: Ernesto
authors.initials: E
authors.lastname: Caballero-Garrido
authors.forename: Felipe
authors.initials: F
authors.lastname: García
authors.forename: Tania
authors.initials: T
authors.lastname: Veliz
authors.forename: Francisco
authors.initials: F
authors.lastname: Arnalich
authors.forename: Pablo
authors.initials: P
authors.lastname: Fuentes-Prior
authors.forename: Francisco
authors.initials: F
authors.lastname: García-Río
authors.forename: Eduardo
authors.initials: E
authors.lastname: López-Collazo
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D002469:Cell Separation; D003550:Cystic Fibrosis / Q000097:blood*; D015232:Dinoprostone / Q000378:metabolism; D015536:Down-Regulation; D004731:Endotoxins / Q000378:metabolism; D005260:Female; D006801:Humans; D008070:Lipopolysaccharides / Q000378:metabolism*; D008168:Lung / Q000382:microbiology; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis*; D009000:Monocytes / Q000166:cytology*; D011971:Receptors, Immunologic / Q000096:biosynthesis*; D000073871:Triggering Receptor Expressed on Myeloid Cells-1
chemical_list: D004731:Endotoxins; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C408842:TREM1 protein, human; D000073871:Triggering Receptor Expressed on Myeloid Cells-1; D015232:Dinoprostone