title: Endotoxin tolerance represents a distinctive state of alternative polarization (M2) in human mononuclear cells.
abstract: Classical (M1) and alternative (M2) polarization of mononuclear cells (MNCs) such as monocyte and macrophages is known to occur in response to challenges within a microenvironment, like the encounter of a pathogen. LPS, also known as endotoxin, is a potent inducer of inflammation and M1 polarization. LPS can also generate an effect in MNCs known as endotoxin tolerance, defined as the reduced capacity of a cell to respond to LPS activation after an initial exposure to this stimulus. Using systems biology approaches in PBMCs, monocytes, and monocyte-derived macrophages involving microarrays and advanced bioinformatic analysis, we determined that gene responses during endotoxin tolerance were similar to those found during M2 polarization, featuring gene and protein expression critical for the development of key M2 MNC functions, including reduced production of proinflammatory mediators, expression of genes involved in phagocytosis, as well as tissue remodeling. Moreover, expression of different metallothionein gene isoforms, known for their role in the control of oxidative stress and in immunomodulation, were also found to be consistently upregulated during endotoxin tolerance. These results demonstrate that after an initial inflammatory stimulus, human MNCs undergo an M2 polarization probably to control hyperinflammation and heal the affected tissue.
authors.affiliation: Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada.
authors.forename: Olga M
authors.initials: OM
authors.lastname: Pena
authors.forename: Jelena
authors.initials: J
authors.lastname: Pistolic
authors.forename: Disha
authors.initials: D
authors.lastname: Raj
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Fjell
authors.forename: Robert E W
authors.initials: RE
authors.lastname: Hancock
mesh_terms: D019295:Computational Biology; D004361:Drug Tolerance / Q000235:genetics; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages; D046228:Microarray Analysis; D009000:Monocytes; D012157:Mononuclear Phagocyte System / Q000276:immunology*; D049490:Systems Biology
chemical_list: D008070:Lipopolysaccharides