title: The kinase Akt1 controls macrophage response to lipopolysaccharide by regulating microRNAs.
abstract: MicroRNAs regulated by lipopolysaccharide (LPS) target genes that contribute to the inflammatory phenotype. Here, we showed that the protein kinase Akt1, which is activated by LPS, positively regulated miRNAs let-7e and miR-181c but negatively regulated miR-155 and miR-125b. In silico analyses and transfection studies revealed that let-7e repressed Toll-like receptor 4 (TLR4), whereas miR-155 repressed SOCS1, two proteins critical for LPS-driven TLR signaling, which regulate endotoxin sensitivity and tolerance. As a result, Akt1(-/-) macrophages exhibited increased responsiveness to LPS in culture and Akt1(-/-) mice did not develop endotoxin tolerance in vivo. Overexpression of let-7e and suppression of miR-155 in Akt1(-/-) macrophages restored sensitivity and tolerance to LPS in culture and in animals. These results indicate that Akt1 regulates the response of macrophages to LPS by controlling miRNA expression.
authors.affiliation: Department of Clinical Chemistry, School of Medicine, University of Crete, Heraklion 71003, Crete, Greece.
authors.forename: Ariadne
authors.initials: A
authors.lastname: Androulidaki
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Iliopoulos
authors.forename: Alicia
authors.initials: A
authors.lastname: Arranz
authors.forename: Christina
authors.initials: C
authors.lastname: Doxaki
authors.forename: Steffen
authors.initials: S
authors.lastname: Schworer
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Zacharioudaki
authors.forename: Andrew N
authors.initials: AN
authors.lastname: Margioris
authors.forename: Philip N
authors.initials: PN
authors.lastname: Tsichlis
authors.forename: Christos
authors.initials: C
authors.lastname: Tsatsanis
mesh_terms: D000818:Animals; D002460:Cell Line; D007108:Immune Tolerance / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology*; D008264:Macrophages / Q000201:enzymology / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000276:immunology / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; D035683:MicroRNAs; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D051197:Toll-Like Receptor 4; C583909:mirnlet7e microRNA, mouse; D051057:Proto-Oncogene Proteins c-akt
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