title: miR-718 represses proinflammatory cytokine production through targeting phosphatase and tensin homolog (PTEN).
abstract: Bacterial sepsis involves a complex interaction between the host immune response and bacterial LPS. LPS binds Toll-like receptor (TLR) 4, which leads to the release of proinflammatory cytokines that are essential for a potent innate immune response against pathogens. The innate immune system is tightly regulated, as excessive inflammation can lead to organ failure and death. MicroRNAs have recently emerged as important regulators of the innate immune system. Here we determined the function of miR-718, which is conserved across mammals and overlaps with the 5' UTR of the interleukin 1 receptor-associated kinase (IRAK1) gene. As IRAK1 is a key component of innate immune signaling pathways that are downstream of most TLRs, we hypothesized that miR-718 helps regulate the innate immune response. Activation of TLR4, but not TLR3, induced the expression of miR-718 in macrophages. miR-718 expression was also induced in the spleens of mice upon LPS injection. miR-718 modulates PI3K/Akt signaling by directly down-regulating phosphatase and tensin homolog (PTEN), thereby promoting phosphorylation of Akt, which leads to a decrease in proinflammatory cytokine production. Phosphorylated Akt induces let-7e expression, which, in turn, down-regulates TLR4 and further diminishes TLR4-mediated proinflammatory signals. Decreased miR-718 expression is associated with bacterial burden duringNeisseria gonorrhoeaeinfection and alters the infection dynamics ofN. gonorrhoeae in vitroFurthermore, miR-718 regulates the induction of LPS tolerance in macrophages. We propose a role for miR-718 in controlling TLR4 signaling and inflammatory cytokine signaling through a negative feedback regulation loop involving down-regulation of TLR4, IRAK1, and NF-κB.
authors.affiliation: From the Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts 01605 and Parisa.Kalantari@tufts.edu.
authors.forename: Parisa
authors.initials: P
authors.lastname: Kalantari
authors.affiliation: the Department of Medicine, Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215.
authors.forename: Omid F
authors.initials: OF
authors.lastname: Harandi
authors.affiliation: From the Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts 01605 and.
authors.forename: Sarika
authors.initials: S
authors.lastname: Agarwal
authors.affiliation: From the Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts 01605 and.
authors.forename: Florentina
authors.initials: F
authors.lastname: Rus
authors.affiliation: From the Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts 01605 and.
authors.forename: Evelyn A
authors.initials: EA
authors.lastname: Kurt-Jones
authors.affiliation: From the Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts 01605 and.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fitzgerald
authors.affiliation: From the Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts 01605 and.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Caffrey
authors.affiliation: From the Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts 01605 and.
authors.forename: Douglas T
authors.initials: DT
authors.lastname: Golenbock
mesh_terms: D020121:5' Untranslated Regions; D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D006069:Gonorrhea / Q000235:genetics / Q000378:metabolism; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009344:Neisseria gonorrhoeae / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism
chemical_list: D020121:5' Untranslated Regions; D016207:Cytokines; D035683:MicroRNAs; C519703:TLR3 protein, mouse; C493487:Tlr4 protein, mouse; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; C542687:mirnlet7 microRNA, mouse; D053592:Interleukin-1 Receptor-Associated Kinases; C507769:Irak1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse
keywords: Akt PKB; Toll-like receptor 4 (TLR4); bacterial pathogenesis; lipopolysaccharide (LPS); miR-718; microRNA (miRNA); phosphatase and tensin homolog (PTEN)