title: miR-148a is upregulated by Twist1 and T-bet and promotes Th1-cell survival by regulating the proapoptotic gene Bim.
abstract: Repeatedly activated T helper 1 (Th1) cells present during chronic inflammation can efficiently adapt to the inflammatory milieu, for example, by expressing the transcription factor Twist1, which limits the immunopathology caused by Th1 cells. Here, we show that in repeatedly activated murine Th1 cells, Twist1 and T-bet induce expression of microRNA-148a (miR-148a). miR-148a regulates expression of the proapoptotic gene Bim, resulting in a decreased Bim/Bcl2 ratio. Inhibition of miR-148a by antagomirs in repeatedly activated Th1 cells increases the expression of Bim, leading to enhanced apoptosis. Knockdown of Bim expression by siRNA in miR-148a antagomir-treated cells restores viability of the Th1 cells, demonstrating that miR-148a controls survival by regulating Bim expression. Thus, Twist1 and T-bet not only control the differentiation and function of Th1 cells, but also their persistence in chronic inflammation.
authors.affiliation: Deutsches Rheuma-Forschungszentrum Berlin (DRFZ), an institute of the Leibniz AssociationBerlin, Berlin, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Haftmann
authors.forename: Anna-Barbara
authors.initials: AB
authors.lastname: Stittrich
authors.forename: Jakob
authors.initials: J
authors.lastname: Zimmermann
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Fang
authors.forename: Kristyna
authors.initials: K
authors.lastname: Hradilkova
authors.forename: Markus
authors.initials: M
authors.lastname: Bardua
authors.forename: Kerstin
authors.initials: K
authors.lastname: Westendorf
authors.forename: Gitta A
authors.initials: GA
authors.lastname: Heinz
authors.forename: René
authors.initials: R
authors.lastname: Riedel
authors.forename: Julia
authors.initials: J
authors.lastname: Siede
authors.forename: Katrin
authors.initials: K
authors.lastname: Lehmann
authors.forename: Esther E
authors.initials: EE
authors.lastname: Weinberger
authors.forename: David
authors.initials: D
authors.lastname: Zimmel
authors.forename: Uta
authors.initials: U
authors.lastname: Lauer
authors.forename: Thomas
authors.initials: T
authors.lastname: Häupl
authors.forename: Joachim
authors.initials: J
authors.lastname: Sieper
authors.forename: Marina
authors.initials: M
authors.lastname: Backhaus
authors.forename: Christian
authors.initials: C
authors.lastname: Neumann
authors.forename: Ute
authors.initials: U
authors.lastname: Hoffmann
authors.forename: Martina
authors.initials: M
authors.lastname: Porstner
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Joachim R
authors.initials: JR
authors.lastname: Grün
authors.forename: Ria
authors.initials: R
authors.lastname: Baumgrass
authors.forename: Mareen
authors.initials: M
authors.lastname: Matz
authors.forename: Max
authors.initials: M
authors.lastname: Löhning
authors.forename: Alexander
authors.initials: A
authors.lastname: Scheffold
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wittmann
authors.forename: Hyun-Dong
authors.initials: HD
authors.lastname: Chang
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Rajewsky
authors.forename: Hans-Martin
authors.initials: HM
authors.lastname: Jäck
authors.forename: Andreas
authors.initials: A
authors.lastname: Radbruch
authors.forename: Mir-Farzin
authors.initials: MF
authors.lastname: Mashreghi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D001172:Arthritis, Rheumatoid / Q000276:immunology; D000072224:Bcl-2-Like Protein 11; D002470:Cell Survival / Q000276:immunology; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D034622:RNA Interference; D034741:RNA, Small Interfering; D020825:T-Box Domain Proteins / Q000235:genetics / Q000502:physiology*; D018417:Th1 Cells / Q000276:immunology*; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism*; D000098815:T-bet Transcription Factor
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D008565:Membrane Proteins; D035683:MicroRNAs; C554644:Mirn148 microRNA, mouse; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D051879:Twist-Related Protein 1; C067250:Twist1 protein, mouse
keywords: Bim; T-bet; Th1; Twist1; miR-148a