title: MiR-150 impairs inflammatory cytokine production by targeting ARRB-2 after blocking CD28/B7 costimulatory pathway.
abstract: MiR-150, a major modulator negatively regulating the development and differentiation of various immune cells, is widely involved in orchestrating inflammation. In transplantation immunity, miR-150 can effectively induce immune tolerance, although the underlying mechanisms have not been fully elucidated. In the current study, we found that miR-150 is elevated after blocking CD28/B7 co-stimulatory signaling pathway and impaired IL-2 production by targeting ARRB2. Further investigation suggested that miR-150 not only repressed the level of ARRB2/PDE4 directly but also prevented AKT/ARRB2/PDE4 trimer recruitment into the lipid raft by inhibiting the activities of PI3K and AKT through the cAMP-PKA-Csk signaling pathway. This leads to the interruption of cAMP degradation and subsequently results in inhibition of the NF-kB pathway and reduced production of both IL-2 and TNF. In conclusion, our study demonstrated that miR-150 can effectively prevent CD28/B7 co-stimulatory signaling transduction, decrease production of inflammatory cytokines, such as IL-2 and TNF, and elicit the induction of immune tolerance. Therefore, miR-150 could become a novel potential therapeutic target in transplantation immunology.
authors.affiliation: The Key Laboratory of Transplantation Immunity, Affiliated Hospital of Xuzhou Medical College, Jiangsu Province, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Sang
authors.affiliation: The Key Laboratory of Transplantation Immunity, Affiliated Hospital of Xuzhou Medical College, Jiangsu Province, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Hematology, Huaibei Miners General Hospital, Anhui Province, China.
authors.forename: Cong
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, Philadelphia College of Osteopathic Medicine, USA.
authors.forename: Dianzheng
authors.initials: D
authors.lastname: Zhang
authors.affiliation: The Key Laboratory of Transplantation Immunity, Affiliated Hospital of Xuzhou Medical College, Jiangsu Province, China.
authors.forename: Cai
authors.initials: C
authors.lastname: Sun
authors.affiliation: The Key Laboratory of Transplantation Immunity, Affiliated Hospital of Xuzhou Medical College, Jiangsu Province, China.
authors.forename: Mingshan
authors.initials: M
authors.lastname: Niu
authors.affiliation: The Key Laboratory of Transplantation Immunity, Affiliated Hospital of Xuzhou Medical College, Jiangsu Province, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: The Key Laboratory of Transplantation Immunity, Affiliated Hospital of Xuzhou Medical College, Jiangsu Province, China.
authors.forename: Xiangyu
authors.initials: X
authors.lastname: Wei
authors.affiliation: The Key Laboratory of Transplantation Immunity, Affiliated Hospital of Xuzhou Medical College, Jiangsu Province, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Pan
authors.affiliation: The Key Laboratory of Transplantation Immunity, Affiliated Hospital of Xuzhou Medical College, Jiangsu Province, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: The Key Laboratory of Transplantation Immunity, Affiliated Hospital of Xuzhou Medical College, Jiangsu Province, China.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Yan
authors.affiliation: The Key Laboratory of Transplantation Immunity, Affiliated Hospital of Xuzhou Medical College, Jiangsu Province, China.
authors.forename: Lingyu
authors.initials: L
authors.lastname: Zeng
authors.affiliation: Department of Medicine, University of Virginia Cancer Center, VA, USA. Electronic address: tploughran@virginia.edu.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Loughran
authors.affiliation: The Key Laboratory of Transplantation Immunity, Affiliated Hospital of Xuzhou Medical College, Jiangsu Province, China. Electronic address: kailinxu616@126.com.
authors.forename: Kailin
authors.initials: K
authors.lastname: Xu
mesh_terms: D060887:B7 Antigens / Q000378:metabolism; D018106:CD28 Antigens / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance; D018836:Inflammation Mediators / Q000378:metabolism*; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism*; D021962:Membrane Microdomains / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics*; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D014181:Transplantation Immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D000071560:beta-Arrestin 2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D060887:B7 Antigens; D018106:CD28 Antigens; D000242:Cyclic AMP; D018836:Inflammation Mediators; D007376:Interleukin-2; D035683:MicroRNAs; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D014409:Tumor Necrosis Factor-alpha; D000071560:beta-Arrestin 2; C000605254:ARRB2 protein, human; C533097:MIR150, human
keywords: CD28/B7 co-stimulatory signaling pathway; Inflammatory cytokine; MicroRNA; T cell