title: MiR-17-92 cluster: an apoptosis inducer or proliferation enhancer.
abstract: Study of the non-coding RNA roles in the regulation of adaptive immune responses through T cells could be the basis of novel therapeutic applications. MicroRNAs (miRNAs) are a class of short non-coding RNAs that control the cell's functions and destination. To investigate the role of miRNAs in T cell activation, herein the expressions of miR-17-92 cluster and its paralogs were studied in naïve CD4(+)T cells that were activated by anti-CD2, -CD3, -CD28 microbeads and induced with or without IL-2. Proliferation and apoptosis rate of the cultured cells were determined by BrdU incorporation assay (ELISA) and propidium iodide staining, respectively. In continuation the expressions of eight miRNAs of the mentioned clusters were analyzed quantitatively. In addition their potential targets were predicted using multiple algorithms; as a confirmation, the transcription of PIK3R3 (a putative target of modulated miRNAs) was evaluated. Stimulation index (SI) of activated cells was decreased on day 6; whereas, the IL-2 induced cells showed increase in SI in the assay time. Evaluation of eight members of the aforementioned cluster showed upregulation of miR-92a-2* (~15 times) in IL-2 un-induced (activated) cells relative to the IL-2 induced cells. In silico investigations revealed that the suggested miRNAs targeted genes that were involved in cell proliferation, survival, and apoptosis. Transcriptional analysis of PIK3R3 illustrated decrease in activated cells relative to IL-2 induced cells. According to our findings, it seems that multiple members of miR-17-92 families in activated CD4(+)T cells inhibited negative regulators of IL-2 such as DUSP, PTPN, and SOCS families after IL-2 induction. According to our findings, it seems that multiple genes of cell proliferation-related families such as MAPK, E2F, AKT, STAT, and JAK as well as PIK3R3 are inhibited by miR-17-92 cluster in activated cells. As FASL is a putative target of over-expressed miRNAs in activated cell, antigen-induced cell death (AICD) might be occurred in FASL-independent manner. Altogether this study suggested that clonal expansion through IL-2 signaling pathway does not depend on the members of miR-17-92 family; while, it appears that AICD in activated CD4(+)T cells without IL-2 induction is affected by these miRNA clusters.
authors.affiliation: Department of Biology, Science and Research Branch, Islamic Azad University, P.O. Box: 1477893855, Tehran, Iran. najmehranji@gmail.com
authors.forename: Najmeh
authors.initials: N
authors.lastname: Ranji
authors.forename: Majid
authors.initials: M
authors.lastname: Sadeghizadeh
authors.forename: Mohammad Ali
authors.initials: MA
authors.lastname: Shokrgozar
authors.forename: Behnaz
authors.initials: B
authors.lastname: Bakhshandeh
authors.forename: Morteza
authors.initials: M
authors.lastname: Karimipour
authors.forename: Amir
authors.initials: A
authors.lastname: Amanzadeh
authors.forename: Keyhan
authors.initials: K
authors.lastname: Azadmanesh
mesh_terms: D017209:Apoptosis / Q000235:genetics*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D050684:E2F Transcription Factors / Q000235:genetics; D053222:Fas Ligand Protein / Q000235:genetics; D005434:Flow Cytometry; D015870:Gene Expression; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D053612:Janus Kinases / Q000235:genetics; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics; D005810:Multigene Family; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050791:STAT Transcription Factors / Q000235:genetics
chemical_list: D050684:E2F Transcription Factors; D053222:Fas Ligand Protein; D007376:Interleukin-2; C549214:MIRN19A microRNA, human; C534451:MIRN20a microRNA, human; C543351:MIRN25 microRNA, human; C541874:MIRN92 microRNA, human; D035683:MicroRNAs; D050791:STAT Transcription Factors; D019869:Phosphatidylinositol 3-Kinases; C523442:PIK3R3 protein, human; D053612:Janus Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases